diff --git a/.eslintignore b/.eslintignore index ac674aa6d..1332d20ac 100644 --- a/.eslintignore +++ b/.eslintignore @@ -1,2 +1,3 @@ node_modules/**/* -build/* \ No newline at end of file +build/* +src/server/routes/api/document/p-limit.js \ No newline at end of file diff --git a/README.md b/README.md index 7f2ad84c7..88642a598 100644 --- a/README.md +++ b/README.md @@ -97,6 +97,8 @@ Demo: Sharing: +- `DOCUMENT_IMAGE_CACHE_SIZE` : number of images to cache in memory +- `DOCUMENT_IMAGE_PLL_LIMIT` : max number of images to be generated in parallel (expensive) - `DOCUMENT_IMAGE_WIDTH` : tweet card image width - `DOCUMENT_IMAGE_HEIGHT` : tweet card image height - `DOCUMENT_IMAGE_PADDING` : padding around tweet card image (prevents twitter cropping issues) diff --git a/neo4j-test/add-nodes-edges.js b/neo4j-test/add-nodes-edges.js new file mode 100644 index 000000000..f6f6d7225 --- /dev/null +++ b/neo4j-test/add-nodes-edges.js @@ -0,0 +1,216 @@ +import { expect } from 'chai'; +import { initDriver, closeDriver } from '../src/neo4j/neo4j-driver.js'; +import { addEdge, addNode, getInteractions, getNeighbouringNodes, neighbourhood } from '../src/neo4j/neo4j-functions'; +import { deleteAllNodesAndEdges, getGeneName, getNumNodes, getNumEdges, getEdge } from '../src/neo4j/test-functions.js'; + +describe('02. Tests for addNode, addEdge and seachByGeneId', function () { + + before('Should create a driver instance and connect to server', async function () { + await initDriver(); + }); + + after('Close driver', async function () { + await closeDriver(); + }); + + beforeEach('Delete nodes and edges', async function () { + await deleteAllNodesAndEdges(); + }); + + it('Make one node', async function () { + expect(await getNumNodes()).to.equal(0); + await addNode('ncbigene:5597', 'MAPK6'); + expect(await getGeneName('ncbigene:5597')).to.equal('MAPK6'); + expect(await getNumNodes()).to.equal(1); + }); + + it('Make an edge between the two nodes', async function () { + expect(await getNumEdges()).equal(0); + await addNode('ncbigene:207', 'AKT'); + await addNode('ncbigene:5597', 'MAPK6'); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'phosphorylation', + [], + 'ncbigene:5597', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '34767444', + 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + expect(await getNumEdges()).to.equal(1); + let edge = await getEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b'); + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.type).to.equal('phosphorylation'); + expect(edge.properties.sourceId).to.equal('ncbigene:5597'); + expect(edge.properties.targetId).to.equal('ncbigene:207'); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.xref).to.equal('a896d611-affe-4b45-a5e1-9bc560ffceab'); + expect(edge.properties.doi).to.equal('10.1126/sciadv.abi6439'); + expect(edge.properties.pmid).to.equal('34767444'); + expect(edge.properties.articleTitle).to.equal('MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + }); + + it('Making a duplicate node fails', async function () { + await addNode('ncbigene:207', 'AKT'); + await addNode('ncbigene:5597', 'MAPK6'); + expect(await getNumNodes()).to.equal(2); + await addNode('ncbigene:5597', 'MAPK6'); + await addNode('ncbigene:5597', 'This is a dummy name'); + expect(await getNumNodes()).to.equal(2); + expect(await getGeneName('ncbigene:5597')).to.equal('MAPK6'); + }); + + it('Making a duplicate edge fails', async function () { + await addNode('ncbigene:207', 'AKT'); + await addNode('ncbigene:5597', 'MAPK6'); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'phosphorylation', + [], + 'ncbigene:5597', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '34767444', + 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + expect(await getNumEdges()).equal(1); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'phosphorylation', + [], + 'ncbigene:5597', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '34767444', + 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'This is a dummy type', + [], + 'nc7', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '3444', + 'MAPK6-AKT signaling '); + expect(await getNumEdges()).equal(1); + let edge = await getEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b'); + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.type).to.equal('phosphorylation'); + expect(edge.properties.sourceId).to.equal('ncbigene:5597'); + expect(edge.properties.targetId).to.equal('ncbigene:207'); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.xref).to.equal('a896d611-affe-4b45-a5e1-9bc560ffceab'); + expect(edge.properties.doi).to.equal('10.1126/sciadv.abi6439'); + expect(edge.properties.pmid).to.equal('34767444'); + expect(edge.properties.articleTitle).to.equal('MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + }); + + it('Ensure searchGeneById works as expected for MAPK6', async function () { + await addNode('ncbigene:207', 'AKT'); + await addNode('ncbigene:5597', 'MAPK6'); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'phosphorylation', + [], + 'ncbigene:5597', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '34767444', + 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + + let mapk6Relationships = await getInteractions('ncbigene:5597'); + + expect(mapk6Relationships.length).to.equal(1); + expect(mapk6Relationships[0].type).to.equal('phosphorylation'); + expect(mapk6Relationships[0].sourceId).to.equal('ncbigene:5597'); + expect(mapk6Relationships[0].targetId).to.equal('ncbigene:207'); + expect(mapk6Relationships[0].sourceComplex).to.equal(''); + expect(mapk6Relationships[0].targetComplex).to.equal(''); + expect(mapk6Relationships[0].component).to.deep.equal([]); + expect(mapk6Relationships[0].xref).to.equal('a896d611-affe-4b45-a5e1-9bc560ffceab'); + expect(mapk6Relationships[0].doi).to.equal('10.1126/sciadv.abi6439'); + expect(mapk6Relationships[0].pmid).to.equal('34767444'); + expect(mapk6Relationships[0].articleTitle).to.equal('MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + + let mapk6NeighbouringNodes = await getNeighbouringNodes('ncbigene:5597'); + + expect(mapk6NeighbouringNodes.length).to.equal(1); + expect(mapk6NeighbouringNodes[0].id).to.equal('ncbigene:207'); + expect(mapk6NeighbouringNodes[0].name).to.equal('AKT'); + }); + + it('Ensure searchGeneById works as expected for AKT', async function () { + await addNode('ncbigene:207', 'AKT'); + await addNode('ncbigene:5597', 'MAPK6'); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'phosphorylation', + [], + 'ncbigene:5597', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '34767444', + 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + + let aktRelationships = await getInteractions('ncbigene:207'); + + expect(aktRelationships.length).to.equal(1); + expect(aktRelationships[0].type).to.equal('phosphorylation'); + expect(aktRelationships[0].sourceId).to.equal('ncbigene:5597'); + expect(aktRelationships[0].targetId).to.equal('ncbigene:207'); + expect(aktRelationships[0].sourceComplex).to.equal(''); + expect(aktRelationships[0].targetComplex).to.equal(''); + expect(aktRelationships[0].component).to.deep.equal([]); + expect(aktRelationships[0].xref).to.equal('a896d611-affe-4b45-a5e1-9bc560ffceab'); + expect(aktRelationships[0].doi).to.equal('10.1126/sciadv.abi6439'); + expect(aktRelationships[0].pmid).to.equal('34767444'); + expect(aktRelationships[0].articleTitle).to.equal('MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + + let aktNeighbouringNodes = await getNeighbouringNodes('ncbigene:207'); + + expect(aktNeighbouringNodes.length).to.equal(1); + expect(aktNeighbouringNodes[0].id).to.equal('ncbigene:5597'); + expect(aktNeighbouringNodes[0].name).to.equal('MAPK6'); + }); + + it('Search for a molecule in an empty database yields null', async function () { + expect(await neighbourhood('ncbigene:207')).to.be.null; + expect(await getInteractions('ncbigene:207')).to.be.null; + expect(await getNeighbouringNodes('ncbigene:207')).to.be.null; + }); + + it('Search for a non-existing molecule in a non-empty database yields null', async function () { + await addNode('ncbigene:207', 'AKT'); + await addNode('ncbigene:5597', 'MAPK6'); + await addEdge('01ef22cc-2a8e-46d4-9060-6bf1c273869b', + 'phosphorylation', + [], + 'ncbigene:5597', + 'ncbigene:207', + '', + '', + 'a896d611-affe-4b45-a5e1-9bc560ffceab', + '10.1126/sciadv.abi6439', + '34767444', + 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.'); + + expect(await neighbourhood('ncbigene:217')).to.be.null; + expect(await getInteractions('ncbigene:217')).to.be.null; + expect(await getNeighbouringNodes('ncbigene:217')).to.be.null; + }); +}); \ No newline at end of file diff --git a/neo4j-test/connect-neo4j.js b/neo4j-test/connect-neo4j.js index da5c96492..c82ecb845 100644 --- a/neo4j-test/connect-neo4j.js +++ b/neo4j-test/connect-neo4j.js @@ -4,7 +4,6 @@ import neo4j from 'neo4j-driver'; import { closeDriver, getDriver, initDriver } from '../src/neo4j/neo4j-driver.js'; describe('01. Initiate Driver', () => { - it('initDriver Should initialize and return a driver', () => { const driver = initDriver(); expect(driver).an.instanceof(neo4j.Driver); diff --git a/neo4j-test/doc-tests-complex.js b/neo4j-test/doc-tests-complex.js new file mode 100644 index 000000000..57aae6d8a --- /dev/null +++ b/neo4j-test/doc-tests-complex.js @@ -0,0 +1,538 @@ +import { expect } from 'chai'; +import rdbFix from 'rethinkdb-fixtures'; +import r from 'rethinkdb'; +import _ from 'lodash'; + +import { loadDoc } from '../src/server/routes/api/document/index.js'; +import { initDriver, closeDriver } from '../src/neo4j/neo4j-driver.js'; +import { addDocumentToNeo4j, convertUUIDtoId } from '../src/neo4j/neo4j-document.js'; +import { deleteAllNodesAndEdges, getGeneName, getNumNodes, getNumEdges, getEdge, getEdgeByIdAndEndpoints } from '../src/neo4j/test-functions.js'; +import { neighbourhoodWithoutComplexes } from '../src/neo4j/neo4j-functions.js'; + +import complex1 from './document/complex_tests_1.json'; +import complex2 from './document/complex_tests_2.json'; +import complex3 from './document/complex_tests_3.json'; +import complex4 from './document/complex_tests_4.json'; +import complex5 from './document/complex_tests_5.json'; +import complex6 from './document/complex_tests_6.json'; + +let rdbConn; +let dbFix; +let testDb; +const dbName = 'factoid-neo4j-test'; +const dbTables = ['document', 'element']; // Match fixture (JSON) keys + +describe('05. Tests for Documents with Complexes', function () { + + before('Create a Neo4j driver instance and connect to server. Connect to RDB', async function () { + await initDriver(); + + rdbConn = await r.connect({ host: 'localhost', db: dbName }); + const exists = await r.dbList().contains(dbName).run(rdbConn); + if (!exists) { + await r.dbCreate(dbName).run(rdbConn); + } + testDb = r.db(dbName); + dbFix = rdbFix({ + db: dbName, + clear: true //clear tables before inserting. + }); + }); + + after('Close Neo4j driver and RDB connection', async function () { + await closeDriver(); + await rdbConn.close(); + }); + + beforeEach('Delete nodes and edges from Neo4j', async function () { + await deleteAllNodesAndEdges(); + }); + + afterEach('Drop documents from RDB', async function () { + await dbFix.Delete(dbTables); + }); + + it('Two nodes in one complex', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(complex1); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity() && !ele.isComplex()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + let arrComplexEdges = myDoc.elements().filter(ele => ele.isComplex()); + + expect(await getNumNodes()).to.equal(2); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(1); + + expect(arrEdges.length).to.equal(0); + + expect(arrComplexEdges.length).to.equal(1); + let complexId = arrComplexEdges[0].id(); + let edge1 = await getEdgeByIdAndEndpoints('ncbigene:22882', 'ncbigene:3091', complexId); + expect(edge1.properties.type).to.equal('binding'); + expect(edge1.type).to.equal('INTERACTION'); + expect(edge1.properties.component).to.deep.equal(['ncbigene:22882', 'ncbigene:3091']); + expect(edge1.properties.sourceComplex).to.equal(''); + expect(edge1.properties.targetComplex).to.equal(''); + expect(edge1.properties.xref).to.equal(myDoc.id()); + expect(edge1.properties.doi).to.equal(myDoc.citation().doi); + expect(edge1.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge1.properties.articleTitle).to.equal(myDoc.citation().title); + + expect(await neighbourhoodWithoutComplexes('ncbigene:22882')).to.be.null; + expect(await neighbourhoodWithoutComplexes('ncbigene:3091')).to.be.null; + }); + + it('Three nodes in one complex, edges between them', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(complex2); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity() && !ele.isComplex()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + let arrComplexEdges = myDoc.elements().filter(ele => ele.isComplex()); + + expect(await getNumNodes()).to.equal(3); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(6); + + expect(arrEdges.length).to.equal(3); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + + expect(arrComplexEdges.length).to.equal(1); // There is one complex in the document, 3 edges + const complexId = arrComplexEdges[0].id(); + const edge1 = await getEdgeByIdAndEndpoints('ncbigene:3303', 'ncbigene:7157', complexId); + expect(edge1.properties.type).to.equal('binding'); + expect(edge1.type).to.equal('INTERACTION'); + expect(edge1.properties.component).to.deep.equal(['ncbigene:3303', 'ncbigene:7157', 'ncbigene:3326']); + expect(edge1.properties.sourceComplex).to.equal(''); + expect(edge1.properties.targetComplex).to.equal(''); + + const edge2 = await getEdgeByIdAndEndpoints('ncbigene:3303', 'ncbigene:3326', complexId); + expect(edge2.properties.type).to.equal('binding'); + expect(edge2.type).to.equal('INTERACTION'); + expect(edge2.properties.component).to.deep.equal(['ncbigene:3303', 'ncbigene:7157', 'ncbigene:3326']); + expect(edge2.properties.sourceComplex).to.equal(''); + expect(edge2.properties.targetComplex).to.equal(''); + + const edge3 = await getEdgeByIdAndEndpoints('ncbigene:7157', 'ncbigene:3326', complexId); + expect(edge3.properties.type).to.equal('binding'); + expect(edge3.type).to.equal('INTERACTION'); + expect(edge3.properties.component).to.deep.equal(['ncbigene:3303', 'ncbigene:7157', 'ncbigene:3326']); + expect(edge3.properties.sourceComplex).to.equal(''); + expect(edge3.properties.targetComplex).to.equal(''); + + let record = await neighbourhoodWithoutComplexes('ncbigene:3303'); + let testNodes = record.map(row => row.get('m').properties); + expect(testNodes.length).to.equal(2); + expect(_.find(testNodes, { id: 'ncbigene:7157' })).to.be.not.undefined; + expect(_.find(testNodes, { id: 'ncbigene:3326' })).to.be.not.undefined; + let testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(2); + expect(_.find(testEdges, { id: 'b6e4c90d-4870-4c64-8abf-b6e16b0738f7' })).to.be.not.undefined; + expect(_.find(testEdges, { id: '7ba76f35-faaa-4622-ae37-5aff0d802eed' })).to.be.not.undefined; + + record = await neighbourhoodWithoutComplexes('ncbigene:7157'); + testNodes = record.map(row => row.get('m').properties); + expect(_.find(testNodes, { id: 'ncbigene:3303' })).to.be.not.undefined; + expect(_.find(testNodes, { id: 'ncbigene:3326' })).to.be.not.undefined; + expect(testNodes.length).to.equal(2); + testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(2); + expect(_.find(testEdges, { id: 'b6e4c90d-4870-4c64-8abf-b6e16b0738f7' })).to.be.not.undefined; + expect(_.find(testEdges, { id: 'eb40318c-9a0e-45f6-a81e-21836fd9e9e3' })).to.be.not.undefined; + + record = await neighbourhoodWithoutComplexes('ncbigene:3326'); + testNodes = record.map(row => row.get('m').properties); + expect(testNodes.length).to.equal(2); + expect(_.find(testNodes, { id: 'ncbigene:7157' })).to.be.not.undefined; + expect(_.find(testNodes, { id: 'ncbigene:3303' })).to.be.not.undefined; + testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(2); + expect(_.find(testEdges, { id: '7ba76f35-faaa-4622-ae37-5aff0d802eed' })).to.be.not.undefined; + expect(_.find(testEdges, { id: 'eb40318c-9a0e-45f6-a81e-21836fd9e9e3' })).to.be.not.undefined; + }); + + it('Two nodes in one complex, 1 node interacting with a non-complex', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(complex3); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity() && !ele.isComplex()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + let arrComplexEdges = myDoc.elements().filter(ele => ele.isComplex()); + + expect(await getNumNodes()).to.equal(3); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(2); + + expect(arrEdges.length).to.equal(1); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + + expect(arrComplexEdges.length).to.equal(1); // There is one complex in the document, 1 edge + const complexId = arrComplexEdges[0].id(); + const edge1 = await getEdgeByIdAndEndpoints('ncbigene:90550', 'ncbigene:27173', complexId); + expect(edge1.properties.type).to.equal('binding'); + expect(edge1.type).to.equal('INTERACTION'); + expect(edge1.properties.component).to.deep.equal(['ncbigene:90550', 'ncbigene:27173']); + expect(edge1.properties.sourceComplex).to.equal(''); + expect(edge1.properties.targetComplex).to.equal(''); + + const record = await neighbourhoodWithoutComplexes('ncbigene:27173'); + const testNodes = record.map(row => row.get('m').properties); + expect(testNodes.length).to.equal(1); + expect(_.find(testNodes, { id: 'ncbigene:10059' })).to.be.not.undefined; + const testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(1); + expect(_.find(testEdges, { id: 'abce49de-663c-4a5b-8bc5-de1ec79a63d7' })).to.be.not.undefined; + }); + + it('Two complexes, 1 node from each interacting with a node from the other complex', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(complex4); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity() && !ele.isComplex()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + let arrComplexEdges = myDoc.elements().filter(ele => ele.isComplex()); + + expect(await getNumNodes()).to.equal(4); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(4); + + expect(arrEdges.length).to.equal(2); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + + expect(arrComplexEdges.length).to.equal(2); // There are 2 complexes in this document + const complexId1 = arrComplexEdges[0].id(); + const edge1 = await getEdgeByIdAndEndpoints('ncbigene:55215', 'ncbigene:2177', complexId1); + expect(edge1.properties.type).to.equal('binding'); + expect(edge1.type).to.equal('INTERACTION'); + expect(edge1.properties.component).to.deep.equal(['ncbigene:55215', 'ncbigene:2177']); + expect(edge1.properties.sourceComplex).to.equal(''); + expect(edge1.properties.targetComplex).to.equal(''); + + const complexId2 = arrComplexEdges[1].id(); + const edge2 = await getEdgeByIdAndEndpoints('ncbigene:57599', 'ncbigene:7398', complexId2); + expect(edge2.properties.type).to.equal('binding'); + expect(edge2.type).to.equal('INTERACTION'); + expect(edge2.properties.component).to.deep.equal(['ncbigene:57599', 'ncbigene:7398']); + expect(edge2.properties.sourceComplex).to.equal(''); + expect(edge2.properties.targetComplex).to.equal(''); + + let record = await neighbourhoodWithoutComplexes('ncbigene:55215'); + let testNodes = record.map(row => row.get('m').properties); + expect(testNodes.length).to.equal(1); + expect(_.find(testNodes, { id: 'ncbigene:57599' })).to.be.not.undefined; + let testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(1); + expect(_.find(testEdges, { id: 'b38116a2-5002-48b0-b156-32bcbff764a4' })).to.be.not.undefined; + + record = await neighbourhoodWithoutComplexes('ncbigene:7398'); + testNodes = record.map(row => row.get('m').properties); + expect(testNodes.length).to.equal(1); + expect(_.find(testNodes, { id: 'ncbigene:2177' })).to.be.not.undefined; + testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(1); + expect(_.find(testEdges, { id: '8ee9fb94-b3b8-4212-bddc-d46f1a079164' })).to.be.not.undefined; + + }); + + it('One complex interacting with one non-complex', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(complex5); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity() && !ele.isComplex()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + let arrComplexEdges = myDoc.elements().filter(ele => ele.isComplex()); + + expect(await getNumNodes()).to.equal(3); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(3); + + expect(arrComplexEdges.length).to.equal(1); // There is one complex in this document + const complexId1 = arrComplexEdges[0].id(); + const edge1 = await getEdgeByIdAndEndpoints('ncbigene:11335', 'ncbigene:648791', complexId1); + expect(edge1.properties.type).to.equal('binding'); + expect(edge1.type).to.equal('INTERACTION'); + expect(edge1.properties.component).to.deep.equal(['ncbigene:11335', 'ncbigene:648791']); + expect(edge1.properties.sourceComplex).to.equal(''); + expect(edge1.properties.targetComplex).to.equal(''); + + expect(arrEdges.length).to.equal(1); + const interactionEdgesId = arrEdges[0].id(); + const interactionEdge1 = await getEdgeByIdAndEndpoints('ncbigene:11335', 'ncbigene:8737', interactionEdgesId); + expect(interactionEdge1.properties.type).to.equal(arrEdges[0].type()); + expect(interactionEdge1.type).to.equal('INTERACTION'); + expect(interactionEdge1.properties.component).to.deep.equal([]); + expect(interactionEdge1.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge1.properties.targetComplex).to.equal(''); + + const interactionEdge2 = await getEdgeByIdAndEndpoints('ncbigene:648791', 'ncbigene:8737', interactionEdgesId); + expect(interactionEdge2.properties.type).to.equal(arrEdges[0].type()); + expect(interactionEdge2.type).to.equal('INTERACTION'); + expect(interactionEdge2.properties.component).to.deep.equal([]); + expect(interactionEdge2.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge2.properties.targetComplex).to.equal(''); + + expect(await neighbourhoodWithoutComplexes('ncbigene:11335')).to.be.null; + expect(await neighbourhoodWithoutComplexes('ncbigene:648791')).to.be.null; + expect(await neighbourhoodWithoutComplexes('ncbigene:8737')).to.be.null; + }); + + it('One complex interacting with another complex', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(complex6); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity() && !ele.isComplex()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + let arrComplexEdges = myDoc.elements().filter(ele => ele.isComplex()); + + expect(await getNumNodes()).to.equal(5); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(11); + + expect(arrEdges.length).to.equal(2); + + let edge = await getEdge('3b8e906f-d7ea-476b-a15c-4d383a603f22'); + expect(edge.properties.type).to.equal('interaction'); + expect(edge.properties.sourceId).to.equal('ncbigene:64112'); + expect(edge.properties.targetId).to.equal('ncbigene:84557'); + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + + + expect(arrComplexEdges.length).to.equal(2); // There are 2 complexes in this document + const complexId1 = arrComplexEdges[0].id(); + const edge1 = await getEdgeByIdAndEndpoints('ncbigene:84557', 'ncbigene:64112', complexId1); + expect(edge1.properties.type).to.equal('binding'); + expect(edge1.type).to.equal('INTERACTION'); + expect(edge1.properties.component).to.deep.equal(['ncbigene:84557', 'ncbigene:64112']); + expect(edge1.properties.sourceComplex).to.equal(''); + expect(edge1.properties.targetComplex).to.equal(''); + + const complexId2 = arrComplexEdges[1].id(); + const edge2 = await getEdgeByIdAndEndpoints('ncbigene:9474', 'ncbigene:9140', complexId2); + expect(edge2.properties.type).to.equal('binding'); + expect(edge2.type).to.equal('INTERACTION'); + expect(edge2.properties.component).to.deep.equal(['ncbigene:9474', 'ncbigene:9140', 'ncbigene:55054']); + expect(edge2.properties.sourceComplex).to.equal(''); + expect(edge2.properties.targetComplex).to.equal(''); + + const edge3 = await getEdgeByIdAndEndpoints('ncbigene:9474', 'ncbigene:55054', complexId2); + expect(edge3.properties.type).to.equal('binding'); + expect(edge3.type).to.equal('INTERACTION'); + expect(edge3.properties.component).to.deep.equal(['ncbigene:9474', 'ncbigene:9140', 'ncbigene:55054']); + expect(edge3.properties.sourceComplex).to.equal(''); + expect(edge3.properties.targetComplex).to.equal(''); + + const edge4 = await getEdgeByIdAndEndpoints('ncbigene:9140', 'ncbigene:55054', complexId2); + expect(edge4.properties.type).to.equal('binding'); + expect(edge4.type).to.equal('INTERACTION'); + expect(edge4.properties.component).to.deep.equal(['ncbigene:9474', 'ncbigene:9140', 'ncbigene:55054']); + expect(edge4.properties.sourceComplex).to.equal(''); + expect(edge4.properties.targetComplex).to.equal(''); + + const interactionEdgesId = '002147fb-ea3d-4b4c-a486-b968b317259a'; + + const interactionEdge1 = await getEdgeByIdAndEndpoints('ncbigene:64112', 'ncbigene:9474', interactionEdgesId); + expect(interactionEdge1.properties.type).to.equal('binding'); + expect(interactionEdge1.type).to.equal('INTERACTION'); + expect(interactionEdge1.properties.component).to.deep.equal([]); + expect(interactionEdge1.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge1.properties.targetComplex).to.equal(complexId2); + + const interactionEdge2 = await getEdgeByIdAndEndpoints('ncbigene:64112', 'ncbigene:9140', interactionEdgesId); + expect(interactionEdge2.properties.type).to.equal('binding'); + expect(interactionEdge2.type).to.equal('INTERACTION'); + expect(interactionEdge2.properties.component).to.deep.equal([]); + expect(interactionEdge2.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge2.properties.targetComplex).to.equal(complexId2); + + const interactionEdge3 = await getEdgeByIdAndEndpoints('ncbigene:64112', 'ncbigene:55054', interactionEdgesId); + expect(interactionEdge3.properties.type).to.equal('binding'); + expect(interactionEdge3.type).to.equal('INTERACTION'); + expect(interactionEdge3.properties.component).to.deep.equal([]); + expect(interactionEdge3.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge3.properties.targetComplex).to.equal(complexId2); + + const interactionEdge4 = await getEdgeByIdAndEndpoints('ncbigene:84557', 'ncbigene:9474', interactionEdgesId); + expect(interactionEdge4.properties.type).to.equal('binding'); + expect(interactionEdge4.type).to.equal('INTERACTION'); + expect(interactionEdge4.properties.component).to.deep.equal([]); + expect(interactionEdge4.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge4.properties.targetComplex).to.equal(complexId2); + + const interactionEdge5 = await getEdgeByIdAndEndpoints('ncbigene:84557', 'ncbigene:9140', interactionEdgesId); + expect(interactionEdge5.properties.type).to.equal('binding'); + expect(interactionEdge5.type).to.equal('INTERACTION'); + expect(interactionEdge5.properties.component).to.deep.equal([]); + expect(interactionEdge5.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge5.properties.targetComplex).to.equal(complexId2); + + const interactionEdge6 = await getEdgeByIdAndEndpoints('ncbigene:84557', 'ncbigene:55054', interactionEdgesId); + expect(interactionEdge6.properties.type).to.equal('binding'); + expect(interactionEdge6.type).to.equal('INTERACTION'); + expect(interactionEdge6.properties.component).to.deep.equal([]); + expect(interactionEdge6.properties.sourceComplex).to.equal(complexId1); + expect(interactionEdge6.properties.targetComplex).to.equal(complexId2); + + expect(await neighbourhoodWithoutComplexes('ncbigene:9474')).to.be.null; + + const record = await neighbourhoodWithoutComplexes('ncbigene:64112'); + const testNodes = record.map(row => row.get('m').properties); + expect(testNodes.length).to.equal(1); + expect(_.find(testNodes, { id: 'ncbigene:84557' })).to.not.be.undefined; + const testEdges = record.map(row => row.get('r').properties); + expect(testEdges.length).to.equal(1); + expect(_.find(testEdges, { id: '3b8e906f-d7ea-476b-a15c-4d383a603f22'})).to.not.be.undefined; + + }); +}); \ No newline at end of file diff --git a/neo4j-test/doc-tests.js b/neo4j-test/doc-tests.js new file mode 100644 index 000000000..90974ff06 --- /dev/null +++ b/neo4j-test/doc-tests.js @@ -0,0 +1,329 @@ +import { expect } from 'chai'; +import rdbFix from 'rethinkdb-fixtures'; +import r from 'rethinkdb'; + +import { loadDoc } from '../src/server/routes/api/document/index.js'; +import { initDriver, closeDriver } from '../src/neo4j/neo4j-driver.js'; +import { addDocumentToNeo4j, convertUUIDtoId } from '../src/neo4j/neo4j-document.js'; +import { deleteAllNodesAndEdges, getGeneName, getNumNodes, getNumEdges, getEdge } from '../src/neo4j/test-functions.js'; + +import fixture from './document/testDoc.json'; +import goult1 from './document/doct_tests_1.json'; +import goult2 from './document/doct_tests_2.json'; +import goult3 from './document/doct_tests_3.json'; +import goult4 from './document/doct_tests_4.json'; +import goult5 from './document/doct_tests_5.json'; + +let rdbConn; +let dbFix; +let testDb; +const dbName = 'factoid-neo4j-test'; +const dbTables = ['document', 'element']; // Match fixture (JSON) keys + +describe('03. Tests for Documents', function () { + + before('Create a Neo4j driver instance and connect to server. Connect to RDB', async function () { + await initDriver(); + + rdbConn = await r.connect({ host: 'localhost', db: dbName }); + const exists = await r.dbList().contains(dbName).run(rdbConn); + if (!exists) { + await r.dbCreate(dbName).run(rdbConn); + } + testDb = r.db(dbName); + dbFix = rdbFix({ + db: dbName, + clear: true //clear tables before inserting. + }); + }); + + after('Close Neo4j driver and RDB connection', async function () { + await closeDriver(); + await rdbConn.close(); + }); + + beforeEach('Delete nodes and edges from Neo4j', async function () { + await deleteAllNodesAndEdges(); + }); + + afterEach('Drop dummy Doc', async function () { + await dbFix.Delete(dbTables); + }); + + it('Add the elements of MAPK6-AKT1 dummy doc to Neo4j db', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(fixture); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + + expect(await getNumNodes()).to.equal(2); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(1); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + }); + + it('Add the elements of Goult 1 doc to Neo4j db', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(goult1); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + + expect(await getNumNodes()).to.equal(2); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(1); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + }); + + it('Add the elements of Goult 2 doc to Neo4j db', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(goult2); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + + expect(await getNumNodes()).to.equal(3); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(2); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + }); + + it('Add the elements of Goult 3 doc to Neo4j db', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(goult3); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + + expect(await getNumNodes()).to.equal(2); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(2); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + }); + + it('Add the elements of Goult 4 doc to Neo4j db', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(goult4); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + + expect(await getNumNodes()).to.equal(4); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(4); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + }); + + it('Add the elements of Goult 5 doc to Neo4j db', async function () { + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + const { document } = await dbFix.Insert(goult5); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + const fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + + expect(await getNumNodes()).to.equal(0); + expect(await getNumEdges()).to.equal(0); + await addDocumentToNeo4j(myDoc); + + let arrNodes = myDoc.elements().filter(ele => ele.isEntity()); + let arrEdges = myDoc.elements().filter(ele => !(ele.isEntity())); + + expect(await getNumNodes()).equal(5); + for (const n of arrNodes) { + let id = `${n.association().dbPrefix}:${n.association().id}`; + expect(await getGeneName(id)).to.equal(`${n.association().name}`); + } + + expect(await getNumEdges()).to.equal(5); + for (const e of arrEdges) { + let edge = await getEdge(e.id()); + expect(edge.properties.type).to.equal(e.type()); + if (e.association().getSource()) { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.association().getSource().id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.association().getTarget().id())); + } else { + expect(edge.properties.sourceId).to.equal(convertUUIDtoId(myDoc, e.elements()[0].id())); + expect(edge.properties.targetId).to.equal(convertUUIDtoId(myDoc, e.elements()[1].id())); + } + expect(edge.type).to.equal('INTERACTION'); + expect(edge.properties.component).to.deep.equal([]); + expect(edge.properties.sourceComplex).to.equal(''); + expect(edge.properties.targetComplex).to.equal(''); + expect(edge.properties.xref).to.equal(myDoc.id()); + expect(edge.properties.doi).to.equal(myDoc.citation().doi); + expect(edge.properties.pmid).to.equal(myDoc.citation().pmid); + expect(edge.properties.articleTitle).to.equal(myDoc.citation().title); + } + }); + +}); \ No newline at end of file diff --git a/neo4j-test/doct_tests_1.json b/neo4j-test/doct_tests_1.json new file mode 100644 index 000000000..9d32863d1 --- /dev/null +++ b/neo4j-test/doct_tests_1.json @@ -0,0 +1,15119 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-02-13T11:20:08.504Z", + "_newestOpId": "788f515c-7082-48df-9607-8b2f4e54fd1b", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Kindler syndrome is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding t kindlin-1. Kindlin-1 localizes to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of Kindler syndrome show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective integrin activation, cell adhesion, and migration. However, roles for kindlin-1 beyond integrin activation remain poorly defined. In this study we show that skin and keratinocytes from Kindler syndrome patients have significantly reduced expression levels of the EGFR, resulting in defective EGF-dependent signaling and cell migration. Mechanistically, we show that kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner and that formation of this complex is required for EGF-dependent migration. We further show that kindlin-1 acts to protect EGFR from lysosomal-mediated degradation. This shows a new role for kindlin-1 that has implications for understanding Kindler syndrome disease pathology.", + "ArticleTitle": "Kindlin-1 Regulates Epidermal Growth Factor Receptor Signaling.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Magdalene", + "Identifier": [], + "Initials": "M", + "LastName": "Michael" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK; St. Johns Institute of Dermatology, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rumena", + "Identifier": [], + "Initials": "R", + "LastName": "Begum" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Grace K", + "Identifier": [], + "Initials": "GK", + "LastName": "Chan" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, Kent, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Austin J", + "Identifier": [], + "Initials": "AJ", + "LastName": "Whitewood" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Nikon Imaging Centre, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Daniel R", + "Identifier": [], + "Initials": "DR", + "LastName": "Matthews" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, Kent, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Benjamin T", + "Identifier": [], + "Initials": "BT", + "LastName": "Goult" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "John A", + "Identifier": [], + "Initials": "JA", + "LastName": "McGrath" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "St. Johns Institute of Dermatology, King's College London, Guy's Campus, London, UK; Nikon Imaging Centre, King's College London, Guy's Campus, London, UK. Electronic address: maddy.parsons@kcl.ac.uk.", + "email": [ + "maddy.parsons@kcl.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Maddy", + "Identifier": [], + "Initials": "M", + "LastName": "Parsons" + } + ], + "Journal": { + "ISOAbbreviation": "J Invest Dermatol", + "ISSN": { + "IssnType": "Electronic", + "value": "1523-1747" + }, + "JournalIssue": { + "Issue": "2", + "PubDate": { + "Day": null, + "Month": "Feb", + "Year": "2019" + }, + "Volume": "139" + }, + "Title": "The Journal of investigative dermatology" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "D066255", + "value": "EGF Family of Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "C475301", + "value": "FERMT1 protein, human" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D008565", + "value": "Membrane Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D009363", + "value": "Neoplasm Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "C512478", + "value": "EGFR protein, human" + }, + "RegistryNumber": "EC 2.7.10.1" + }, + { + "NameOfSubstance": { + "UI": "D066246", + "value": "ErbB Receptors" + }, + "RegistryNumber": "EC 2.7.10.1" + } + ], + "InvestigatorList": [], + "KeywordList": [], + "MeshheadingList": [ + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D001768", + "value": "Blister" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000473", + "value": "pathology" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D002460", + "value": "Cell Line" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D002465", + "value": "Cell Movement" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D066255", + "value": "EGF Family of Proteins" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D004820", + "value": "Epidermolysis Bullosa" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000473", + "value": "pathology" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D066246", + "value": "ErbB Receptors" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D006801", + "value": "Humans" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D015603", + "value": "Keratinocytes" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000473", + "value": "pathology" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D008247", + "value": "Lysosomes" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D008565", + "value": "Membrane Proteins" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D009363", + "value": "Neoplasm Proteins" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D010510", + "value": "Periodontal Diseases" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000473", + "value": "pathology" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D010787", + "value": "Photosensitivity Disorders" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000473", + "value": "pathology" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D059748", + "value": "Proteolysis" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D015398", + "value": "Signal Transduction" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D012867", + "value": "Skin" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000473", + "value": "pathology" + } + ] + } + ] + }, + "PubmedData": { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "30248333" + }, + { + "IdType": "pmc", + "id": "PMC6345584" + }, + { + "IdType": "doi", + "id": "10.1016/j.jid.2018.08.020" + }, + { + "IdType": "pii", + "id": "S0022-202X(18)32587-9" + } + ], + "History": [ + { + "PubMedPubDate": { + "Day": "7", + "Month": "5", + "Year": "2018" + }, + "PubStatus": "received" + }, + { + "PubMedPubDate": { + "Day": "9", + "Month": "8", + "Year": "2018" + }, + "PubStatus": "revised" + }, + { + "PubMedPubDate": { + "Day": "10", + "Month": "8", + "Year": "2018" + }, + "PubStatus": "accepted" + }, + { + "PubMedPubDate": { + "Day": "25", + "Month": "9", + "Year": "2018" + }, + "PubStatus": "pubmed" + }, + { + "PubMedPubDate": { + "Day": "1", + "Month": "1", + "Year": "2020" + }, + "PubStatus": "medline" + }, + { + "PubMedPubDate": { + "Day": "25", + "Month": "9", + "Year": "2018" + }, + "PubStatus": "entrez" + } + ], + "ReferenceList": [ + { + "Reference": [ + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "14987263" + } + ], + "Citation": "Ashton G.H. 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Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome. J Invest Dermatol. 2008;128:2156–2165." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC2603460" + }, + { + "IdType": "pubmed", + "id": "18997731" + } + ], + "Citation": "Larjava H., Plow E.F., Wu C. Kindlins: essential regulators of integrin signalling and cell-matrix adhesion. EMBO Rep. 2008;9:1203–1208." + }, + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "26037143" + } + ], + "Citation": "Liu Z., Lu D., Wang X., Wan J., Liu C., Zhang H. Kindlin-2 phosphorylation by Src at Y193 enhances Src activity and is involved in migfilin recruitment to the focal adhesions. 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J Cell Sci. 2016;129:17–27." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC1180579" + }, + { + "IdType": "pubmed", + "id": "12789646" + } + ], + "Citation": "Siegel D.H., Ashton G.H., Penagos H.G., Lee J.V., Feiler H.S., Wilhelmsen K.C. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet. 2003;73:174–187." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC4180094" + }, + { + "IdType": "pubmed", + "id": "24215440" + } + ], + "Citation": "Singh B., Coffey R.J. Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells. Annu Rev Physiol. 2014;76:275–300." + }, + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "21336475" + } + ], + "Citation": "Techanukul T., Sethuraman G., Zlotogorski A., Horev L., Macarov M., Trainer A. Novel and recurrent FERMT1 gene mutations in Kindler syndrome. Acta Derm Venereol. 2011;91:267–270." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC2697853" + }, + { + "IdType": "pubmed", + "id": "18454678" + } + ], + "Citation": "Wiebe C.B., Petricca G., Hakkinen L., Jiang G., Wu C., Larjava H.S. Kindler syndrome and periodontal disease: review of the literature and a 12-year follow-up case. J Periodontol. 2008;79:961–966." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC2856911" + }, + { + "IdType": "pubmed", + "id": "20404115" + } + ], + "Citation": "Worth D.C., Hodivala-Dilke K., Robinson S.D., King S.J., Morton P.E., Gertler F.B. αvβ3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration. J Cell Biol. 2010;189:369–383." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC3352952" + }, + { + "IdType": "pubmed", + "id": "22564415" + } + ], + "Citation": "Zanet J., Jayo A., Plaza S., Millard T., Parsons M., Stramer B. Fascin promotes filopodia formation independent of its role in actin bundling. J Cell Biol. 2012;197:477–486." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC5756539" + }, + { + "IdType": "pubmed", + "id": "27427485" + } + ], + "Citation": "Zhang G., Gu Y., Begum R., Chen H., Gao X., McGrath J.A. Kindlin-1 regulates keratinocyte electrotaxis. J Invest Dermatol. 2016;136:2229–2239." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Magdalene", + "LastName": "Michael", + "abbrevName": "Michael M", + "email": null, + "isCollectiveName": false, + "name": "Magdalene Michael", + "orcid": "0000-0003-2577-729X" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum", + "orcid": null + }, + { + "ForeName": "Grace", + "LastName": "Chan", + "abbrevName": "Chan GK", + "email": null, + "isCollectiveName": false, + "name": "Grace K Chan", + "orcid": "0000-0002-7163-8285" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood AJ", + "email": null, + "isCollectiveName": false, + "name": "Austin J Whitewood", + "orcid": "0000-0002-8255-8248" + }, + { + "ForeName": "Daniel", + "LastName": "Matthews", + "abbrevName": "Matthews DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Matthews", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult", + "orcid": "0000-0002-3438-2807" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath", + "orcid": "0000-0002-3708-9964" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons", + "orcid": "0000-0002-2021-8379" + } + ], + "caption": "cell adhesion, Kindler syndrome, ", + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1644751208, + "entries": [ + { + "id": "1df25530-cd6f-45b9-8e4a-246651c639e3" + }, + { + "id": "95c4cbb1-bdff-473e-9203-8ebca2d44747" + }, + { + "id": "f4b557ff-2219-45a8-bffb-5b7691e6b6bd" + } + ], + "id": "df9348dc-2126-45ff-a379-138b5589bcc8", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1644751240, + "liveId": "d673c61c-2dd8-472b-8e54-7b5a02b0ff65", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "29563556", + "pubmed": { + "ISODate": "2018-03-21T00:00:00.000Z", + "abstract": "MicroScale Thermophoresis (MST) is a frequently used method for the quantitative characterization of intermolecular interactions with several advantages over other technologies. One of these is its capability to determine equilibrium constants in solution including complex biological matrices such as cell lysates. MST requires one binding partner to be fluorescent, which is typically achieved by labeling target proteins with a suitable fluorophore. Here, we present a near-native, site-specific in situ labeling strategy for MST experiments that enables reliable measurements in cell lysates and that has distinct advantages over routine covalent labeling techniques. To this end, we exploited the high-affinity interaction of tris-NTA with oligohistidine-tags, which are popular for purification, immobilization or detection of recombinant proteins. We used various DYE-tris-NTA conjugates to successfully label His-tagged proteins that were either purified or a component of cell lysate. The RED-tris-NTA was identified as the optimal dye conjugate with a high affinity towards oligohistidine-tags, a high fluorescence signal and an optimal signal-to-noise ratio in MST binding experiments. Owing to its emission in the red region of the spectrum, it also enables reliable measurements in complex biological matrices such as cell lysates allowing a more physiologically realistic assessment and eliminating the need for protein purification.", + "authors": { + "abbreviation": "Tanja Bartoschik, Stefanie Galinec, Christian Kleusch, ..., Nuska Tschammer", + "authorList": [ + { + "ForeName": "Tanja", + "LastName": "Bartoschik", + "abbrevName": "Bartoschik T", + "email": null, + "isCollectiveName": false, + "name": "Tanja Bartoschik" + }, + { + "ForeName": "Stefanie", + "LastName": "Galinec", + "abbrevName": "Galinec S", + "email": null, + "isCollectiveName": false, + "name": "Stefanie Galinec" + }, + { + "ForeName": "Christian", + "LastName": "Kleusch", + "abbrevName": "Kleusch C", + "email": null, + "isCollectiveName": false, + "name": "Christian Kleusch" + }, + { + "ForeName": "Katarzyna", + "LastName": "Walkiewicz", + "abbrevName": "Walkiewicz K", + "email": null, + "isCollectiveName": false, + "name": "Katarzyna Walkiewicz" + }, + { + "ForeName": "Dennis", + "LastName": "Breitsprecher", + "abbrevName": "Breitsprecher D", + "email": null, + "isCollectiveName": false, + "name": "Dennis Breitsprecher" + }, + { + "ForeName": "Sebastian", + "LastName": "Weigert", + "abbrevName": "Weigert S", + "email": null, + "isCollectiveName": false, + "name": "Sebastian Weigert" + }, + { + "ForeName": "Yves", + "LastName": "Muller", + "abbrevName": "Muller YA", + "email": null, + "isCollectiveName": false, + "name": "Yves A Muller" + }, + { + "ForeName": "Changjiang", + "LastName": "You", + "abbrevName": "You C", + "email": null, + "isCollectiveName": false, + "name": "Changjiang You" + }, + { + "ForeName": "Jacob", + "LastName": "Piehler", + "abbrevName": "Piehler J", + "email": null, + "isCollectiveName": false, + "name": "Jacob Piehler" + }, + { + "ForeName": "Thomas", + "LastName": "Vercruysse", + "abbrevName": "Vercruysse T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Vercruysse" + }, + { + "ForeName": "Dirk", + "LastName": "Daelemans", + "abbrevName": "Daelemans D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Daelemans" + }, + { + "ForeName": "Nuska", + "LastName": "Tschammer", + "abbrevName": "Tschammer N", + "email": "nuska.tschammer@nanotempertech.com", + "isCollectiveName": false, + "name": "Nuska Tschammer" + } + ], + "contacts": [ + { + "ForeName": "Nuska", + "LastName": "Tschammer", + "email": [ + "nuska.tschammer@nanotempertech.com" + ], + "name": "Nuska Tschammer" + } + ] + }, + "doi": "10.1038/s41598-018-23154-3", + "pmid": "29563556", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Sci Rep 8 2018", + "title": "Near-native, site-specific and purification-free protein labeling for quantitative protein interaction analysis by MicroScale Thermophoresis." + } + }, + { + "pmid": "29180516", + "pubmed": { + "ISODate": "2017-12-15T00:00:00.000Z", + "abstract": "When cell surface receptors engage their cognate ligands in the extracellular space, they become competent to transmit potent signals to the inside of the cell, thereby instigating growth, differentiation, motility and many other processes. In order to control these signals, activated receptors are endocytosed and thoroughly curated by the endosomal network of intracellular vesicles and proteolytic organelles. In this Review, we follow the epidermal growth factor (EGF) receptor (EGFR) from ligand engagement, through its voyage on endosomes and, ultimately, to its destruction in the lysosome. We focus on the spatial and temporal considerations underlying the molecular decisions that govern this complex journey and discuss how additional cellular organelles - particularly the ER - play active roles in the regulation of receptor lifespan. In summarizing the functions of relevant molecules on the endosomes and the ER, we cover the order of molecular events in receptor activation, trafficking and downregulation, and provide an overview of how signaling is controlled at the interface between these organelles.", + "authors": { + "abbreviation": "Jeroen Bakker, Menno Spits, Jacques Neefjes, Ilana Berlin", + "authorList": [ + { + "ForeName": "Jeroen", + "LastName": "Bakker", + "abbrevName": "Bakker J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Bakker" + }, + { + "ForeName": "Menno", + "LastName": "Spits", + "abbrevName": "Spits M", + "email": null, + "isCollectiveName": false, + "name": "Menno Spits" + }, + { + "ForeName": "Jacques", + "LastName": "Neefjes", + "abbrevName": "Neefjes J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Neefjes" + }, + { + "ForeName": "Ilana", + "LastName": "Berlin", + "abbrevName": "Berlin I", + "email": "I.Berlin@lumc.nl", + "isCollectiveName": false, + "name": "Ilana Berlin" + } + ], + "contacts": [ + { + "ForeName": "Ilana", + "LastName": "Berlin", + "email": [ + "I.Berlin@lumc.nl" + ], + "name": "Ilana Berlin" + } + ] + }, + "doi": "10.1242/jcs.209197", + "pmid": "29180516", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "The EGFR odyssey - from activation to destruction in space and time." + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "26729028", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation. Another hallmark of kindlins is their involvement in disease. Mutations in the KINDLIN-1 (also known as FERMT1) gene cause Kindler syndrome (KS)--in which mainly skin and intestine are affected, whereas mutations in the KINDLIN-3 (also known as FERMT3) gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by impaired extravasation of blood effector cells and severe, spontaneous bleedings. Also, aberrant expression of kindlins in various forms of cancer and in tissue fibrosis has been reported. Although the malfunctioning of integrins represent a major cause leading to kindlin-associated diseases, increasing evidence also point to integrin-independent functions of kindlins that play an important role in the pathogenesis of certain disease aspects. Furthermore, isoform-specific kindlin functions have been discovered, explaining, for example, why loss of kindlins differentially affects tissue stem cell homeostasis or tumor development. This Commentary focuses on new and isoform-specific kindlin functions in different tissues and discusses their potential role in disease development and progression.", + "authors": { + "abbreviation": "Emanuel Rognoni, Raphael Ruppert, Reinhard Fässler", + "authorList": [ + { + "ForeName": "Emanuel", + "LastName": "Rognoni", + "abbrevName": "Rognoni E", + "email": null, + "isCollectiveName": false, + "name": "Emanuel Rognoni" + }, + { + "ForeName": "Raphael", + "LastName": "Ruppert", + "abbrevName": "Ruppert R", + "email": null, + "isCollectiveName": false, + "name": "Raphael Ruppert" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": "faessler@biochem.mpg.de", + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [ + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "email": [ + "faessler@biochem.mpg.de" + ], + "name": "Reinhard Fässler" + } + ] + }, + "doi": "10.1242/jcs.161190", + "pmid": "26729028", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "The kindlin family: functions, signaling properties and implications for human disease." + } + }, + { + "pmid": "26037143", + "pubmed": { + "ISODate": "2015-07-08T00:00:00.000Z", + "abstract": "Kindlin-2 regulates external to internal cell signaling by interaction with integrins in a process that involves the tyrosine kinase, Src. However, the underlying mechanisms remain elusive. Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. These findings suggest that Src, Kindlin-2 and Migfilin together constitute a positive feedback loop that controls Src activity and regulates integrin-mediated cellular functions. ", + "authors": { + "abbreviation": "Zhaoli Liu, Danyu Lu, Xiang Wang, ..., Hongquan Zhang", + "authorList": [ + { + "ForeName": "Zhaoli", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaoli Liu" + }, + { + "ForeName": "Danyu", + "LastName": "Lu", + "abbrevName": "Lu D", + "email": null, + "isCollectiveName": false, + "name": "Danyu Lu" + }, + { + "ForeName": "Xiang", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiang Wang" + }, + { + "ForeName": "Junhu", + "LastName": "Wan", + "abbrevName": "Wan J", + "email": null, + "isCollectiveName": false, + "name": "Junhu Wan" + }, + { + "ForeName": "Chang", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Chang Liu" + }, + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": "Hongquan.Zhang@bjmu.edu.cn", + "isCollectiveName": false, + "name": "Hongquan Zhang" + } + ], + "contacts": [ + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "email": [ + "Hongquan.Zhang@bjmu.edu.cn" + ], + "name": "Hongquan Zhang" + } + ] + }, + "doi": "10.1016/j.febslet.2015.05.038", + "pmid": "26037143", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 589 2015", + "title": "Kindlin-2 phosphorylation by Src at Y193 enhances Src activity and is involved in Migfilin recruitment to the focal adhesions." + } + }, + { + "pmid": "25790908", + "pubmed": { + "ISODate": "2015-06-01T00:00:00.000Z", + "abstract": "Epidermal growth factor receptor (EGFR) mediates multiple signaling pathways that regulate cell proliferation, migration and tumor invasion. Kindlin-2 has been known as a focal adhesion molecule that binds to integrin to control cell migration and invasion. However, molecular mechanisms underlying the role of Kindlin-2 in breast cancer progression remain elusive. Here we report that Kindlin-2 interacts with EGFR and mediates EGF-induced breast cancer cell migration. We found that EGF treatment dramatically increases Kindlin-2 expression at both mRNA and protein levels in a variety of cancer cells. Inhibitors specific for EGFR or PI3K blocked Kindlin-2 induction by EGF. Importantly, Kindlin-2 interacted with EGFR kinase domain, which was independent of Kindlin-2 binding to integrin cytoplasmic domain. Intriguingly, Kindlin-2 stabilized EGFR protein by blocking its ubiquitination and degradation. Depletion of Kindlin-2 impaired EGF-induced cell migration. Our results demonstrated that Kindlin-2 participates in EGFR signaling and regulates breast cancer progression. ", + "authors": { + "abbreviation": "Baohui Guo, Jianchao Gao, Jun Zhan, Hongquan Zhang", + "authorList": [ + { + "ForeName": "Baohui", + "LastName": "Guo", + "abbrevName": "Guo B", + "email": null, + "isCollectiveName": false, + "name": "Baohui Guo" + }, + { + "ForeName": "Jianchao", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": null, + "isCollectiveName": false, + "name": "Jianchao Gao" + }, + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": "Hongquan.Zhang@bjmu.edu.cn", + "isCollectiveName": false, + "name": "Hongquan Zhang" + } + ], + "contacts": [ + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "email": [ + "Hongquan.Zhang@bjmu.edu.cn" + ], + "name": "Hongquan Zhang" + } + ] + }, + "doi": "10.1016/j.canlet.2015.03.011", + "pmid": "25790908", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Lett 361 2015", + "title": "Kindlin-2 interacts with and stabilizes EGFR and is required for EGF-induced breast cancer cell migration." + } + }, + { + "pmid": "25237194", + "pubmed": { + "ISODate": "2014-11-07T00:00:00.000Z", + "abstract": "Integrin-mediated cell-extracellular matrix (ECM) adhesion is critical for control of intracellular signaling; however, the mechanisms underlying this \"outside-in\" signaling are incompletely understood. Here we show that depletion of kindlin-2 impairs integrin outside-in signaling. Kindlin-2 is tyrosine-phosphorylated upon cell-ECM adhesion. Furthermore, kindlin-2 binds Src in a cell-ECM adhesion-regulatable fashion. At the molecular level, the kindlin-2·Src interaction is mediated by the kindlin-2 F0 and the Src SH2 and SH3 domains. Src activation increases kindlin-2 tyrosine phosphorylation and the kindlin-2·Src interaction. Conversely, inhibition of Src reduces kindlin-2 tyrosine phosphorylation and diminishes the kindlin-2·Src interaction. Finally, disruption of the kindlin-2·Src interaction, unlike depletion of kindlin-2, impairs neither cell-ECM adhesion nor cell-ECM adhesion-induced focal adhesion kinase Tyr-397 phosphorylation. However, it markedly inhibits cell-ECM adhesion-induced paxillin tyrosine phosphorylation, cell migration, and proliferation. These results suggest that kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch downstream of focal adhesion kinase in the integrin outside-in signaling circuit, relaying signals from cell-ECM adhesion to paxillin that control cell migration and proliferation. ", + "authors": { + "abbreviation": "Hong Qu, Yizeng Tu, Jun-Lin Guan, ..., Chuanyue Wu", + "authorList": [ + { + "ForeName": "Hong", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Qu" + }, + { + "ForeName": "Yizeng", + "LastName": "Tu", + "abbrevName": "Tu Y", + "email": null, + "isCollectiveName": false, + "name": "Yizeng Tu" + }, + { + "ForeName": "Jun-Lin", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "Jun-Lin Guan" + }, + { + "ForeName": "Guozhi", + "LastName": "Xiao", + "abbrevName": "Xiao G", + "email": null, + "isCollectiveName": false, + "name": "Guozhi Xiao" + }, + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": "carywu@pitt.edu", + "isCollectiveName": false, + "name": "Chuanyue Wu" + } + ], + "contacts": [ + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "email": [ + "carywu@pitt.edu" + ], + "name": "Chuanyue Wu" + } + ] + }, + "doi": "10.1074/jbc.M114.580811", + "pmid": "25237194", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "Kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch in the integrin outside-in signaling circuit." + } + }, + { + "pmid": "25086068", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Kindlins are essential FERM-domain-containing focal adhesion (FA) proteins required for proper integrin activation and signaling. Despite the widely accepted importance of each of the three mammalian kindlins in cell adhesion, the molecular basis for their function has yet to be fully elucidated, and the functional differences between isoforms have generally not been examined. Here, we report functional differences between kindlin-2 and -3 (also known as FERMT2 and FERMT3, respectively); GFP-tagged kindlin-2 localizes to FAs whereas kindlin-3 does not, and kindlin-2, but not kindlin-3, can rescue α5β1 integrin activation defects in kindlin-2-knockdown fibroblasts. Using chimeric kindlins, we show that the relatively uncharacterized kindlin-2 F2 subdomain drives FA targeting and integrin activation. We find that the integrin-linked kinase (ILK)-PINCH-parvin complex binds strongly to the kindlin-2 F2 subdomain but poorly to that of kindlin-3. Using a point-mutated kindlin-2, we establish that efficient kindlin-2-mediated integrin activation and FA targeting require binding to the ILK complex. Thus, ILK-complex binding is crucial for normal kindlin-2 function and differential ILK binding contributes to kindlin isoform specificity. ", + "authors": { + "abbreviation": "Clotilde Huet-Calderwood, Nina N Brahme, Nikit Kumar, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Clotilde", + "LastName": "Huet-Calderwood", + "abbrevName": "Huet-Calderwood C", + "email": null, + "isCollectiveName": false, + "name": "Clotilde Huet-Calderwood" + }, + { + "ForeName": "Nina", + "LastName": "Brahme", + "abbrevName": "Brahme NN", + "email": null, + "isCollectiveName": false, + "name": "Nina N Brahme" + }, + { + "ForeName": "Nikit", + "LastName": "Kumar", + "abbrevName": "Kumar N", + "email": null, + "isCollectiveName": false, + "name": "Nikit Kumar" + }, + { + "ForeName": "Amy", + "LastName": "Stiegler", + "abbrevName": "Stiegler AL", + "email": null, + "isCollectiveName": false, + "name": "Amy L Stiegler" + }, + { + "ForeName": "Srikala", + "LastName": "Raghavan", + "abbrevName": "Raghavan S", + "email": null, + "isCollectiveName": false, + "name": "Srikala Raghavan" + }, + { + "ForeName": "Titus", + "LastName": "Boggon", + "abbrevName": "Boggon TJ", + "email": null, + "isCollectiveName": false, + "name": "Titus J Boggon" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": "david.calderwood@yale.edu", + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Calderwood", + "email": [ + "david.calderwood@yale.edu" + ], + "name": "David A Calderwood" + } + ] + }, + "doi": "10.1242/jcs.155879", + "pmid": "25086068", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 127 2014", + "title": "Differences in binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation." + } + }, + { + "pmid": "24691054", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.", + "authors": { + "abbreviation": "Patrick Campbell, Penny E Morton, Takuya Takeichi, ..., John A McGrath", + "authorList": [ + { + "ForeName": "Patrick", + "LastName": "Campbell", + "abbrevName": "Campbell P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Campbell" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Takuya", + "LastName": "Takeichi", + "abbrevName": "Takeichi T", + "email": null, + "isCollectiveName": false, + "name": "Takuya Takeichi" + }, + { + "ForeName": "Amr", + "LastName": "Salam", + "abbrevName": "Salam A", + "email": null, + "isCollectiveName": false, + "name": "Amr Salam" + }, + { + "ForeName": "Nerys", + "LastName": "Roberts", + "abbrevName": "Roberts N", + "email": null, + "isCollectiveName": false, + "name": "Nerys Roberts" + }, + { + "ForeName": "Laura", + "LastName": "Proudfoot", + "abbrevName": "Proudfoot LE", + "email": null, + "isCollectiveName": false, + "name": "Laura E Proudfoot" + }, + { + "ForeName": "Jemima", + "LastName": "Mellerio", + "abbrevName": "Mellerio JE", + "email": null, + "isCollectiveName": false, + "name": "Jemima E Mellerio" + }, + { + "ForeName": "Kingi", + "LastName": "Aminu", + "abbrevName": "Aminu K", + "email": null, + "isCollectiveName": false, + "name": "Kingi Aminu" + }, + { + "ForeName": "Cheryl", + "LastName": "Wellington", + "abbrevName": "Wellington C", + "email": null, + "isCollectiveName": false, + "name": "Cheryl Wellington" + }, + { + "ForeName": "Sachin", + "LastName": "Patil", + "abbrevName": "Patil SN", + "email": null, + "isCollectiveName": false, + "name": "Sachin N Patil" + }, + { + "ForeName": "Masashi", + "LastName": "Akiyama", + "abbrevName": "Akiyama M", + "email": null, + "isCollectiveName": false, + "name": "Masashi Akiyama" + }, + { + "ForeName": "Lu", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lu Liu" + }, + { + "ForeName": "James", + "LastName": "McMillan", + "abbrevName": "McMillan JR", + "email": null, + "isCollectiveName": false, + "name": "James R McMillan" + }, + { + "ForeName": "Sophia", + "LastName": "Aristodemou", + "abbrevName": "Aristodemou S", + "email": null, + "isCollectiveName": false, + "name": "Sophia Aristodemou" + }, + { + "ForeName": "Akemi", + "LastName": "Ishida-Yamamoto", + "abbrevName": "Ishida-Yamamoto A", + "email": null, + "isCollectiveName": false, + "name": "Akemi Ishida-Yamamoto" + }, + { + "ForeName": "Alya", + "LastName": "Abdul-Wahab", + "abbrevName": "Abdul-Wahab A", + "email": null, + "isCollectiveName": false, + "name": "Alya Abdul-Wahab" + }, + { + "ForeName": "Gabriela", + "LastName": "Petrof", + "abbrevName": "Petrof G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Petrof" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Sarawin", + "LastName": "Harnchoowong", + "abbrevName": "Harnchoowong S", + "email": null, + "isCollectiveName": false, + "name": "Sarawin Harnchoowong" + }, + { + "ForeName": "Kristina", + "LastName": "Stone", + "abbrevName": "Stone KL", + "email": null, + "isCollectiveName": false, + "name": "Kristina L Stone" + }, + { + "ForeName": "John", + "LastName": "Harper", + "abbrevName": "Harper JI", + "email": null, + "isCollectiveName": false, + "name": "John I Harper" + }, + { + "ForeName": "W", + "LastName": "Irwin McLean", + "abbrevName": "Irwin McLean WH", + "email": null, + "isCollectiveName": false, + "name": "W H Irwin McLean" + }, + { + "ForeName": "Michael", + "LastName": "Simpson", + "abbrevName": "Simpson MA", + "email": null, + "isCollectiveName": false, + "name": "Michael A Simpson" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": "john.mcgrath@kcl.ac.uk", + "isCollectiveName": false, + "name": "John A McGrath" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "McGrath", + "email": [ + "john.mcgrath@kcl.ac.uk" + ], + "name": "John A McGrath" + } + ] + }, + "doi": "10.1038/jid.2014.164", + "pmid": "24691054", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 134 2014", + "title": "Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR." + } + }, + { + "pmid": "24525752", + "pubmed": { + "ISODate": "2014-03-01T00:00:00.000Z", + "abstract": "Detection and quantification of fluorescently labeled molecules in subcellular compartments is a key step in the analysis of many cell biological processes. Pixel-wise colocalization analyses, however, are not always suitable, because they do not provide object-specific information, and they are vulnerable to noise and background fluorescence. Here we present a versatile protocol for a method named 'Squassh' (segmentation and quantification of subcellular shapes), which is used for detecting, delineating and quantifying subcellular structures in fluorescence microscopy images. The workflow is implemented in freely available, user-friendly software. It works on both 2D and 3D images, accounts for the microscope optics and for uneven image background, computes cell masks and provides subpixel accuracy. The Squassh software enables both colocalization and shape analyses. The protocol can be applied in batch, on desktop computers or computer clusters, and it usually requires <1 min and <5 min for 2D and 3D images, respectively. Basic computer-user skills and some experience with fluorescence microscopy are recommended to successfully use the protocol. ", + "authors": { + "abbreviation": "Aurélien Rizk, Grégory Paul, Pietro Incardona, ..., Ivo F Sbalzarini", + "authorList": [ + { + "ForeName": "Aurélien", + "LastName": "Rizk", + "abbrevName": "Rizk A", + "email": null, + "isCollectiveName": false, + "name": "Aurélien Rizk" + }, + { + "ForeName": "Grégory", + "LastName": "Paul", + "abbrevName": "Paul G", + "email": null, + "isCollectiveName": false, + "name": "Grégory Paul" + }, + { + "ForeName": "Pietro", + "LastName": "Incardona", + "abbrevName": "Incardona P", + "email": null, + "isCollectiveName": false, + "name": "Pietro Incardona" + }, + { + "ForeName": "Milica", + "LastName": "Bugarski", + "abbrevName": "Bugarski M", + "email": null, + "isCollectiveName": false, + "name": "Milica Bugarski" + }, + { + "ForeName": "Maysam", + "LastName": "Mansouri", + "abbrevName": "Mansouri M", + "email": null, + "isCollectiveName": false, + "name": "Maysam Mansouri" + }, + { + "ForeName": "Axel", + "LastName": "Niemann", + "abbrevName": "Niemann A", + "email": null, + "isCollectiveName": false, + "name": "Axel Niemann" + }, + { + "ForeName": "Urs", + "LastName": "Ziegler", + "abbrevName": "Ziegler U", + "email": null, + "isCollectiveName": false, + "name": "Urs Ziegler" + }, + { + "ForeName": "Philipp", + "LastName": "Berger", + "abbrevName": "Berger P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Berger" + }, + { + "ForeName": "Ivo", + "LastName": "Sbalzarini", + "abbrevName": "Sbalzarini IF", + "email": null, + "isCollectiveName": false, + "name": "Ivo F Sbalzarini" + } + ], + "contacts": [] + }, + "doi": "10.1038/nprot.2014.037", + "pmid": "24525752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Protoc 9 2014", + "title": "Segmentation and quantification of subcellular structures in fluorescence microscopy images using Squassh." + } + }, + { + "pmid": "24215440", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "A largely unilamellar epithelial layer lines body cavities and organ ducts such as the digestive tract and kidney tubules. This polarized epithelium is composed of biochemically and functionally separate apical and basolateral surfaces. The epidermal growth factor receptor (EGFR) signaling pathway is a critical regulator of epithelial homeostasis and is perturbed in a number of epithelial disorders. It is underappreciated that in vivo EGFR signaling is most often initiated by cell-surface delivery and processing of one of seven transmembrane ligands, resulting in release of the soluble form that binds EGFR. In polarized epithelial cells, EGFR is restricted largely to the basolateral surface, and apical or basolateral ligand delivery therefore has important biological consequences. In vitro approaches have been used to study the biosynthesis, cell-surface delivery, proteolytic processing, and release of soluble EGFR ligands in polarized epithelial cells. We review these results, discuss their relevance to normal physiology, and demonstrate the pathophysiological consequences of aberrant trafficking. These studies have uncovered a rich diversity of apico-basolateral trafficking mechanisms among the EGFR ligands, provided insights into the pathogenesis of an inherited magnesium-wasting disorder of the kidney (isolated renal hypomagnesemia), and identified a new mode of EGFR ligand signaling via exosomes. ", + "authors": { + "abbreviation": "Bhuminder Singh, Robert J Coffey", + "authorList": [ + { + "ForeName": "Bhuminder", + "LastName": "Singh", + "abbrevName": "Singh B", + "email": "robert.coffey@vanderbilt.edu", + "isCollectiveName": false, + "name": "Bhuminder Singh" + }, + { + "ForeName": "Robert", + "LastName": "Coffey", + "abbrevName": "Coffey RJ", + "email": null, + "isCollectiveName": false, + "name": "Robert J Coffey" + } + ], + "contacts": [ + { + "ForeName": "Bhuminder", + "LastName": "Singh", + "email": [ + "robert.coffey@vanderbilt.edu", + "bhuminder.singh@vanderbilt.edu" + ], + "name": "Bhuminder Singh" + } + ] + }, + "doi": "10.1146/annurev-physiol-021113-170406", + "pmid": "24215440", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Annu Rev Physiol 76 2014", + "title": "Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells." + } + }, + { + "pmid": "24165133", + "pubmed": { + "ISODate": "2013-12-06T00:00:00.000Z", + "abstract": "Focal adhesions (FAs), sites of tight adhesion to the extracellular matrix, are composed of clusters of transmembrane integrin adhesion receptors and intracellular proteins that link integrins to the actin cytoskeleton and signaling pathways. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. Migfilin, originally identified in a yeast two-hybrid screen for kindlin-2-interacting proteins, is a LIM domain-containing adaptor protein found in FAs and implicated in control of cell adhesion, spreading, and migration. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. Here, using a combination of kindlin knockdown, biochemical pulldown assays, fluorescence microscopy, fluorescence resonance energy transfer (FRET), and fluorescence recovery after photobleaching (FRAP), we have established that the C-terminal LIM domains of migfilin dictate its FA localization, shown that these domains mediate an interaction with kindlin in vitro and in cells, and demonstrated that kindlin is important for normal migfilin dynamics in cells. We also show that when the C-terminal LIM domain region is deleted, then the N-terminal filamin-binding region of the protein, which is capable of targeting migfilin to actin-rich stress fibers, is the predominant driver of migfilin localization. Our work details a correlation between migfilin domains that drive kindlin binding and those that drive FA localization as well as a kindlin dependence on migfilin FA recruitment and mobility. We therefore suggest that the kindlin interaction with migfilin LIM domains drives migfilin FA recruitment, localization, and mobility. ", + "authors": { + "abbreviation": "Nina N Brahme, David S Harburger, Karl Kemp-O'Brien, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Brahme", + "abbrevName": "Brahme NN", + "email": null, + "isCollectiveName": false, + "name": "Nina N Brahme" + }, + { + "ForeName": "David", + "LastName": "Harburger", + "abbrevName": "Harburger DS", + "email": null, + "isCollectiveName": false, + "name": "David S Harburger" + }, + { + "ForeName": "Karl", + "LastName": "Kemp-O'Brien", + "abbrevName": "Kemp-O'Brien K", + "email": null, + "isCollectiveName": false, + "name": "Karl Kemp-O'Brien" + }, + { + "ForeName": "Rachel", + "LastName": "Stewart", + "abbrevName": "Stewart R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Stewart" + }, + { + "ForeName": "Srikala", + "LastName": "Raghavan", + "abbrevName": "Raghavan S", + "email": null, + "isCollectiveName": false, + "name": "Srikala Raghavan" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M113.483016", + "pmid": "24165133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics." + } + }, + { + "pmid": "23747363", + "pubmed": { + "ISODate": "2014-02-01T00:00:00.000Z", + "abstract": "Proteins of the 4.1 family are characteristic of eumetazoan organisms. Invertebrates contain single 4.1 genes and the Drosophila model suggests that 4.1 is essential for animal life. Vertebrates have four paralogues, known as 4.1R, 4.1N, 4.1G and 4.1B, which are additionally duplicated in the ray-finned fish. Protein 4.1R was the first to be discovered: it is a major mammalian erythrocyte cytoskeletal protein, essential to the mechanochemical properties of red cell membranes because it promotes the interaction between spectrin and actin in the membrane cytoskeleton. 4.1R also binds certain phospholipids and is required for the stable cell surface accumulation of a number of erythrocyte transmembrane proteins that span multiple functional classes; these include cell adhesion molecules, transporters and a chemokine receptor. The vertebrate 4.1 proteins are expressed in most tissues, and they are required for the correct cell surface accumulation of a very wide variety of membrane proteins including G-Protein coupled receptors, voltage-gated and ligand-gated channels, as well as the classes identified in erythrocytes. Indeed, such large numbers of protein interactions have been mapped for mammalian 4.1 proteins, most especially 4.1R, that it appears that they can act as hubs for membrane protein organization. The range of critical interactions of 4.1 proteins is reflected in disease relationships that include hereditary anaemias, tumour suppression, control of heartbeat and nervous system function. The 4.1 proteins are defined by their domain structure: apart from the spectrin/actin-binding domain they have FERM and FERM-adjacent domains and a unique C-terminal domain. Both the FERM and C-terminal domains can bind transmembrane proteins, thus they have the potential to be cross-linkers for membrane proteins. The activity of the FERM domain is subject to multiple modes of regulation via binding of regulatory ligands, phosphorylation of the FERM associated domain and differential mRNA splicing. Finally, the spectrum of interactions of the 4.1 proteins overlaps with that of another membrane-cytoskeleton linker, ankyrin. Both ankyrin and 4.1 link to the actin cytoskeleton via spectrin, and we hypothesize that differential regulation of 4.1 proteins and ankyrins allows highly selective control of cell surface protein accumulation and, hence, function. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé ", + "authors": { + "abbreviation": "Anthony J Baines, Hui-Chun Lu, Pauline M Bennett", + "authorList": [ + { + "ForeName": "Anthony", + "LastName": "Baines", + "abbrevName": "Baines AJ", + "email": null, + "isCollectiveName": false, + "name": "Anthony J Baines" + }, + { + "ForeName": "Hui-Chun", + "LastName": "Lu", + "abbrevName": "Lu HC", + "email": null, + "isCollectiveName": false, + "name": "Hui-Chun Lu" + }, + { + "ForeName": "Pauline", + "LastName": "Bennett", + "abbrevName": "Bennett PM", + "email": "pauline.bennett@kcl.ac.uk", + "isCollectiveName": false, + "name": "Pauline M Bennett" + } + ], + "contacts": [ + { + "ForeName": "Pauline", + "LastName": "Bennett", + "email": [ + "pauline.bennett@kcl.ac.uk" + ], + "name": "Pauline M Bennett" + } + ] + }, + "doi": "10.1016/j.bbamem.2013.05.030", + "pmid": "23747363", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochim Biophys Acta 1838 2014", + "title": "The Protein 4.1 family: hub proteins in animals for organizing membrane proteins." + } + }, + { + "pmid": "22974990", + "pubmed": { + "ISODate": "2012-09-11T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Paolo Maiuri, Emmanuel Terriac, Perrine Paul-Gilloteaux, ..., Manuel Théry", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Maiuri", + "abbrevName": "Maiuri P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Maiuri" + }, + { + "ForeName": "Emmanuel", + "LastName": "Terriac", + "abbrevName": "Terriac E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Terriac" + }, + { + "ForeName": "Perrine", + "LastName": "Paul-Gilloteaux", + "abbrevName": "Paul-Gilloteaux P", + "email": null, + "isCollectiveName": false, + "name": "Perrine Paul-Gilloteaux" + }, + { + "ForeName": "Timothée", + "LastName": "Vignaud", + "abbrevName": "Vignaud T", + "email": null, + "isCollectiveName": false, + "name": "Timothée Vignaud" + }, + { + "ForeName": "Krista", + "LastName": "McNally", + "abbrevName": "McNally K", + "email": null, + "isCollectiveName": false, + "name": "Krista McNally" + }, + { + "ForeName": "James", + "LastName": "Onuffer", + "abbrevName": "Onuffer J", + "email": null, + "isCollectiveName": false, + "name": "James Onuffer" + }, + { + "ForeName": "Kurt", + "LastName": "Thorn", + "abbrevName": "Thorn K", + "email": null, + "isCollectiveName": false, + "name": "Kurt Thorn" + }, + { + "ForeName": "Phuong", + "LastName": "Nguyen", + "abbrevName": "Nguyen PA", + "email": null, + "isCollectiveName": false, + "name": "Phuong A Nguyen" + }, + { + "ForeName": "Nefeli", + "LastName": "Georgoulia", + "abbrevName": "Georgoulia N", + "email": null, + "isCollectiveName": false, + "name": "Nefeli Georgoulia" + }, + { + "ForeName": "Daniel", + "LastName": "Soong", + "abbrevName": "Soong D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Soong" + }, + { + "ForeName": "Asier", + "LastName": "Jayo", + "abbrevName": "Jayo A", + "email": null, + "isCollectiveName": false, + "name": "Asier Jayo" + }, + { + "ForeName": "Nina", + "LastName": "Beil", + "abbrevName": "Beil N", + "email": null, + "isCollectiveName": false, + "name": "Nina Beil" + }, + { + "ForeName": "Jürgen", + "LastName": "Beneke", + "abbrevName": "Beneke J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Beneke" + }, + { + "ForeName": "Joleen", + "LastName": "Lim", + "abbrevName": "Lim JC", + "email": null, + "isCollectiveName": false, + "name": "Joleen Chooi Hong Lim" + }, + { + "ForeName": "Chloe", + "LastName": "Sim", + "abbrevName": "Sim CP", + "email": null, + "isCollectiveName": false, + "name": "Chloe Pei-Ying Sim" + }, + { + "ForeName": "Yeh-Shiu", + "LastName": "Chu", + "abbrevName": "Chu YS", + "email": null, + "isCollectiveName": false, + "name": "Yeh-Shiu Chu" + }, + { + "ForeName": null, + "LastName": null, + "abbrevName": "WCR participants", + "email": null, + "isCollectiveName": true, + "name": "WCR participants" + }, + { + "ForeName": "Andrea", + "LastName": "Jiménez-Dalmaroni", + "abbrevName": "Jiménez-Dalmaroni A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Jiménez-Dalmaroni" + }, + { + "ForeName": "Jean-François", + "LastName": "Joanny", + "abbrevName": "Joanny JF", + "email": null, + "isCollectiveName": false, + "name": "Jean-François Joanny" + }, + { + "ForeName": "Jean-Paul", + "LastName": "Thiery", + "abbrevName": "Thiery JP", + "email": null, + "isCollectiveName": false, + "name": "Jean-Paul Thiery" + }, + { + "ForeName": "Holger", + "LastName": "Erfle", + "abbrevName": "Erfle H", + "email": null, + "isCollectiveName": false, + "name": "Holger Erfle" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Timothy", + "LastName": "Mitchison", + "abbrevName": "Mitchison TJ", + "email": null, + "isCollectiveName": false, + "name": "Timothy J Mitchison" + }, + { + "ForeName": "Wendell", + "LastName": "Lim", + "abbrevName": "Lim WA", + "email": null, + "isCollectiveName": false, + "name": "Wendell A Lim" + }, + { + "ForeName": "Ana-Maria", + "LastName": "Lennon-Duménil", + "abbrevName": "Lennon-Duménil AM", + "email": null, + "isCollectiveName": false, + "name": "Ana-Maria Lennon-Duménil" + }, + { + "ForeName": "Matthieu", + "LastName": "Piel", + "abbrevName": "Piel M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Piel" + }, + { + "ForeName": "Manuel", + "LastName": "Théry", + "abbrevName": "Théry M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Théry" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2012.07.052", + "pmid": "22974990", + "pubTypes": [ + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 22 2012", + "title": "The first World Cell Race." + } + }, + { + "pmid": "22718763", + "pubmed": { + "ISODate": "2012-08-10T00:00:00.000Z", + "abstract": "Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways.", + "authors": { + "abbreviation": "Jong Hyun Kim, Aibing Wang, Mary Anne Conti, Robert S Adelstein", + "authorList": [ + { + "ForeName": "Jong", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": "nr.kimjohn@gmail.com", + "isCollectiveName": false, + "name": "Jong Hyun Kim" + }, + { + "ForeName": "Aibing", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aibing Wang" + }, + { + "ForeName": "Mary", + "LastName": "Conti", + "abbrevName": "Conti MA", + "email": null, + "isCollectiveName": false, + "name": "Mary Anne Conti" + }, + { + "ForeName": "Robert", + "LastName": "Adelstein", + "abbrevName": "Adelstein RS", + "email": null, + "isCollectiveName": false, + "name": "Robert S Adelstein" + } + ], + "contacts": [ + { + "ForeName": "Jong", + "LastName": "Kim", + "email": [ + "nr.kimjohn@gmail.com" + ], + "name": "Jong Hyun Kim" + } + ] + }, + "doi": "10.1074/jbc.M111.304824", + "pmid": "22718763", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Nonmuscle myosin II is required for internalization of the epidermal growth factor receptor and modulation of downstream signaling." + } + }, + { + "pmid": "22564415", + "pubmed": { + "ISODate": "2012-05-14T00:00:00.000Z", + "abstract": "Fascin is an evolutionarily conserved actin-binding protein that plays a key role in forming filopodia. It is widely thought that this function involves fascin directly bundling actin filaments, which is controlled by an N-terminal regulatory serine residue. In this paper, by studying cellular processes in Drosophila melanogaster that require fascin activity, we identify a regulatory residue within the C-terminal region of the protein (S289). Unexpectedly, although mutation (S289A) of this residue disrupted the actin-bundling capacity of fascin, fascin S289A fully rescued filopodia formation in fascin mutant flies. Live imaging of migrating macrophages in vivo revealed that this mutation restricted the localization of fascin to the distal ends of filopodia. The corresponding mutation of human fascin (S274) similarly affected its interaction with actin and altered filopodia dynamics within carcinoma cells. These data reveal an evolutionarily conserved role for this regulatory region and unveil a function for fascin, uncoupled from actin bundling, at the distal end of filopodia.", + "authors": { + "abbreviation": "Jennifer Zanet, Asier Jayo, Serge Plaza, ..., Brian Stramer", + "authorList": [ + { + "ForeName": "Jennifer", + "LastName": "Zanet", + "abbrevName": "Zanet J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Zanet" + }, + { + "ForeName": "Asier", + "LastName": "Jayo", + "abbrevName": "Jayo A", + "email": null, + "isCollectiveName": false, + "name": "Asier Jayo" + }, + { + "ForeName": "Serge", + "LastName": "Plaza", + "abbrevName": "Plaza S", + "email": null, + "isCollectiveName": false, + "name": "Serge Plaza" + }, + { + "ForeName": "Tom", + "LastName": "Millard", + "abbrevName": "Millard T", + "email": null, + "isCollectiveName": false, + "name": "Tom Millard" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Brian", + "LastName": "Stramer", + "abbrevName": "Stramer B", + "email": null, + "isCollectiveName": false, + "name": "Brian Stramer" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201110135", + "pmid": "22564415", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 197 2012", + "title": "Fascin promotes filopodia formation independent of its role in actin bundling." + } + }, + { + "pmid": "22418300", + "pubmed": { + "ISODate": "2012-02-27T00:00:00.000Z", + "abstract": "We present a novel approach for three-dimensional localization of single molecules using adaptive optics. A 52-actuator deformable mirror is used to both correct aberrations and induce two-dimensional astigmatism in the point-spread-function. The dependence of the z-localization precision on the degree of astigmatism is discussed. We achieve a z-localization precision of 40 nm for fluorescent proteins and 20 nm for fluorescent dyes, over an axial depth of ~800 nm. We illustrate the capabilities of our approach for three-dimensional high-resolution microscopy with super-resolution images of actin filaments in fixed cells and single-molecule tracking of quantum-dot labeled transmembrane proteins in live HeLa cells.", + "authors": { + "abbreviation": "Ignacio Izeddin, Mohamed El Beheiry, Jordi Andilla, ..., Maxime Dahan", + "authorList": [ + { + "ForeName": "Ignacio", + "LastName": "Izeddin", + "abbrevName": "Izeddin I", + "email": null, + "isCollectiveName": false, + "name": "Ignacio Izeddin" + }, + { + "ForeName": "Mohamed", + "LastName": "El Beheiry", + "abbrevName": "El Beheiry M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed El Beheiry" + }, + { + "ForeName": "Jordi", + "LastName": "Andilla", + "abbrevName": "Andilla J", + "email": null, + "isCollectiveName": false, + "name": "Jordi Andilla" + }, + { + "ForeName": "Daniel", + "LastName": "Ciepielewski", + "abbrevName": "Ciepielewski D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Ciepielewski" + }, + { + "ForeName": "Xavier", + "LastName": "Darzacq", + "abbrevName": "Darzacq X", + "email": null, + "isCollectiveName": false, + "name": "Xavier Darzacq" + }, + { + "ForeName": "Maxime", + "LastName": "Dahan", + "abbrevName": "Dahan M", + "email": null, + "isCollectiveName": false, + "name": "Maxime Dahan" + } + ], + "contacts": [] + }, + "doi": "10.1364/OE.20.004957", + "pmid": "22418300", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Opt Express 20 2012", + "title": "PSF shaping using adaptive optics for three-dimensional single-molecule super-resolution imaging and tracking." + } + }, + { + "pmid": "22351767", + "pubmed": { + "ISODate": "2012-04-20T00:00:00.000Z", + "abstract": "Talin, which is composed of head (THD) and rod domains, plays an important role in cell adhesion events in diverse species including most metazoans and Dictyostelium discoideum. Talin is abundant in the cytosol; however, it mediates adhesion by associating with integrins in the plasma membrane where it forms a primary link between integrins and the actin cytoskeleton. Cells modulate the partitioning of talin between the plasma membrane and the cytosol to control cell adhesion. Here, we combine nuclear magnetic resonance spectroscopy (NMR) with subcellular fractionation to characterize two distinct THD-rod domain interactions that control the interaction of talin with the actin cytoskeleton or its localization to the plasma membrane. An interaction between a discrete vinculin-binding region of the rod (VBS1/2a; Tln1(482-787)), and the THD restrains talin from interacting with the plasma membrane. Furthermore, we show that vinculin binding to VBS1/2a results in talin recruitment to the plasma membrane. Thus, we have structurally defined specific inter-domain interactions between THD and the talin rod domain that regulate the subcellular localization of talin.", + "authors": { + "abbreviation": "Asoka Banno, Benjamin T Goult, HoSup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Asoka", + "LastName": "Banno", + "abbrevName": "Banno A", + "email": null, + "isCollectiveName": false, + "name": "Asoka Banno" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "HoSup", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "HoSup Lee" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.341214", + "pmid": "22351767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Subcellular localization of talin is regulated by inter-domain interactions." + } + }, + { + "pmid": "22328497", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Integrin-β1-null keratinocytes can adhere to fibronectin through integrin αvβ6, but form large peripheral focal adhesions and exhibit defective cell spreading. Here we report that, in addition to the reduced avidity of αvβ6 integrin binding to fibronectin, the inability of integrin β6 to efficiently bind and recruit kindlin-2 to focal adhesions directly contributes to these phenotypes. Kindlins regulate integrins through direct interactions with the integrin-β cytoplasmic tail and keratinocytes express kindlin-1 and kindlin-2. Notably, although both kindlins localize to focal adhesions in wild-type cells, only kindlin-1 localizes to the integrin-β6-rich adhesions of integrin-β1-null cells. Rescue of these cells with wild-type and chimeric integrin constructs revealed a correlation between kindlin-2 recruitment and cell spreading. Furthermore, despite the presence of kindlin-1, knockdown of kindlin-2 in wild-type keratinocytes impaired cell spreading. Our data reveal unexpected functional consequences of differences in the association of two homologous kindlin isoforms with two closely related integrins, and suggest that despite their similarities, different kindlins are likely to have unique functions.", + "authors": { + "abbreviation": "Aditi Bandyopadhyay, Gerson Rothschild, Sean Kim, ..., Srikala Raghavan", + "authorList": [ + { + "ForeName": "Aditi", + "LastName": "Bandyopadhyay", + "abbrevName": "Bandyopadhyay A", + "email": null, + "isCollectiveName": false, + "name": "Aditi Bandyopadhyay" + }, + { + "ForeName": "Gerson", + "LastName": "Rothschild", + "abbrevName": "Rothschild G", + "email": null, + "isCollectiveName": false, + "name": "Gerson Rothschild" + }, + { + "ForeName": "Sean", + "LastName": "Kim", + "abbrevName": "Kim S", + "email": null, + "isCollectiveName": false, + "name": "Sean Kim" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Srikala", + "LastName": "Raghavan", + "abbrevName": "Raghavan S", + "email": null, + "isCollectiveName": false, + "name": "Srikala Raghavan" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.096214", + "pmid": "22328497", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 125 2012", + "title": "Functional differences between kindlin-1 and kindlin-2 in keratinocytes." + } + }, + { + "pmid": "22235127", + "pubmed": { + "ISODate": "2012-03-02T00:00:00.000Z", + "abstract": "The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin β subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin β tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin β subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in αIIbβ3 integrin activation, but not for kindlin binding to integrin β tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well β-integrin tails contribute to the ability of kindlins to activate integrins.", + "authors": { + "abbreviation": "Mohamed Bouaouina, Benjamin T Goult, Clotilde Huet-Calderwood, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Clotilde", + "LastName": "Huet-Calderwood", + "abbrevName": "Huet-Calderwood C", + "email": null, + "isCollectiveName": false, + "name": "Clotilde Huet-Calderwood" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Nina", + "LastName": "Brahme", + "abbrevName": "Brahme NN", + "email": null, + "isCollectiveName": false, + "name": "Nina N Brahme" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.330845", + "pmid": "22235127", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "20378539", + "pubmed": { + "ISODate": "2010-06-11T00:00:00.000Z", + "abstract": "Integrin activation is crucial for numerous cellular responses, including cell adhesion, migration, and survival. Recent studies in mice have specifically emphasized the vital role of kindlin-3 in integrin activation. Kindlin-3 deficiency in humans also has now been documented and includes symptoms of bleeding, frequent infections, and osteopetrosis, which are consequences of an inability to activate beta1, beta2, and beta3 integrins. To date, kindlin-3 was thought to be restricted to hematopoietic cells. In this article, we demonstrate that kindlin-3 is present in human endothelial cells derived from various anatomical origins. The mRNA and protein for KINDLIN-3 was detected in endothelial cells by reverse transcription-PCR and Western blots. When subjected to sequencing by mass spectrometry, the protein was identified as authentic kindlin-3 and unequivocally distinguished from KINDLIN-1 and KINDLIN-2 or any other known protein. By quantitative real time PCR, the level of kindlin-3 in endothelial cells was 20-50% of that of kindlin-2. Using knockdown approaches, we show that kindlin-3 plays a role in integrin-mediated adhesion of endothelial cells. This function depends upon the integrin and substrate and is distinct from that of kindlin-2. Formation of tube-like structures in Matrigel also was impaired by kindlin-3 knockdown. Mechanistically, the distinct functions of the kindlins can be traced to differences in their subcellular localization in integrin-containing adhesion structures. Thus, the prevailing view that individual kindlins exert their functions in a cell type-specific manner must now be modified to consider distinct functions of the different family members within the same cell type.", + "authors": { + "abbreviation": "Katarzyna Bialkowska, Yan-Qing Ma, Kamila Bledzka, ..., Edward F Plow", + "authorList": [ + { + "ForeName": "Katarzyna", + "LastName": "Bialkowska", + "abbrevName": "Bialkowska K", + "email": null, + "isCollectiveName": false, + "name": "Katarzyna Bialkowska" + }, + { + "ForeName": "Yan-Qing", + "LastName": "Ma", + "abbrevName": "Ma YQ", + "email": null, + "isCollectiveName": false, + "name": "Yan-Qing Ma" + }, + { + "ForeName": "Kamila", + "LastName": "Bledzka", + "abbrevName": "Bledzka K", + "email": null, + "isCollectiveName": false, + "name": "Kamila Bledzka" + }, + { + "ForeName": "Khalid", + "LastName": "Sossey-Alaoui", + "abbrevName": "Sossey-Alaoui K", + "email": null, + "isCollectiveName": false, + "name": "Khalid Sossey-Alaoui" + }, + { + "ForeName": "Lahoucine", + "LastName": "Izem", + "abbrevName": "Izem L", + "email": null, + "isCollectiveName": false, + "name": "Lahoucine Izem" + }, + { + "ForeName": "Xiaoxia", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoxia Zhang" + }, + { + "ForeName": "Nikolay", + "LastName": "Malinin", + "abbrevName": "Malinin N", + "email": null, + "isCollectiveName": false, + "name": "Nikolay Malinin" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.085746", + "pmid": "20378539", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "The integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell." + } + }, + { + "pmid": "19804783", + "pubmed": { + "ISODate": "2009-12-18T00:00:00.000Z", + "abstract": "The integrin family of heterodimeric cell adhesion molecules exists in both low- and high-affinity states, and integrin activation requires binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to membrane-proximal sequences in the beta-integrin cytoplasmic domain. However, it has recently become apparent that the kindlin family of FERM domain proteins is also essential for talin-induced integrin activation. FERM domains are typically composed of F1, F2, and F3 domains, but the talin FERM domain is atypical in that it contains a large insert in F1 and is preceded by a previously unrecognized domain, F0. Initial sequence alignments showed that the kindlin FERM domain was most similar to the talin FERM domain, but the homology appeared to be restricted to the F2 and F3 domains. Based on a detailed characterization of the talin FERM domain, we have reinvestigated the sequence relationship with kindlins and now show that kindlins do indeed contain the same domain structure as the talin FERM domain. However, the kindlin F1 domain contains an even larger insert than that in talin F1 that disrupts the sequence alignment. The insert, which varies in length between different kindlins, is not conserved and, as in talin, is largely unstructured. We have determined the structure of the kindlin-1 F0 domain by NMR, which shows that it adopts the same ubiquitin-like fold as the talin F0 and F1 domains. Comparison of the kindlin-1 and talin F0 domains identifies the probable interface with the kindlin-1 F1 domain. Potential sites of interaction of kindlin F0 with other proteins are discussed, including sites that differ between kindlin-1, kindlin-2, and kindlin-3. We also demonstrate that F0 is required for the ability of kindlin-1 to support talin-induced alphaIIbbeta3 integrin activation and for the localization of kindlin-1 to focal adhesions.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, David S Harburger, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "David", + "LastName": "Harburger", + "abbrevName": "Harburger DS", + "email": null, + "isCollectiveName": false, + "name": "David S Harburger" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Nicholas", + "LastName": "Anthis", + "abbrevName": "Anthis NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicholas J Anthis" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2009.09.061", + "pmid": "19804783", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 394 2009", + "title": "The structure of the N-terminus of kindlin-1: a domain important for alphaiibbeta3 integrin activation." + } + }, + { + "pmid": "19766491", + "pubmed": { + "ISODate": "2009-10-01T00:00:00.000Z", + "abstract": "Kindlins are a group of proteins that have recently attracted attention for their ability to bind and activate integrins. Moreover, they have also been linked to inherited and acquired human diseases including Kindler syndrome, leukocyte adhesion deficiency, and cancer. Although most studies have focused on kindlins as key regulatory components of cell-extracellular matrix junctions such as focal adhesions, preliminary data suggest the involvement of additional cellular compartments in mediating their functions, particularly at cell-cell contacts and the nucleus. Investigating the many roles of kindlins is likely to expand and sharpen our view on the versatility of integrin-mediated cell adhesion, the nuclear function of focal adhesion proteins, and the crosstalk between cell-cell and cell-matrix adhesions in health and disease.", + "authors": { + "abbreviation": "Alexander Meves, Christopher Stremmel, Kay Gottschalk, Reinhard Fässler", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Meves", + "abbrevName": "Meves A", + "email": "meves.alexander@mayo.edu", + "isCollectiveName": false, + "name": "Alexander Meves" + }, + { + "ForeName": "Christopher", + "LastName": "Stremmel", + "abbrevName": "Stremmel C", + "email": null, + "isCollectiveName": false, + "name": "Christopher Stremmel" + }, + { + "ForeName": "Kay", + "LastName": "Gottschalk", + "abbrevName": "Gottschalk K", + "email": null, + "isCollectiveName": false, + "name": "Kay Gottschalk" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [ + { + "ForeName": "Alexander", + "LastName": "Meves", + "email": [ + "meves.alexander@mayo.edu" + ], + "name": "Alexander Meves" + } + ] + }, + "doi": "10.1016/j.tcb.2009.07.006", + "pmid": "19766491", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Trends Cell Biol 19 2009", + "title": "The Kindlin protein family: new members to the club of focal adhesion proteins." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "18997731", + "pubmed": { + "ISODate": "2008-12-01T00:00:00.000Z", + "abstract": "Integrin-mediated cell-ECM (extracellular matrix) adhesion is a fundamental process that controls cell behaviour. For correct cell-ECM adhesion, both the ligand-binding affinity and the spatial organization of integrins must be precisely controlled; how integrins are regulated, however, is not completely understood. Kindlins constitute a family of evolutionarily conserved cytoplasmic components of cell-ECM adhesions that bind to beta-integrin cytoplasmic tails directly and cooperate with talin in integrin activation. In addition, kindlins interact with many components of cell-ECM adhesions--such as migfilin and integrin-linked kinase--to promote cytoskeletal reorganization. Loss of kindlins causes severe defects in integrin signalling, cell-ECM adhesion and cytoskeletal organization, resulting in early embryonic lethality (kindlin-2), postnatal lethality (kindlin-3) and Kindler syndrome (kindlin-1). It is therefore clear that kindlins, together with several other integrin-proximal proteins, are essential for integrin signalling and cell-ECM adhesion regulation.", + "authors": { + "abbreviation": "Hannu Larjava, Edward F Plow, Chuanyue Wu", + "authorList": [ + { + "ForeName": "Hannu", + "LastName": "Larjava", + "abbrevName": "Larjava H", + "email": null, + "isCollectiveName": false, + "name": "Hannu Larjava" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": null, + "isCollectiveName": false, + "name": "Chuanyue Wu" + } + ], + "contacts": [] + }, + "doi": "10.1038/embor.2008.202", + "pmid": "18997731", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "EMBO Rep 9 2008", + "title": "Kindlins: essential regulators of integrin signalling and cell-matrix adhesion." + } + }, + { + "pmid": "18652585", + "pubmed": { + "ISODate": "2008-11-01T00:00:00.000Z", + "abstract": "BACKGROUND: The Kindler syndrome (KS) protein kindlin-1 is a member of a protein complex that links cortical actin to integrins on the surface of basal keratinocytes. Loss of kindlin-1 leads to abnormalities of cell adhesion and motility, and to skin blistering and progressive poikiloderma as clinical symptoms. OBJECTIVES: Here we investigated a severely affected patient, disclosed the mutation that caused the disease and delineated its biological consequences. METHODS: Mutation screening of the kindlin-1 gene, KIND1 (now called FERMT1), was performed with polymerase chain reaction (PCR) amplification of all exons and sequencing. Mutated kindlin-1 was characterized by reverse transcriptase (RT)-PCR and immunoblotting, and genotype-phenotype correlations were analysed using immunohistochemical staining of skin biopsies and keratinocytes from the patient's skin. Cell adhesion and motility were assessed with functional tests. RESULTS: We disclosed a splice site mutation in the first position of intron 13 of the FERMT1 gene, which caused skipping of exon 13. The short transcript partially escaped nonsense-mediated mRNA decay and was translated into a truncated protein. CONCLUSION: A C-terminally truncated kindlin-1 in keratinocytes could not function correctly even if it were expressed.", + "authors": { + "abbreviation": "C Has, R J Ludwig, C Herz, ..., L Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Ludwig", + "abbrevName": "Ludwig RJ", + "email": null, + "isCollectiveName": false, + "name": "R J Ludwig" + }, + { + "ForeName": "C", + "LastName": "Herz", + "abbrevName": "Herz C", + "email": null, + "isCollectiveName": false, + "name": "C Herz" + }, + { + "ForeName": "J", + "LastName": "Kern", + "abbrevName": "Kern JS", + "email": null, + "isCollectiveName": false, + "name": "J S Kern" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "F", + "LastName": "Ochsendorf", + "abbrevName": "Ochsendorf FR", + "email": null, + "isCollectiveName": false, + "name": "F R Ochsendorf" + }, + { + "ForeName": "R", + "LastName": "Kaufmann", + "abbrevName": "Kaufmann R", + "email": null, + "isCollectiveName": false, + "name": "R Kaufmann" + }, + { + "ForeName": "H", + "LastName": "Schumann", + "abbrevName": "Schumann H", + "email": null, + "isCollectiveName": false, + "name": "H Schumann" + }, + { + "ForeName": "J", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "J Kohlhase" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08760.x", + "pmid": "18652585", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 159 2008", + "title": "C-terminally truncated kindlin-1 leads to abnormal adhesion and migration of keratinocytes." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "18454678", + "pubmed": { + "ISODate": "2008-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: The association of aggressive periodontitis with Kindler syndrome was based on a single case in 1996 and later confirmed with a larger population. Since then, significant research has greatly increased our understanding of the molecular pathology of this disorder. We review recent advances in the molecular mechanisms of the syndrome and present a maintenance case report of a patient who has been followed in our clinic. METHODS: A female patient who was diagnosed with Kindler syndrome and aggressive periodontitis at the age of 16 years has been followed and treated in our clinic for 12 years. Her main treatment has been maintenance therapy following her initial treatment and restorative work previously documented. Gingival biopsies obtained during the recent extraction of hopeless maxillary molars were used for histologic assessment of gingival tissue attachment apparatus and to isolate gingival fibroblasts. Reverse transcription-polymerase chain reaction (RT-PCR) was performed using these cells to confirm the lack of expression of kindlin-1. RESULTS: RT-PCR showed the total loss of kindlin-1 mRNA in cultured gingival fibroblasts, supporting the clinical diagnosis of Kindler syndrome. Tissue biopsies revealed atypical pocket epithelium. Maintenance therapy has been moderately successful. Teeth that were recently lost had a poor prognosis at the initial assessment. The patient's gingiva and oral mucosa continue to be fragile with episodes of sloughing and inflammation. CONCLUSIONS: Periodontitis in Kindler syndrome responds to maintenance therapy, but the gingiva and oral mucosa continue to display an abnormal appearance with white patches. Histologic findings suggest that the junctional epithelium in Kindler syndrome may be abnormal and could explain why these patients have periodontal disease. Attachment loss progressed around teeth with an initial guarded or poor prognosis. Teeth that started with a good or fair prognosis continue to have a fair prognosis. Limited dental implant treatment is being considered.", + "authors": { + "abbreviation": "Colin B Wiebe, Giorgio Petricca, Lari Häkkinen, ..., Hannu S Larjava", + "authorList": [ + { + "ForeName": "Colin", + "LastName": "Wiebe", + "abbrevName": "Wiebe CB", + "email": null, + "isCollectiveName": false, + "name": "Colin B Wiebe" + }, + { + "ForeName": "Giorgio", + "LastName": "Petricca", + "abbrevName": "Petricca G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Petricca" + }, + { + "ForeName": "Lari", + "LastName": "Häkkinen", + "abbrevName": "Häkkinen L", + "email": null, + "isCollectiveName": false, + "name": "Lari Häkkinen" + }, + { + "ForeName": "Guoqiao", + "LastName": "Jiang", + "abbrevName": "Jiang G", + "email": null, + "isCollectiveName": false, + "name": "Guoqiao Jiang" + }, + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": null, + "isCollectiveName": false, + "name": "Chuanyue Wu" + }, + { + "ForeName": "Hannu", + "LastName": "Larjava", + "abbrevName": "Larjava HS", + "email": null, + "isCollectiveName": false, + "name": "Hannu S Larjava" + } + ], + "contacts": [] + }, + "doi": "10.1902/jop.2008.070167", + "pmid": "18454678", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Periodontol 79 2008", + "title": "Kindler syndrome and periodontal disease: review of the literature and a 12-year follow-up case." + } + }, + { + "pmid": "17925226", + "pubmed": { + "ISODate": "2007-10-01T00:00:00.000Z", + "abstract": "Here, we report a direct interaction between the beta1 integrin cytoplasmic tail and Rab25, a GTPase that has been linked to tumor aggressiveness and metastasis. Rab25 promotes a mode of migration on 3D matrices that is characterized by the extension of long pseudopodia, and the association of the GTPase with alpha5beta1 promotes localization of vesicles that deliver integrin to the plasma membrane at pseudopodial tips as well as the retention of a pool of cycling alpha5beta1 at the cell front. Furthermore, Rab25-driven tumor-cell invasion into a 3D extracellular matrix environment is strongly dependent on ligation of fibronectin by alpha5beta1 integrin and the capacity of Rab25 to interact with beta1 integrin. These data indicate that Rab25 contributes to tumor progression by directing the localization of integrin-recycling vesicles and thereby enhancing the ability of tumor cells to invade the extracellular matrix.", + "authors": { + "abbreviation": "Patrick T Caswell, Heather J Spence, Maddy Parsons, ..., Jim C Norman", + "authorList": [ + { + "ForeName": "Patrick", + "LastName": "Caswell", + "abbrevName": "Caswell PT", + "email": null, + "isCollectiveName": false, + "name": "Patrick T Caswell" + }, + { + "ForeName": "Heather", + "LastName": "Spence", + "abbrevName": "Spence HJ", + "email": null, + "isCollectiveName": false, + "name": "Heather J Spence" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Dominic", + "LastName": "White", + "abbrevName": "White DP", + "email": null, + "isCollectiveName": false, + "name": "Dominic P White" + }, + { + "ForeName": "Katherine", + "LastName": "Clark", + "abbrevName": "Clark K", + "email": null, + "isCollectiveName": false, + "name": "Katherine Clark" + }, + { + "ForeName": "Kwai", + "LastName": "Cheng", + "abbrevName": "Cheng KW", + "email": null, + "isCollectiveName": false, + "name": "Kwai Wa Cheng" + }, + { + "ForeName": "Gordon", + "LastName": "Mills", + "abbrevName": "Mills GB", + "email": null, + "isCollectiveName": false, + "name": "Gordon B Mills" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Anthea", + "LastName": "Messent", + "abbrevName": "Messent AJ", + "email": null, + "isCollectiveName": false, + "name": "Anthea J Messent" + }, + { + "ForeName": "Kurt", + "LastName": "Anderson", + "abbrevName": "Anderson KI", + "email": null, + "isCollectiveName": false, + "name": "Kurt I Anderson" + }, + { + "ForeName": "Mary", + "LastName": "McCaffrey", + "abbrevName": "McCaffrey MW", + "email": null, + "isCollectiveName": false, + "name": "Mary W McCaffrey" + }, + { + "ForeName": "Bradford", + "LastName": "Ozanne", + "abbrevName": "Ozanne BW", + "email": null, + "isCollectiveName": false, + "name": "Bradford W Ozanne" + }, + { + "ForeName": "Jim", + "LastName": "Norman", + "abbrevName": "Norman JC", + "email": null, + "isCollectiveName": false, + "name": "Jim C Norman" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2007.08.012", + "pmid": "17925226", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 13 2007", + "title": "Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments." + } + }, + { + "pmid": "17460733", + "pubmed": { + "ISODate": "2007-09-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Joey E Lai-Cheong, Lu Liu, Gomathy Sethuraman, ..., John A McGrath", + "authorList": [ + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "Lu", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lu Liu" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Rajesh", + "LastName": "Kumar", + "abbrevName": "Kumar R", + "email": null, + "isCollectiveName": false, + "name": "Rajesh Kumar" + }, + { + "ForeName": "Vinod", + "LastName": "Sharma", + "abbrevName": "Sharma VK", + "email": null, + "isCollectiveName": false, + "name": "Vinod K Sharma" + }, + { + "ForeName": "Siva", + "LastName": "Reddy", + "abbrevName": "Reddy SR", + "email": null, + "isCollectiveName": false, + "name": "Siva R Reddy" + }, + { + "ForeName": "Anders", + "LastName": "Vahlquist", + "abbrevName": "Vahlquist A", + "email": null, + "isCollectiveName": false, + "name": "Anders Vahlquist" + }, + { + "ForeName": "Sandra", + "LastName": "Pather", + "abbrevName": "Pather S", + "email": null, + "isCollectiveName": false, + "name": "Sandra Pather" + }, + { + "ForeName": "Ken", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "Ken Arita" + }, + { + "ForeName": "Vesarat", + "LastName": "Wessagowit", + "abbrevName": "Wessagowit V", + "email": null, + "isCollectiveName": false, + "name": "Vesarat Wessagowit" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.jid.5700830", + "pmid": "17460733", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016420", + "value": "Comment" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 127 2007", + "title": "Five new homozygous mutations in the KIND1 gene in Kindler syndrome." + } + }, + { + "pmid": "17012746", + "pubmed": { + "ISODate": "2006-11-24T00:00:00.000Z", + "abstract": "A novel family of focal adhesion proteins, the kindlins, is involved in attachment of the actin cytoskeleton to the plasma membrane and in integrin-mediated cellular processes. Deficiency of kindlin-1, as a result of loss-of-function mutations in the KIND1 gene, causes Kindler syndrome, an autosomal recessive genodermatosis characterized by skin blistering, progressive skin atrophy, photosensitivity and, occasionally, carcinogenesis. Here we characterized authentic and recombinantly expressed kindlin-1 and show that it is localized in basal epidermal keratinocytes in a polar fashion, close to the cell surface facing the basement membrane, in the areas between the hemidesmosomes. We identified two forms of kindlin-1 in keratinocytes, with apparent molecular masses of 78 and 74 kDa, corresponding to phosphorylated and desphosphorylated forms of the protein. In kindlin-1-deficient skin, basal keratinocytes show multiple abnormalities: cell polarity is lost, proliferation is strongly reduced, and several cells undergo apoptosis. In vitro, deficiency of kindlin-1 in keratinocytes leads to strongly reduced cell proliferation, decreased adhesion, undirected motility, and intense protrusion activity of the plasma membrane. Taken together, these results show that kindlin-1 plays a role in keratinocyte adhesion, polarization, proliferation, and migration. It is involved in organization and anchorage of the actin cytoskeleton to integrin-associated signaling platforms.", + "authors": { + "abbreviation": "Corinna Herz, Monique Aumailley, Carsten Schulte, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Corinna", + "LastName": "Herz", + "abbrevName": "Herz C", + "email": null, + "isCollectiveName": false, + "name": "Corinna Herz" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + }, + { + "ForeName": "Carsten", + "LastName": "Schulte", + "abbrevName": "Schulte C", + "email": null, + "isCollectiveName": false, + "name": "Carsten Schulte" + }, + { + "ForeName": "Ursula", + "LastName": "Schlötzer-Schrehardt", + "abbrevName": "Schlötzer-Schrehardt U", + "email": null, + "isCollectiveName": false, + "name": "Ursula Schlötzer-Schrehardt" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M606259200", + "pmid": "17012746", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 281 2006", + "title": "Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "12789646", + "pubmed": { + "ISODate": "2003-07-01T00:00:00.000Z", + "abstract": "Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed \"KIND1\" [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.", + "authors": { + "abbreviation": "Dawn H Siegel, Gabrielle H S Ashton, Homero G Penagos, ..., Ervin H Epstein", + "authorList": [ + { + "ForeName": "Dawn", + "LastName": "Siegel", + "abbrevName": "Siegel DH", + "email": null, + "isCollectiveName": false, + "name": "Dawn H Siegel" + }, + { + "ForeName": "Gabrielle", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": null, + "isCollectiveName": false, + "name": "Gabrielle H S Ashton" + }, + { + "ForeName": "Homero", + "LastName": "Penagos", + "abbrevName": "Penagos HG", + "email": null, + "isCollectiveName": false, + "name": "Homero G Penagos" + }, + { + "ForeName": "James", + "LastName": "Lee", + "abbrevName": "Lee JV", + "email": null, + "isCollectiveName": false, + "name": "James V Lee" + }, + { + "ForeName": "Heidi", + "LastName": "Feiler", + "abbrevName": "Feiler HS", + "email": null, + "isCollectiveName": false, + "name": "Heidi S Feiler" + }, + { + "ForeName": "Kirk", + "LastName": "Wilhelmsen", + "abbrevName": "Wilhelmsen KC", + "email": null, + "isCollectiveName": false, + "name": "Kirk C Wilhelmsen" + }, + { + "ForeName": "Andrew", + "LastName": "South", + "abbrevName": "South AP", + "email": null, + "isCollectiveName": false, + "name": "Andrew P South" + }, + { + "ForeName": "Frances", + "LastName": "Smith", + "abbrevName": "Smith FJ", + "email": null, + "isCollectiveName": false, + "name": "Frances J D Smith" + }, + { + "ForeName": "Alan", + "LastName": "Prescott", + "abbrevName": "Prescott AR", + "email": null, + "isCollectiveName": false, + "name": "Alan R Prescott" + }, + { + "ForeName": "Vesarat", + "LastName": "Wessagowit", + "abbrevName": "Wessagowit V", + "email": null, + "isCollectiveName": false, + "name": "Vesarat Wessagowit" + }, + { + "ForeName": "Noritaka", + "LastName": "Oyama", + "abbrevName": "Oyama N", + "email": null, + "isCollectiveName": false, + "name": "Noritaka Oyama" + }, + { + "ForeName": "Masashi", + "LastName": "Akiyama", + "abbrevName": "Akiyama M", + "email": null, + "isCollectiveName": false, + "name": "Masashi Akiyama" + }, + { + "ForeName": "Daifullah", + "LastName": "Al Aboud", + "abbrevName": "Al Aboud D", + "email": null, + "isCollectiveName": false, + "name": "Daifullah Al Aboud" + }, + { + "ForeName": "Khalid", + "LastName": "Al Aboud", + "abbrevName": "Al Aboud K", + "email": null, + "isCollectiveName": false, + "name": "Khalid Al Aboud" + }, + { + "ForeName": "Ahmad", + "LastName": "Al Githami", + "abbrevName": "Al Githami A", + "email": null, + "isCollectiveName": false, + "name": "Ahmad Al Githami" + }, + { + "ForeName": "Khalid", + "LastName": "Al Hawsawi", + "abbrevName": "Al Hawsawi K", + "email": null, + "isCollectiveName": false, + "name": "Khalid Al Hawsawi" + }, + { + "ForeName": "Abla", + "LastName": "Al Ismaily", + "abbrevName": "Al Ismaily A", + "email": null, + "isCollectiveName": false, + "name": "Abla Al Ismaily" + }, + { + "ForeName": "Raouf", + "LastName": "Al-Suwaid", + "abbrevName": "Al-Suwaid R", + "email": null, + "isCollectiveName": false, + "name": "Raouf Al-Suwaid" + }, + { + "ForeName": "David", + "LastName": "Atherton", + "abbrevName": "Atherton DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Atherton" + }, + { + "ForeName": "Ruggero", + "LastName": "Caputo", + "abbrevName": "Caputo R", + "email": null, + "isCollectiveName": false, + "name": "Ruggero Caputo" + }, + { + "ForeName": "Jo-David", + "LastName": "Fine", + "abbrevName": "Fine JD", + "email": null, + "isCollectiveName": false, + "name": "Jo-David Fine" + }, + { + "ForeName": "Ilona", + "LastName": "Frieden", + "abbrevName": "Frieden IJ", + "email": null, + "isCollectiveName": false, + "name": "Ilona J Frieden" + }, + { + "ForeName": "Elaine", + "LastName": "Fuchs", + "abbrevName": "Fuchs E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Fuchs" + }, + { + "ForeName": "Richard", + "LastName": "Haber", + "abbrevName": "Haber RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Haber" + }, + { + "ForeName": "Takashi", + "LastName": "Harada", + "abbrevName": "Harada T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Harada" + }, + { + "ForeName": "Yasuo", + "LastName": "Kitajima", + "abbrevName": "Kitajima Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuo Kitajima" + }, + { + "ForeName": "Susan", + "LastName": "Mallory", + "abbrevName": "Mallory SB", + "email": null, + "isCollectiveName": false, + "name": "Susan B Mallory" + }, + { + "ForeName": "Hideoki", + "LastName": "Ogawa", + "abbrevName": "Ogawa H", + "email": null, + "isCollectiveName": false, + "name": "Hideoki Ogawa" + }, + { + "ForeName": "Sedef", + "LastName": "Sahin", + "abbrevName": "Sahin S", + "email": null, + "isCollectiveName": false, + "name": "Sedef Sahin" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + }, + { + "ForeName": "Yasushi", + "LastName": "Suga", + "abbrevName": "Suga Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Suga" + }, + { + "ForeName": "Gianluca", + "LastName": "Tadini", + "abbrevName": "Tadini G", + "email": null, + "isCollectiveName": false, + "name": "Gianluca Tadini" + }, + { + "ForeName": "Kikuo", + "LastName": "Tsuchiya", + "abbrevName": "Tsuchiya K", + "email": null, + "isCollectiveName": false, + "name": "Kikuo Tsuchiya" + }, + { + "ForeName": "Colin", + "LastName": "Wiebe", + "abbrevName": "Wiebe CB", + "email": null, + "isCollectiveName": false, + "name": "Colin B Wiebe" + }, + { + "ForeName": "Fenella", + "LastName": "Wojnarowska", + "abbrevName": "Wojnarowska F", + "email": null, + "isCollectiveName": false, + "name": "Fenella Wojnarowska" + }, + { + "ForeName": "Adel", + "LastName": "Zaghloul", + "abbrevName": "Zaghloul AB", + "email": null, + "isCollectiveName": false, + "name": "Adel B Zaghloul" + }, + { + "ForeName": "Takahiro", + "LastName": "Hamada", + "abbrevName": "Hamada T", + "email": null, + "isCollectiveName": false, + "name": "Takahiro Hamada" + }, + { + "ForeName": "Rajeev", + "LastName": "Mallipeddi", + "abbrevName": "Mallipeddi R", + "email": null, + "isCollectiveName": false, + "name": "Rajeev Mallipeddi" + }, + { + "ForeName": "Robin", + "LastName": "Eady", + "abbrevName": "Eady RA", + "email": null, + "isCollectiveName": false, + "name": "Robin A J Eady" + }, + { + "ForeName": "W", + "LastName": "McLean", + "abbrevName": "McLean WH", + "email": null, + "isCollectiveName": false, + "name": "W H Irwin McLean" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Ervin", + "LastName": "Epstein", + "abbrevName": "Epstein EH", + "email": null, + "isCollectiveName": false, + "name": "Ervin H Epstein" + } + ], + "contacts": [] + }, + "doi": "10.1086/376609", + "pmid": "12789646", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Am J Hum Genet 73 2003", + "title": "Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome." + } + }, + { + "pmid": "12754251", + "pubmed": { + "ISODate": "2003-08-01T00:00:00.000Z", + "abstract": "Ligand-induced down-regulation controls the signaling potency of the epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation. However, the role of endogenous Cbl in EGFR down-regulation and the precise step in the endocytic pathway regulated by Cbl remain unclear. Using Cbl-/- mouse embryonic fibroblast cell lines, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and efficient degradation of EGFR. Further analyses using Chinese hamster ovary cells with a temperature-sensitive defect in ubiquitinylation confirm a crucial role of the ubiquitin machinery in Cbl-mediated EGFR degradation. However, internalization into early endosomes did not require Cbl function or an intact ubiquitin pathway. Confocal immunolocalization studies indicated that Cbl-dependent ubiquitinylation plays a critical role at the early endosome to late endosome/lysosome sorting step of EGFR down-regulation. These findings establish Cbl as the major endogenous ubiquitin ligase responsible for EGFR degradation, and show that the critical role of Cbl-mediated ubiquitinylation is at the level of endosomal sorting, rather than at the level of internalization.", + "authors": { + "abbreviation": "Lei Duan, Yuko Miura, Manjari Dimri, ..., Hamid Band", + "authorList": [ + { + "ForeName": "Lei", + "LastName": "Duan", + "abbrevName": "Duan L", + "email": null, + "isCollectiveName": false, + "name": "Lei Duan" + }, + { + "ForeName": "Yuko", + "LastName": "Miura", + "abbrevName": "Miura Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Miura" + }, + { + "ForeName": "Manjari", + "LastName": "Dimri", + "abbrevName": "Dimri M", + "email": null, + "isCollectiveName": false, + "name": "Manjari Dimri" + }, + { + "ForeName": "Biswanath", + "LastName": "Majumder", + "abbrevName": "Majumder B", + "email": null, + "isCollectiveName": false, + "name": "Biswanath Majumder" + }, + { + "ForeName": "Ingrid", + "LastName": "Dodge", + "abbrevName": "Dodge IL", + "email": null, + "isCollectiveName": false, + "name": "Ingrid L Dodge" + }, + { + "ForeName": "Alagarsamy", + "LastName": "Reddi", + "abbrevName": "Reddi AL", + "email": null, + "isCollectiveName": false, + "name": "Alagarsamy L Reddi" + }, + { + "ForeName": "Amiya", + "LastName": "Ghosh", + "abbrevName": "Ghosh A", + "email": null, + "isCollectiveName": false, + "name": "Amiya Ghosh" + }, + { + "ForeName": "Norvin", + "LastName": "Fernandes", + "abbrevName": "Fernandes N", + "email": null, + "isCollectiveName": false, + "name": "Norvin Fernandes" + }, + { + "ForeName": "Pengcheng", + "LastName": "Zhou", + "abbrevName": "Zhou P", + "email": null, + "isCollectiveName": false, + "name": "Pengcheng Zhou" + }, + { + "ForeName": "Karen", + "LastName": "Mullane-Robinson", + "abbrevName": "Mullane-Robinson K", + "email": null, + "isCollectiveName": false, + "name": "Karen Mullane-Robinson" + }, + { + "ForeName": "Navin", + "LastName": "Rao", + "abbrevName": "Rao N", + "email": null, + "isCollectiveName": false, + "name": "Navin Rao" + }, + { + "ForeName": "Stephen", + "LastName": "Donoghue", + "abbrevName": "Donoghue S", + "email": null, + "isCollectiveName": false, + "name": "Stephen Donoghue" + }, + { + "ForeName": "Rick", + "LastName": "Rogers", + "abbrevName": "Rogers RA", + "email": null, + "isCollectiveName": false, + "name": "Rick A Rogers" + }, + { + "ForeName": "David", + "LastName": "Bowtell", + "abbrevName": "Bowtell D", + "email": null, + "isCollectiveName": false, + "name": "David Bowtell" + }, + { + "ForeName": "Mayumi", + "LastName": "Naramura", + "abbrevName": "Naramura M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Naramura" + }, + { + "ForeName": "Hua", + "LastName": "Gu", + "abbrevName": "Gu H", + "email": null, + "isCollectiveName": false, + "name": "Hua Gu" + }, + { + "ForeName": "Vimla", + "LastName": "Band", + "abbrevName": "Band V", + "email": null, + "isCollectiveName": false, + "name": "Vimla Band" + }, + { + "ForeName": "Hamid", + "LastName": "Band", + "abbrevName": "Band H", + "email": null, + "isCollectiveName": false, + "name": "Hamid Band" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M304474200", + "pmid": "12754251", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 278 2003", + "title": "Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis." + } + }, + { + "pmid": "12717446", + "pubmed": { + "ISODate": "2003-05-01T00:00:00.000Z", + "abstract": "The epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase (RTK) superfamily and is involved in regulating cell proliferation, differentiation and motility. Growth factor binding induces receptor oligomerization at the plasma membrane, which leads to activation of the intrinsic RTK activity and trans-phosphorylation of tyrosine residues in the intracellular part of the receptor. These residues are docking sites for proteins containing Src homology domain 2 and phosphotyrosine-binding domains that relay the signal inside the cell. In response to EGF attached to beads, lateral propagation of EGFR phosphorylation occurs at the plasma membrane, representing an early amplification step in EGFR signalling. Here we have investigated an underlying reaction network that couples RTK activity to protein tyrosine phosphatase (PTP) inhibition by reactive oxygen species. Mathematical analysis of the chemical kinetic equations of the minimal reaction network detects general properties of this system that can be observed experimentally by imaging EGFR phosphorylation in cells. The existence of a bistable state in this reaction network explains a threshold response and how a high proportion of phosphorylated receptors can be maintained in plasma membrane regions that are not exposed to ligand.", + "authors": { + "abbreviation": "Andrew R Reynolds, Christian Tischer, Peter J Verveer, ..., Philippe I H Bastiaens", + "authorList": [ + { + "ForeName": "Andrew", + "LastName": "Reynolds", + "abbrevName": "Reynolds AR", + "email": null, + "isCollectiveName": false, + "name": "Andrew R Reynolds" + }, + { + "ForeName": "Christian", + "LastName": "Tischer", + "abbrevName": "Tischer C", + "email": null, + "isCollectiveName": false, + "name": "Christian Tischer" + }, + { + "ForeName": "Peter", + "LastName": "Verveer", + "abbrevName": "Verveer PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Verveer" + }, + { + "ForeName": "Oliver", + "LastName": "Rocks", + "abbrevName": "Rocks O", + "email": null, + "isCollectiveName": false, + "name": "Oliver Rocks" + }, + { + "ForeName": "Philippe", + "LastName": "Bastiaens", + "abbrevName": "Bastiaens PI", + "email": null, + "isCollectiveName": false, + "name": "Philippe I H Bastiaens" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb981", + "pmid": "12717446", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 5 2003", + "title": "EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation." + } + }, + { + "pmid": "12668616", + "pubmed": { + "ISODate": "2003-04-15T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare autosomal-recessive genodermatosis characterized by bullous poikiloderma with photosensitivity. We report the localization to chromosome 20p12.3 by homozygosity mapping and the identification of a new gene, which we propose to name kindlerin. We found four different homozygous mutations in four consanguineous families from North Africa and Senegal; three are expected to lead to premature stop codons and truncated proteins and the fourth involves a splice site. We were unable to identify a mutation in kindlerin in a fifth consanguineous family from Algeria with a similar phenotype and in which the patient was homozygous for the markers in the 20p12.3 interval. The kindlerin protein contains several domains which are shared by a diverse group of peripheral membrane proteins that function as membrane-cytoskeleton linkers: two regions homologous to band 4.1 domain of which one includes a FERM domain with a NPKY sequence motif, and a third region with a PH or pleckstrin homology domain. Kindlerin might be involved in the bidirectional signaling between integrin molecules in the membrane and the cytoskeleton, and could be involved in cell adhesion processes via integrin signaling.", + "authors": { + "abbreviation": "Florence Jobard, Bakar Bouadjar, Frédéric Caux, ..., Judith Fischer", + "authorList": [ + { + "ForeName": "Florence", + "LastName": "Jobard", + "abbrevName": "Jobard F", + "email": null, + "isCollectiveName": false, + "name": "Florence Jobard" + }, + { + "ForeName": "Bakar", + "LastName": "Bouadjar", + "abbrevName": "Bouadjar B", + "email": null, + "isCollectiveName": false, + "name": "Bakar Bouadjar" + }, + { + "ForeName": "Frédéric", + "LastName": "Caux", + "abbrevName": "Caux F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Caux" + }, + { + "ForeName": "Smail", + "LastName": "Hadj-Rabia", + "abbrevName": "Hadj-Rabia S", + "email": null, + "isCollectiveName": false, + "name": "Smail Hadj-Rabia" + }, + { + "ForeName": "Christina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Christina Has" + }, + { + "ForeName": "Fumi", + "LastName": "Matsuda", + "abbrevName": "Matsuda F", + "email": null, + "isCollectiveName": false, + "name": "Fumi Matsuda" + }, + { + "ForeName": "Jean", + "LastName": "Weissenbach", + "abbrevName": "Weissenbach J", + "email": null, + "isCollectiveName": false, + "name": "Jean Weissenbach" + }, + { + "ForeName": "Mark", + "LastName": "Lathrop", + "abbrevName": "Lathrop M", + "email": null, + "isCollectiveName": false, + "name": "Mark Lathrop" + }, + { + "ForeName": "Jean-François", + "LastName": "Prud'homme", + "abbrevName": "Prud'homme JF", + "email": null, + "isCollectiveName": false, + "name": "Jean-François Prud'homme" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddg097", + "pmid": "12668616", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mol Genet 12 2003", + "title": "Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome." + } + } + ], + "relatedPapers": [ + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2022-02-13T11:20:18.247Z", + "_newestOpId": "100998dd-3d29-4b28-8e63-02e1349340d5", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "607900" + }, + { + "db": "HGNC", + "id": "HGNC:15889" + }, + { + "db": "Ensembl", + "id": "ENSG00000101311" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.754701, + "id": "55612", + "name": "FERMT1", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200100, + "shortSynonyms": [ + "FERMT1", + "C20orf42", + "DTGCU2", + "KIND1", + "UNC112A", + "URP1", + "kindlin 1", + "kindlerin", + "kindlin syndrome protein", + "FERM domain containing kindlin 1", + "unc-112-related protein 1" + ], + "synonyms": [ + "C20orf42", + "DTGCU2", + "KIND1", + "UNC112A", + "URP1", + "fermitin family homolog 1", + "UNC112 related protein 1", + "fermitin family member 1", + "kindlerin", + "kindlin 1", + "kindlin syndrome protein", + "unc-112-related protein 1", + "FERM domain containing kindlin 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "1df25530-cd6f-45b9-8e4a-246651c639e3", + "liveId": "8f17b1de-eb8f-4df1-a52f-f37f1ba64ba7", + "lock": null, + "locked": false, + "name": "Kindlin-1", + "position": { + "x": 164.0506329113924, + "y": 100.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + }, + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-13T11:20:36.940Z", + "_newestOpId": "4ba689a9-b813-4399-ba3b-ee46ffd10070", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "1df25530-cd6f-45b9-8e4a-246651c639e3" + }, + { + "group": "unsigned", + "id": "95c4cbb1-bdff-473e-9203-8ebca2d44747" + } + ], + "id": "f4b557ff-2219-45a8-bffb-5b7691e6b6bd", + "liveId": "d3295da6-d497-4e45-8e1c-88ef00cd0322", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-13T11:20:27.354Z", + "_newestOpId": "5270a386-72a2-46a4-931d-a3d5a297cb50", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "131550" + }, + { + "db": "HGNC", + "id": "HGNC:3236" + }, + { + "db": "Ensembl", + "id": "ENSG00000146648" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.857173, + "formulae": null, + "id": "1956", + "inchi": null, + "inchiKey": null, + "mass": null, + "monoisotopicMass": null, + "name": "EGFR", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "ERBB", + "ERBB1", + "ERRP", + "HER1", + "NISBD2", + "EGFR vIII", + "cell proliferation-inducing protein 61", + "epidermal growth factor receptor", + "PIG61", + "proto-oncogene c-ErbB-1" + ], + "summary": null, + "synonyms": [ + "ERBB", + "ERBB1", + "ERRP", + "HER1", + "NISBD2", + "PIG61", + "mENA", + "epidermal growth factor receptor", + "EGFR vIII", + "avian erythroblastic leukemia viral (v-erb-b) oncogene homolog", + "cell growth inhibiting protein 40", + "cell proliferation-inducing protein 61", + "epidermal growth factor receptor tyrosine kinase domain", + "erb-b2 receptor tyrosine kinase 1", + "proto-oncogene c-ErbB-1", + "receptor tyrosine-protein kinase erbB-1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "95c4cbb1-bdff-473e-9203-8ebca2d44747", + "liveId": "aac0431d-6675-4130-9a22-d637502f0320", + "lock": null, + "locked": false, + "name": "EGFR", + "position": { + "x": 250.126582278481, + "y": 127.59493670886076 + }, + "relatedPapers": [ + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + } + ], + "secret": "read-only", + "type": "protein" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/complex_tests_1.json b/neo4j-test/document/complex_tests_1.json new file mode 100644 index 000000000..f99e8a075 --- /dev/null +++ b/neo4j-test/document/complex_tests_1.json @@ -0,0 +1,25779 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-12-10T08:42:45.919Z", + "_newestOpId": "d5a827ec-0a9c-490b-979c-738cc340fdda", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth, and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia-inducible factor (HIF) family members and positively regulated HIF1α activity in TNBC. Integrated ChIP-seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1α coregulated genes, overexpression of AP2B1, COX20, KDM3A, or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581, and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.", + "ArticleTitle": "ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.", + "email": null + }, + { + "Affiliation": "Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Wentong", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0003-0047-1198" + } + ], + "Initials": "W", + "LastName": "Fang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Chengheng", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-9073-3835" + } + ], + "Initials": "C", + "LastName": "Liao" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rachel", + "Identifier": [], + "Initials": "R", + "LastName": "Shi" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel hill, United States.", + "email": null + }, + { + "Affiliation": "Department of Genetics, Neuroscience Center; 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Nature Communications. 2019;10:5177. doi: 10.1038/s41467-019-13168-4." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Wentong", + "LastName": "Fang", + "abbrevName": "Fang W", + "email": null, + "isCollectiveName": false, + "name": "Wentong Fang", + "orcid": "0000-0003-0047-1198" + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": "0000-0002-9073-3835" + }, + { + "ForeName": "Rachel", + "LastName": "Shi", + "abbrevName": "Shi R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Shi", + "orcid": null + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Travis", + "LastName": "Ptacek", + "abbrevName": "Ptacek TS", + "email": null, + "isCollectiveName": false, + "name": "Travis S Ptacek", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Youqiong", + "LastName": "Ye", + "abbrevName": "Ye Y", + "email": null, + "isCollectiveName": false, + "name": "Youqiong Ye", + "orcid": null + }, + { + "ForeName": "Leng", + "LastName": "Han", + "abbrevName": "Han L", + "email": null, + "isCollectiveName": false, + "name": "Leng Han", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Lei", + "LastName": "Bao", + "abbrevName": "Bao L", + "email": null, + "isCollectiveName": false, + "name": "Lei Bao", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Ortiz", + "abbrevName": "Ortiz CL", + "email": null, + "isCollectiveName": false, + "name": "Christopher Llynard Ortiz", + "orcid": "0000-0002-3114-7369" + }, + { + "ForeName": "Hong-Rui", + "LastName": "Lin", + "abbrevName": "Lin HR", + "email": null, + "isCollectiveName": false, + "name": "Hong-Rui Lin", + "orcid": null + }, + { + "ForeName": "Ujjawal", + "LastName": "Manocha", + "abbrevName": "Manocha U", + "email": null, + "isCollectiveName": false, + "name": "Ujjawal Manocha", + "orcid": null + }, + { + "ForeName": "Weibo", + "LastName": "Luo", + "abbrevName": "Luo W", + "email": null, + "isCollectiveName": false, + "name": "Weibo Luo", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Peng", + "abbrevName": "Peng Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Peng", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Lee-Wei", + "LastName": "Yang", + "abbrevName": "Yang LW", + "email": null, + "isCollectiveName": false, + "name": "Lee-Wei Yang", + "orcid": "0000-0002-3971-6386" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1670661765, + "entries": [ + { + "id": "13f57ee3-df7d-4ec8-b8ca-0efdd62f99d5" + }, + { + "id": "3295573e-31b2-40c4-99f1-4dbf6a34990a" + }, + { + "id": "3fd6a28f-483e-4eb4-ab6f-0a9025bd9cd1" + } + ], + "id": "71478983-b540-43b3-a552-2085dd6b0659", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1670661992, + "liveId": "8ac6d9c1-a12e-4fc8-ad55-0b80e8a3f84c", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "33299191", + "pubmed": { + "ISODate": "2020-12-01T00:00:00.000Z", + "abstract": "Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we introduce an in vivo barcoding strategy that is capable of determining the metastatic potential of human cancer cell lines in mouse xenografts at scale. We validated the robustness, scalability and reproducibility of the method and applied it to 500 cell lines1,2 spanning 21 types of solid tumour. We created a first-generation metastasis map (MetMap) that reveals organ-specific patterns of metastasis, enabling these patterns to be associated with clinical and genomic features. We demonstrate the utility of MetMap by investigating the molecular basis of breast cancers capable of metastasizing to the brain-a principal cause of death in patients with this type of cancer. Breast cancers capable of metastasizing to the brain showed evidence of altered lipid metabolism. Perturbation of lipid metabolism in these cells curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a resource to support metastasis research.", + "authors": { + "abbreviation": "Xin Jin, Zelalem Demere, Karthik Nair, ..., Todd R Golub", + "authorList": [ + { + "ForeName": "Xin", + "LastName": "Jin", + "abbrevName": "Jin X", + "email": "xjin@broadinstitute.org", + "isCollectiveName": false, + "name": "Xin Jin", + "orcid": "0000-0003-4167-1743" + }, + { + "ForeName": "Zelalem", + "LastName": "Demere", + "abbrevName": "Demere Z", + "email": null, + "isCollectiveName": false, + "name": "Zelalem Demere", + "orcid": null + }, + { + "ForeName": "Karthik", + "LastName": "Nair", + "abbrevName": "Nair K", + "email": null, + "isCollectiveName": false, + "name": "Karthik Nair", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ali", + "abbrevName": "Ali A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ali", + "orcid": null + }, + { + "ForeName": "Gino", + "LastName": "Ferraro", + "abbrevName": "Ferraro GB", + "email": null, + "isCollectiveName": false, + "name": "Gino B Ferraro", + "orcid": "0000-0002-1587-4259" + }, + { + "ForeName": "Ted", + "LastName": "Natoli", + "abbrevName": "Natoli T", + "email": null, + "isCollectiveName": false, + "name": "Ted Natoli", + "orcid": null + }, + { + "ForeName": "Amy", + "LastName": "Deik", + "abbrevName": "Deik A", + "email": null, + "isCollectiveName": false, + "name": "Amy Deik", + "orcid": null + }, + { + "ForeName": "Lia", + "LastName": "Petronio", + "abbrevName": "Petronio L", + "email": null, + "isCollectiveName": false, + "name": "Lia Petronio", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Tang", + "abbrevName": "Tang AA", + "email": null, + "isCollectiveName": false, + "name": "Andrew A Tang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhu", + "orcid": null + }, + { + "ForeName": "Li", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Li Wang", + "orcid": null + }, + { + "ForeName": "Danny", + "LastName": "Rosenberg", + "abbrevName": "Rosenberg D", + "email": null, + "isCollectiveName": false, + "name": "Danny Rosenberg", + "orcid": null + }, + { + "ForeName": "Vamsi", + "LastName": "Mangena", + "abbrevName": "Mangena V", + "email": null, + "isCollectiveName": false, + "name": "Vamsi Mangena", + "orcid": "0000-0003-2662-0366" + }, + { + "ForeName": "Jennifer", + "LastName": "Roth", + "abbrevName": "Roth J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Roth", + "orcid": null + }, + { + "ForeName": "Kwanghun", + "LastName": "Chung", + "abbrevName": "Chung K", + "email": null, + "isCollectiveName": false, + "name": "Kwanghun Chung", + "orcid": "0000-0002-8167-3340" + }, + { + "ForeName": "Rakesh", + "LastName": "Jain", + "abbrevName": "Jain RK", + "email": null, + "isCollectiveName": false, + "name": "Rakesh K Jain", + "orcid": "0000-0001-7571-3548" + }, + { + "ForeName": "Clary", + "LastName": "Clish", + "abbrevName": "Clish CB", + "email": null, + "isCollectiveName": false, + "name": "Clary B Clish", + "orcid": "0000-0001-8259-9245" + }, + { + "ForeName": "Matthew", + "LastName": "Vander Heiden", + "abbrevName": "Vander Heiden MG", + "email": null, + "isCollectiveName": false, + "name": "Matthew G Vander Heiden", + "orcid": "0000-0002-6702-4192" + }, + { + "ForeName": "Todd", + "LastName": "Golub", + "abbrevName": "Golub TR", + "email": "golub@broadinstitute.org", + "isCollectiveName": false, + "name": "Todd R Golub", + "orcid": "0000-0003-0113-2403" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Jin", + "email": [ + "xjin@broadinstitute.org" + ], + "name": "Xin Jin" + }, + { + "ForeName": "Todd", + "LastName": "Golub", + "email": [ + "golub@broadinstitute.org" + ], + "name": "Todd R Golub" + } + ] + }, + "doi": "10.1038/s41586-020-2969-2", + "pmid": "33299191", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Nature 588 2020", + "title": "A metastasis map of human cancer cell lines." + } + }, + { + "pmid": "32690540", + "pubmed": { + "ISODate": "2020-11-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC. SIGNIFICANCE: We provide evidence from unbiased screens that BBOX1 is a potential therapeutic target in TNBC and that genetic knockdown or pharmacologic inhibition of BBOX1 leads to decreased TNBC cell fitness. This study lays the foundation for developing effective BBOX1 inhibitors for treatment of this lethal disease.This article is highlighted in the In This Issue feature, p. 1611.", + "authors": { + "abbreviation": "Chengheng Liao, Yang Zhang, Cheng Fan, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Yang", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yang Zhang", + "orcid": "0000-0002-6595-8995" + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Laura", + "LastName": "Herring", + "abbrevName": "Herring LE", + "email": null, + "isCollectiveName": false, + "name": "Laura E Herring", + "orcid": "0000-0003-4496-7312" + }, + { + "ForeName": "Juan", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Juan Liu", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "Locasale", + "abbrevName": "Locasale JW", + "email": null, + "isCollectiveName": false, + "name": "Jason W Locasale", + "orcid": "0000-0002-7766-3502" + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zhou", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": "0000-0002-5777-3325" + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": "0000-0001-5600-5634" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Travis", + "LastName": "Ptacek", + "abbrevName": "Ptacek TS", + "email": null, + "isCollectiveName": false, + "name": "Travis S Ptacek", + "orcid": null + }, + { + "ForeName": "Victor", + "LastName": "Andrianov", + "abbrevName": "Andrianov VG", + "email": null, + "isCollectiveName": false, + "name": "Victor G Andrianov", + "orcid": null + }, + { + "ForeName": "Einars", + "LastName": "Loza", + "abbrevName": "Loza E", + "email": null, + "isCollectiveName": false, + "name": "Einars Loza", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Peng", + "abbrevName": "Peng Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Peng", + "orcid": "0000-0001-5765-6260" + }, + { + "ForeName": "Huanghe", + "LastName": "Yang", + "abbrevName": "Yang H", + "email": null, + "isCollectiveName": false, + "name": "Huanghe Yang", + "orcid": null + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "Qing.Zhang@UTSouthwestern.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "Qing.Zhang@UTSouthwestern.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1158/2159-8290.CD-20-0288", + "pmid": "32690540", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 10 2020", + "title": "Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "32354028", + "pubmed": { + "ISODate": "2020-04-28T00:00:00.000Z", + "abstract": "Lysine-specific histone demethylase 3 (KDM3) subfamily proteins are H3K9me2/me1 histone demethylases that promote gene expression. The KDM3 subfamily primarily consists of four proteins (KDM3A-D). All four proteins contain the catalytic Jumonji C domain (JmjC) at their C-termini, but whether KDM3C has demethylase activity is under debate. In addition, KDM3 proteins contain a zinc-finger domain for DNA binding and an LXXLL motif for interacting with nuclear receptors. Of the KDM3 proteins, KDM3A is especially deregulated or overexpressed in multiple cancers, making it a potential cancer therapeutic target. However, no KDM3A-selective inhibitors have been identified to date because of the lack of structural information. Uncovering the distinct physiological and pathological functions of KDM3A and their structure will give insight into the development of novel selective inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM3A in cancer. We also discuss existing KDM3A-related inhibitors and review their potential as therapeutic agents for overcoming cancer.", + "authors": { + "abbreviation": "Jung Yoo, Yu Hyun Jeon, Ha Young Cho, ..., So Hee Kwon", + "authorList": [ + { + "ForeName": "Jung", + "LastName": "Yoo", + "abbrevName": "Yoo J", + "email": null, + "isCollectiveName": false, + "name": "Jung Yoo", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Jeon", + "abbrevName": "Jeon YH", + "email": null, + "isCollectiveName": false, + "name": "Yu Hyun Jeon", + "orcid": null + }, + { + "ForeName": "Ha", + "LastName": "Cho", + "abbrevName": "Cho HY", + "email": null, + "isCollectiveName": false, + "name": "Ha Young Cho", + "orcid": null + }, + { + "ForeName": "Sang", + "LastName": "Lee", + "abbrevName": "Lee SW", + "email": null, + "isCollectiveName": false, + "name": "Sang Wu Lee", + "orcid": null + }, + { + "ForeName": "Go", + "LastName": "Kim", + "abbrevName": "Kim GW", + "email": null, + "isCollectiveName": false, + "name": "Go Woon Kim", + "orcid": null + }, + { + "ForeName": "Dong", + "LastName": "Lee", + "abbrevName": "Lee DH", + "email": null, + "isCollectiveName": false, + "name": "Dong Hoon Lee", + "orcid": null + }, + { + "ForeName": "So", + "LastName": "Kwon", + "abbrevName": "Kwon SH", + "email": null, + "isCollectiveName": false, + "name": "So Hee Kwon", + "orcid": "0000-0002-3753-4415" + } + ], + "contacts": [] + }, + "doi": "10.3390/cancers12051098", + "pmid": "32354028", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cancers (Basel) 12 2020", + "title": "Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target." + } + }, + { + "pmid": "32023483", + "pubmed": { + "ISODate": "2020-03-19T00:00:00.000Z", + "abstract": "von Hippel-Lindau (VHL) is a critical tumor suppressor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypoxia-inducible factor 2α (HIF2α). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of-function mutations displayed elevated SFMBT1 protein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degradation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prognosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its oncogenic phenotype. Therefore, the pVHL-SFMBT1-SPHK1 axis serves as a potential therapeutic avenue for ccRCC.", + "authors": { + "abbreviation": "Xijuan Liu, Jeremy M Simon, Haibiao Xie, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": null + }, + { + "ForeName": "Haibiao", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haibiao Xie", + "orcid": null + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Travis", + "LastName": "Ptacek", + "abbrevName": "Ptacek TS", + "email": null, + "isCollectiveName": false, + "name": "Travis S Ptacek", + "orcid": null + }, + { + "ForeName": "Laura", + "LastName": "Herring", + "abbrevName": "Herring L", + "email": null, + "isCollectiveName": false, + "name": "Laura Herring", + "orcid": null + }, + { + "ForeName": "Xianming", + "LastName": "Tan", + "abbrevName": "Tan X", + "email": null, + "isCollectiveName": false, + "name": "Xianming Tan", + "orcid": null + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": null + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Wu", + "abbrevName": "Wu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wu", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Kirschner", + "abbrevName": "Kirschner MW", + "email": null, + "isCollectiveName": false, + "name": "Marc W Kirschner", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Gong", + "abbrevName": "Gong K", + "email": null, + "isCollectiveName": false, + "name": "Kan Gong", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "Qing.Zhang@UTSouthwestern.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "Qing.Zhang@UTSouthwestern.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1016/j.molcel.2020.01.009", + "pmid": "32023483", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Mol Cell 77 2020", + "title": "Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss." + } + }, + { + "pmid": "31810986", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss. SIGNIFICANCE: The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer.See related commentary by Bakouny and Barbie, p. 348.This article is highlighted in the In This Issue feature, p. 327.", + "authors": { + "abbreviation": "Lianxin Hu, Haibiao Xie, Xijuan Liu, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Haibiao", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haibiao Xie", + "orcid": null + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Frances", + "LastName": "Potjewyd", + "abbrevName": "Potjewyd F", + "email": null, + "isCollectiveName": false, + "name": "Frances Potjewyd", + "orcid": null + }, + { + "ForeName": "Lindsey", + "LastName": "James", + "abbrevName": "James LI", + "email": null, + "isCollectiveName": false, + "name": "Lindsey I James", + "orcid": "0000-0002-6034-7116" + }, + { + "ForeName": "Emily", + "LastName": "Wilkerson", + "abbrevName": "Wilkerson EM", + "email": null, + "isCollectiveName": false, + "name": "Emily M Wilkerson", + "orcid": null + }, + { + "ForeName": "Laura", + "LastName": "Herring", + "abbrevName": "Herring LE", + "email": null, + "isCollectiveName": false, + "name": "Laura E Herring", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Johnny", + "LastName": "Cabrera", + "abbrevName": "Cabrera JC", + "email": null, + "isCollectiveName": false, + "name": "Johnny Castillo Cabrera", + "orcid": null + }, + { + "ForeName": "Kai", + "LastName": "Hong", + "abbrevName": "Hong K", + "email": null, + "isCollectiveName": false, + "name": "Kai Hong", + "orcid": "0000-0001-5521-4418" + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Xianming", + "LastName": "Tan", + "abbrevName": "Tan X", + "email": null, + "isCollectiveName": false, + "name": "Xianming Tan", + "orcid": null + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Gong", + "abbrevName": "Gong K", + "email": "Qing.Zhang@UTSouthwestern.edu", + "isCollectiveName": false, + "name": "Kan Gong", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "Qing.Zhang@UTSouthwestern.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Kan", + "LastName": "Gong", + "email": [ + "Qing.Zhang@UTSouthwestern.edu", + "gongkan_pku@126.com" + ], + "name": "Kan Gong" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "Qing.Zhang@UTSouthwestern.edu", + "gongkan_pku@126.com" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1158/2159-8290.CD-19-0837", + "pmid": "31810986", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Cancer Discov 10 2020", + "title": "TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss." + } + }, + { + "pmid": "31752220", + "pubmed": { + "ISODate": "2019-11-18T00:00:00.000Z", + "abstract": "Industrial production of bioethanol from lignocellulosic materials (LCM's) is reliant on a microorganism being tolerant to the stresses inherent to fermentation. Previous work has highlighted the importance of a cytochrome oxidase chaperone gene (COX20) in improving yeast tolerance to acetic acid, a common inhibitory compound produced during pre-treatment of LCM's. The presence of acetic acid has been shown to induce oxidative stress and programmed cell death, so the role of COX20 in oxidative stress was determined. Analysis using flow cytometry revealed that COX20 expression was associated with reduced levels of reactive oxygen species (ROS) in hydrogen peroxide and metal-induced stress, and there was a reduction in apoptotic and necrotic cells when compared with a strain without COX20. Results on the functionality of COX20 have revealed that overexpression of COX20 induced respiratory growth in Δimp1 and Δcox18, two genes whose presence is essential for yeast respiratory growth. COX20 also has a role in protecting the yeast cell against programmed cell death.", + "authors": { + "abbreviation": "Ethiraju Keerthiraju, Chenyu Du, Gregory Tucker, Darren Greetham", + "authorList": [ + { + "ForeName": "Ethiraju", + "LastName": "Keerthiraju", + "abbrevName": "Keerthiraju E", + "email": null, + "isCollectiveName": false, + "name": "Ethiraju Keerthiraju", + "orcid": null + }, + { + "ForeName": "Chenyu", + "LastName": "Du", + "abbrevName": "Du C", + "email": null, + "isCollectiveName": false, + "name": "Chenyu Du", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Tucker", + "abbrevName": "Tucker G", + "email": null, + "isCollectiveName": false, + "name": "Gregory Tucker", + "orcid": null + }, + { + "ForeName": "Darren", + "LastName": "Greetham", + "abbrevName": "Greetham D", + "email": null, + "isCollectiveName": false, + "name": "Darren Greetham", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/microorganisms7110575", + "pmid": "31752220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Microorganisms 7 2019", + "title": "A Role for COX20 in Tolerance to Oxidative Stress and Programmed Cell Death in Saccharomyces cerevisiae." + } + }, + { + "pmid": "31729379", + "pubmed": { + "ISODate": "2019-11-15T00:00:00.000Z", + "abstract": "Protein hydroxylation affects protein stability, activity, and interactome, therefore contributing to various diseases including cancers. However, the transiency of the hydroxylation reaction hinders the identification of hydroxylase substrates. By developing an enzyme-substrate trapping strategy coupled with TAP-TAG or orthogonal GST- purification followed by mass spectrometry, we identify adenylosuccinate lyase (ADSL) as an EglN2 hydroxylase substrate in triple negative breast cancer (TNBC). ADSL expression is higher in TNBC than other breast cancer subtypes or normal breast tissues. ADSL knockout impairs TNBC cell proliferation and invasiveness in vitro and in vivo. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. Hydroxylation-proficient ADSL, by affecting adenosine levels, represses the expression of the long non-coding RNA MIR22HG, thus upregulating cMYC protein level. Our findings highlight the role of ADSL hydroxylation in controlling cMYC and TNBC tumorigenesis.", + "authors": { + "abbreviation": "Giada Zurlo, Xijuan Liu, Mamoru Takada, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Travis", + "LastName": "Ptacek", + "abbrevName": "Ptacek TS", + "email": null, + "isCollectiveName": false, + "name": "Travis S Ptacek", + "orcid": null + }, + { + "ForeName": "Javier", + "LastName": "Rodriguez", + "abbrevName": "Rodriguez J", + "email": null, + "isCollectiveName": false, + "name": "Javier Rodriguez", + "orcid": null + }, + { + "ForeName": "Alex", + "LastName": "von Kriegsheim", + "abbrevName": "von Kriegsheim A", + "email": null, + "isCollectiveName": false, + "name": "Alex von Kriegsheim", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Juan Liu", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "Locasale", + "abbrevName": "Locasale JW", + "email": null, + "isCollectiveName": false, + "name": "Jason W Locasale", + "orcid": "0000-0002-7766-3502" + }, + { + "ForeName": "Adam", + "LastName": "Robinson", + "abbrevName": "Robinson A", + "email": null, + "isCollectiveName": false, + "name": "Adam Robinson", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": "0000-0001-6438-9113" + }, + { + "ForeName": "Jessica", + "LastName": "Holler", + "abbrevName": "Holler JM", + "email": null, + "isCollectiveName": false, + "name": "Jessica M Holler", + "orcid": null + }, + { + "ForeName": "Baek", + "LastName": "Kim", + "abbrevName": "Kim B", + "email": null, + "isCollectiveName": false, + "name": "Baek Kim", + "orcid": "0000-0001-7986-4335" + }, + { + "ForeName": "Marie", + "LastName": "Zikánová", + "abbrevName": "Zikánová M", + "email": null, + "isCollectiveName": false, + "name": "Marie Zikánová", + "orcid": null + }, + { + "ForeName": "Jörgen", + "LastName": "Bierau", + "abbrevName": "Bierau J", + "email": null, + "isCollectiveName": false, + "name": "Jörgen Bierau", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": null + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "Qing.Zhang@utsouthwestern.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "Qing.Zhang@utsouthwestern.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1038/s41467-019-13168-4", + "pmid": "31729379", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer." + } + }, + { + "pmid": "31294857", + "pubmed": { + "ISODate": "2019-11-05T00:00:00.000Z", + "abstract": "Seven free base porphyrins employed in dye-sensitized photoelectrosynthetic cells are investigated with the aim of benchmarking the ability of different density functional theory (DFT) and time-dependent DFT approaches in reproducing their structure, vertical, and E0-0 excitation energies and the energy levels alignment (red-ox properties) at the interface with the TiO2 . We find that both vertical and E0-0 excitation energies are accurately reproduced by range-separated functionals, among which the ωB97X-D delivers the lowest absolute deviations from experiments. When the dye/TiO2 interface is modeled, the physical interfacial energetics is only obtained when the B3LYP functional is employed; on the other hand, M06-2X (54% of exchange) and the two long-range corrected approaches tested (CAM-B3LYP and ωB97X-D) excessively destabilize the semiconductor conduction band levels with respect to the dye's lowest unoccupied molecular orbitals (LUMOs), predicting no pathway for electron injection. © 2019 Wiley Periodicals, Inc.", + "authors": { + "abbreviation": "Syrine Daoudi, Abderrahmane Semmeq, Michael Badawi, ..., Mariachiara Pastore", + "authorList": [ + { + "ForeName": "Syrine", + "LastName": "Daoudi", + "abbrevName": "Daoudi S", + "email": null, + "isCollectiveName": false, + "name": "Syrine Daoudi", + "orcid": null + }, + { + "ForeName": "Abderrahmane", + "LastName": "Semmeq", + "abbrevName": "Semmeq A", + "email": null, + "isCollectiveName": false, + "name": "Abderrahmane Semmeq", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Badawi", + "abbrevName": "Badawi M", + "email": null, + "isCollectiveName": false, + "name": "Michael Badawi", + "orcid": null + }, + { + "ForeName": "Xavier", + "LastName": "Assfeld", + "abbrevName": "Assfeld X", + "email": null, + "isCollectiveName": false, + "name": "Xavier Assfeld", + "orcid": "0000-0003-4227-6825" + }, + { + "ForeName": "Youssef", + "LastName": "Arfaoui", + "abbrevName": "Arfaoui Y", + "email": null, + "isCollectiveName": false, + "name": "Youssef Arfaoui", + "orcid": null + }, + { + "ForeName": "Mariachiara", + "LastName": "Pastore", + "abbrevName": "Pastore M", + "email": null, + "isCollectiveName": false, + "name": "Mariachiara Pastore", + "orcid": "0000-0003-4793-1964" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcc.26027", + "pmid": "31294857", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Comput Chem 40 2019", + "title": "Electronic structure and optical properties of isolated and TiO2 -grafted free base porphyrins for water oxidation: A challenging test case for DFT and TD-DFT." + } + }, + { + "pmid": "30664679", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Pathway enrichment analysis helps researchers gain mechanistic insight into gene lists generated from genome-scale (omics) experiments. This method identifies biological pathways that are enriched in a gene list more than would be expected by chance. We explain the procedures of pathway enrichment analysis and present a practical step-by-step guide to help interpret gene lists resulting from RNA-seq and genome-sequencing experiments. The protocol comprises three major steps: definition of a gene list from omics data, determination of statistically enriched pathways, and visualization and interpretation of the results. We describe how to use this protocol with published examples of differentially expressed genes and mutated cancer genes; however, the principles can be applied to diverse types of omics data. The protocol describes innovative visualization techniques, provides comprehensive background and troubleshooting guidelines, and uses freely available and frequently updated software, including g:Profiler, Gene Set Enrichment Analysis (GSEA), Cytoscape and EnrichmentMap. The complete protocol can be performed in ~4.5 h and is designed for use by biologists with no prior bioinformatics training.", + "authors": { + "abbreviation": "Jüri Reimand, Ruth Isserlin, Veronique Voisin, ..., Gary D Bader", + "authorList": [ + { + "ForeName": "Jüri", + "LastName": "Reimand", + "abbrevName": "Reimand J", + "email": null, + "isCollectiveName": false, + "name": "Jüri Reimand", + "orcid": null + }, + { + "ForeName": "Ruth", + "LastName": "Isserlin", + "abbrevName": "Isserlin R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Isserlin", + "orcid": "0000-0002-6805-2080" + }, + { + "ForeName": "Veronique", + "LastName": "Voisin", + "abbrevName": "Voisin V", + "email": null, + "isCollectiveName": false, + "name": "Veronique Voisin", + "orcid": null + }, + { + "ForeName": "Mike", + "LastName": "Kucera", + "abbrevName": "Kucera M", + "email": null, + "isCollectiveName": false, + "name": "Mike Kucera", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Tannus-Lopes", + "abbrevName": "Tannus-Lopes C", + "email": null, + "isCollectiveName": false, + "name": "Christian Tannus-Lopes", + "orcid": null + }, + { + "ForeName": "Asha", + "LastName": "Rostamianfar", + "abbrevName": "Rostamianfar A", + "email": null, + "isCollectiveName": false, + "name": "Asha Rostamianfar", + "orcid": null + }, + { + "ForeName": "Lina", + "LastName": "Wadi", + "abbrevName": "Wadi L", + "email": null, + "isCollectiveName": false, + "name": "Lina Wadi", + "orcid": null + }, + { + "ForeName": "Mona", + "LastName": "Meyer", + "abbrevName": "Meyer M", + "email": null, + "isCollectiveName": false, + "name": "Mona Meyer", + "orcid": null + }, + { + "ForeName": "Jeff", + "LastName": "Wong", + "abbrevName": "Wong J", + "email": null, + "isCollectiveName": false, + "name": "Jeff Wong", + "orcid": null + }, + { + "ForeName": "Changjiang", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": null, + "isCollectiveName": false, + "name": "Changjiang Xu", + "orcid": null + }, + { + "ForeName": "Daniele", + "LastName": "Merico", + "abbrevName": "Merico D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Merico", + "orcid": "0000-0002-3728-4401" + }, + { + "ForeName": "Gary", + "LastName": "Bader", + "abbrevName": "Bader GD", + "email": "gary.bader@utoronto.ca", + "isCollectiveName": false, + "name": "Gary D Bader", + "orcid": "0000-0003-0185-8861" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Bader", + "email": [ + "gary.bader@utoronto.ca" + ], + "name": "Gary D Bader" + } + ] + }, + "doi": "10.1038/s41596-018-0103-9", + "pmid": "30664679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Protoc 14 2019", + "title": "Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, Cytoscape and EnrichmentMap." + } + }, + { + "pmid": "30656193", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency.", + "authors": { + "abbreviation": "Maria G Otero, Emmanuelle Tiongson, Frank Diaz, ..., Tyler Mark Pierson", + "authorList": [ + { + "ForeName": "Maria", + "LastName": "Otero", + "abbrevName": "Otero MG", + "email": null, + "isCollectiveName": false, + "name": "Maria G Otero", + "orcid": null + }, + { + "ForeName": "Emmanuelle", + "LastName": "Tiongson", + "abbrevName": "Tiongson E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuelle Tiongson", + "orcid": null + }, + { + "ForeName": "Frank", + "LastName": "Diaz", + "abbrevName": "Diaz F", + "email": null, + "isCollectiveName": false, + "name": "Frank Diaz", + "orcid": null + }, + { + "ForeName": "Katrina", + "LastName": "Haude", + "abbrevName": "Haude K", + "email": null, + "isCollectiveName": false, + "name": "Katrina Haude", + "orcid": null + }, + { + "ForeName": "Karin", + "LastName": "Panzer", + "abbrevName": "Panzer K", + "email": null, + "isCollectiveName": false, + "name": "Karin Panzer", + "orcid": null + }, + { + "ForeName": "Ashley", + "LastName": "Collier", + "abbrevName": "Collier A", + "email": null, + "isCollectiveName": false, + "name": "Ashley Collier", + "orcid": null + }, + { + "ForeName": "Jaemin", + "LastName": "Kim", + "abbrevName": "Kim J", + "email": null, + "isCollectiveName": false, + "name": "Jaemin Kim", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Adams", + "abbrevName": "Adams D", + "email": null, + "isCollectiveName": false, + "name": "David Adams", + "orcid": null + }, + { + "ForeName": "Cynthia", + "LastName": "Tifft", + "abbrevName": "Tifft CJ", + "email": null, + "isCollectiveName": false, + "name": "Cynthia J Tifft", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Cui", + "abbrevName": "Cui H", + "email": null, + "isCollectiveName": false, + "name": "Hong Cui", + "orcid": null + }, + { + "ForeName": "Francisca", + "LastName": "Millian Zamora", + "abbrevName": "Millian Zamora F", + "email": null, + "isCollectiveName": false, + "name": "Francisca Millian Zamora", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Au", + "abbrevName": "Au MG", + "email": null, + "isCollectiveName": false, + "name": "Margaret G Au", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Graham", + "abbrevName": "Graham JM", + "email": null, + "isCollectiveName": false, + "name": "John M Graham", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Buckley", + "abbrevName": "Buckley DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Buckley", + "orcid": null + }, + { + "ForeName": "Richard", + "LastName": "Lewis", + "abbrevName": "Lewis R", + "email": null, + "isCollectiveName": false, + "name": "Richard Lewis", + "orcid": null + }, + { + "ForeName": "Camilo", + "LastName": "Toro", + "abbrevName": "Toro C", + "email": null, + "isCollectiveName": false, + "name": "Camilo Toro", + "orcid": null + }, + { + "ForeName": "Renkui", + "LastName": "Bai", + "abbrevName": "Bai R", + "email": null, + "isCollectiveName": false, + "name": "Renkui Bai", + "orcid": null + }, + { + "ForeName": "Lesley", + "LastName": "Turner", + "abbrevName": "Turner L", + "email": null, + "isCollectiveName": false, + "name": "Lesley Turner", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Mathews", + "abbrevName": "Mathews KD", + "email": null, + "isCollectiveName": false, + "name": "Katherine D Mathews", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Gahl", + "abbrevName": "Gahl W", + "email": null, + "isCollectiveName": false, + "name": "William Gahl", + "orcid": null + }, + { + "ForeName": "Tyler", + "LastName": "Pierson", + "abbrevName": "Pierson TM", + "email": null, + "isCollectiveName": false, + "name": "Tyler Mark Pierson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/acn3.661", + "pmid": "30656193", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Ann Clin Transl Neurol 6 2019", + "title": "Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy." + } + }, + { + "pmid": "30026228", + "pubmed": { + "ISODate": "2018-07-20T00:00:00.000Z", + "abstract": "Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.", + "authors": { + "abbreviation": "Jing Zhang, Tao Wu, Jeremy Simon, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": "0000-0001-6438-9113" + }, + { + "ForeName": "Tao", + "LastName": "Wu", + "abbrevName": "Wu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wu", + "orcid": "0000-0001-5380-3905" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon J", + "email": null, + "isCollectiveName": false, + "name": "Jeremy Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": "0000-0002-3961-9009" + }, + { + "ForeName": "Ryoichi", + "LastName": "Saito", + "abbrevName": "Saito R", + "email": null, + "isCollectiveName": false, + "name": "Ryoichi Saito", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Xian-De", + "LastName": "Liu", + "abbrevName": "Liu XD", + "email": null, + "isCollectiveName": false, + "name": "Xian-De Liu", + "orcid": "0000-0002-9639-0458" + }, + { + "ForeName": "Eric", + "LastName": "Jonasch", + "abbrevName": "Jonasch E", + "email": null, + "isCollectiveName": false, + "name": "Eric Jonasch", + "orcid": "0000-0003-0943-2806" + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Xiaosai", + "LastName": "Yao", + "abbrevName": "Yao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaosai Yao", + "orcid": "0000-0001-9729-0726" + }, + { + "ForeName": "Bin", + "LastName": "Teh", + "abbrevName": "Teh BT", + "email": null, + "isCollectiveName": false, + "name": "Bin Tean Teh", + "orcid": "0000-0003-1514-1124" + }, + { + "ForeName": "Patrick", + "LastName": "Tan", + "abbrevName": "Tan P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Tan", + "orcid": null + }, + { + "ForeName": "Xingnan", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xingnan Zheng", + "orcid": "0000-0003-3034-4421" + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": "0000-0001-5337-4901" + }, + { + "ForeName": "Cortney", + "LastName": "Lawrence", + "abbrevName": "Lawrence C", + "email": null, + "isCollectiveName": false, + "name": "Cortney Lawrence", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Fan", + "abbrevName": "Fan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Fan", + "orcid": "0000-0003-3842-2391" + }, + { + "ForeName": "Jiang", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiang Geng", + "orcid": "0000-0002-7202-2167" + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Kai", + "LastName": "Hong", + "abbrevName": "Hong K", + "email": null, + "isCollectiveName": false, + "name": "Kai Hong", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Joel", + "LastName": "Parker", + "abbrevName": "Parker JS", + "email": null, + "isCollectiveName": false, + "name": "Joel S Parker", + "orcid": "0000-0003-2080-6901" + }, + { + "ForeName": "J", + "LastName": "Auman", + "abbrevName": "Auman JT", + "email": null, + "isCollectiveName": false, + "name": "J Todd Auman", + "orcid": "0000-0002-9328-8829" + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "W", + "LastName": "Rathmell", + "abbrevName": "Rathmell WK", + "email": null, + "isCollectiveName": false, + "name": "W Kimryn Rathmell", + "orcid": "0000-0002-4984-0225" + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Kirschner", + "abbrevName": "Kirschner MW", + "email": null, + "isCollectiveName": false, + "name": "Marc W Kirschner", + "orcid": "0000-0001-6540-6130" + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": "0000-0002-0574-4856" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": "0000-0003-1246-1333" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "qing_zhang@med.unc.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "qing_zhang@med.unc.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1126/science.aap8411", + "pmid": "30026228", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 361 2018", + "title": "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma." + } + }, + { + "pmid": "29788355", + "pubmed": { + "ISODate": "2018-07-02T00:00:00.000Z", + "abstract": "Homology modelling has matured into an important technique in structural biology, significantly contributing to narrowing the gap between known protein sequences and experimentally determined structures. Fully automated workflows and servers simplify and streamline the homology modelling process, also allowing users without a specific computational expertise to generate reliable protein models and have easy access to modelling results, their visualization and interpretation. Here, we present an update to the SWISS-MODEL server, which pioneered the field of automated modelling 25 years ago and been continuously further developed. Recently, its functionality has been extended to the modelling of homo- and heteromeric complexes. Starting from the amino acid sequences of the interacting proteins, both the stoichiometry and the overall structure of the complex are inferred by homology modelling. Other major improvements include the implementation of a new modelling engine, ProMod3 and the introduction a new local model quality estimation method, QMEANDisCo. SWISS-MODEL is freely available at https://swissmodel.expasy.org.", + "authors": { + "abbreviation": "Andrew Waterhouse, Martino Bertoni, Stefan Bienert, ..., Torsten Schwede", + "authorList": [ + { + "ForeName": "Andrew", + "LastName": "Waterhouse", + "abbrevName": "Waterhouse A", + "email": null, + "isCollectiveName": false, + "name": "Andrew Waterhouse", + "orcid": null + }, + { + "ForeName": "Martino", + "LastName": "Bertoni", + "abbrevName": "Bertoni M", + "email": null, + "isCollectiveName": false, + "name": "Martino Bertoni", + "orcid": null + }, + { + "ForeName": "Stefan", + "LastName": "Bienert", + "abbrevName": "Bienert S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Bienert", + "orcid": null + }, + { + "ForeName": "Gabriel", + "LastName": "Studer", + "abbrevName": "Studer G", + "email": null, + "isCollectiveName": false, + "name": "Gabriel Studer", + "orcid": null + }, + { + "ForeName": "Gerardo", + "LastName": "Tauriello", + "abbrevName": "Tauriello G", + "email": null, + "isCollectiveName": false, + "name": "Gerardo Tauriello", + "orcid": null + }, + { + "ForeName": "Rafal", + "LastName": "Gumienny", + "abbrevName": "Gumienny R", + "email": null, + "isCollectiveName": false, + "name": "Rafal Gumienny", + "orcid": null + }, + { + "ForeName": "Florian", + "LastName": "Heer", + "abbrevName": "Heer FT", + "email": null, + "isCollectiveName": false, + "name": "Florian T Heer", + "orcid": null + }, + { + "ForeName": "Tjaart", + "LastName": "de Beer", + "abbrevName": "de Beer TAP", + "email": null, + "isCollectiveName": false, + "name": "Tjaart A P de Beer", + "orcid": null + }, + { + "ForeName": "Christine", + "LastName": "Rempfer", + "abbrevName": "Rempfer C", + "email": null, + "isCollectiveName": false, + "name": "Christine Rempfer", + "orcid": null + }, + { + "ForeName": "Lorenza", + "LastName": "Bordoli", + "abbrevName": "Bordoli L", + "email": null, + "isCollectiveName": false, + "name": "Lorenza Bordoli", + "orcid": null + }, + { + "ForeName": "Rosalba", + "LastName": "Lepore", + "abbrevName": "Lepore R", + "email": null, + "isCollectiveName": false, + "name": "Rosalba Lepore", + "orcid": null + }, + { + "ForeName": "Torsten", + "LastName": "Schwede", + "abbrevName": "Schwede T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Schwede", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1093/nar/gky427", + "pmid": "29788355", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 46 2018", + "title": "SWISS-MODEL: homology modelling of protein structures and complexes." + } + }, + { + "pmid": "29629903", + "pubmed": { + "ISODate": "2018-05-01T00:00:00.000Z", + "abstract": "Altered epigenetic reprogramming contributes to breast cancer progression and metastasis. How the epigenetic reader mediates breast cancer progression remains poorly understood. Here, we showed that the epigenetic reader zinc finger MYND-type containing 8 (ZMYND8) is induced by HIF-1 and HIF-2 in breast cancer cells and also upregulated in human breast tumors, and is correlated with poor survival of patients with breast cancer. Genetic deletion of ZMYND8 decreases breast cancer cell colony formation, migration, and invasion in vitro, and inhibits breast tumor growth and metastasis to the lungs in mice. The ZMYND8's oncogenic effect in breast cancer requires HIF-1 and HIF-2. We further showed that ZMYND8 interacts with HIF-1α and HIF-2α and enhances elongation of the global HIF-induced oncogenic genes by increasing recruitment of BRD4 and subsequent release of paused RNA polymerase II in breast cancer cells. ZMYND8 acetylation at lysines 1007 and 1034 by p300 is required for HIF activation and breast cancer progression and metastasis. These findings uncover a primary epigenetic mechanism of HIF activation and HIF-mediated breast cancer progression, and discover a possible molecular target for the diagnosis and treatment of breast cancer.", + "authors": { + "abbreviation": "Yan Chen, Bo Zhang, Lei Bao, ..., Weibo Luo", + "authorList": [ + { + "ForeName": "Yan", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Chen", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bo Zhang", + "orcid": null + }, + { + "ForeName": "Lei", + "LastName": "Bao", + "abbrevName": "Bao L", + "email": null, + "isCollectiveName": false, + "name": "Lei Bao", + "orcid": null + }, + { + "ForeName": "Lai", + "LastName": "Jin", + "abbrevName": "Jin L", + "email": null, + "isCollectiveName": false, + "name": "Lai Jin", + "orcid": null + }, + { + "ForeName": "Mingming", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mingming Yang", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Peng", + "abbrevName": "Peng Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Peng", + "orcid": null + }, + { + "ForeName": "Ashwani", + "LastName": "Kumar", + "abbrevName": "Kumar A", + "email": null, + "isCollectiveName": false, + "name": "Ashwani Kumar", + "orcid": null + }, + { + "ForeName": "Jennifer", + "LastName": "Wang", + "abbrevName": "Wang JE", + "email": null, + "isCollectiveName": false, + "name": "Jennifer E Wang", + "orcid": null + }, + { + "ForeName": "Chenliang", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Chenliang Wang", + "orcid": null + }, + { + "ForeName": "Xuan", + "LastName": "Zou", + "abbrevName": "Zou X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Zou", + "orcid": null + }, + { + "ForeName": "Chao", + "LastName": "Xing", + "abbrevName": "Xing C", + "email": null, + "isCollectiveName": false, + "name": "Chao Xing", + "orcid": null + }, + { + "ForeName": "Yingfei", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingfei Wang", + "orcid": null + }, + { + "ForeName": "Weibo", + "LastName": "Luo", + "abbrevName": "Luo W", + "email": null, + "isCollectiveName": false, + "name": "Weibo Luo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI95089", + "pmid": "29629903", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 128 2018", + "title": "ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis." + } + }, + { + "pmid": "28263959", + "pubmed": { + "ISODate": "2017-04-01T00:00:00.000Z", + "abstract": "We introduce Salmon, a lightweight method for quantifying transcript abundance from RNA-seq reads. Salmon combines a new dual-phase parallel inference algorithm and feature-rich bias models with an ultra-fast read mapping procedure. It is the first transcriptome-wide quantifier to correct for fragment GC-content bias, which, as we demonstrate here, substantially improves the accuracy of abundance estimates and the sensitivity of subsequent differential expression analysis.", + "authors": { + "abbreviation": "Rob Patro, Geet Duggal, Michael I Love, ..., Carl Kingsford", + "authorList": [ + { + "ForeName": "Rob", + "LastName": "Patro", + "abbrevName": "Patro R", + "email": null, + "isCollectiveName": false, + "name": "Rob Patro", + "orcid": null + }, + { + "ForeName": "Geet", + "LastName": "Duggal", + "abbrevName": "Duggal G", + "email": null, + "isCollectiveName": false, + "name": "Geet Duggal", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Love", + "abbrevName": "Love MI", + "email": null, + "isCollectiveName": false, + "name": "Michael I Love", + "orcid": null + }, + { + "ForeName": "Rafael", + "LastName": "Irizarry", + "abbrevName": "Irizarry RA", + "email": null, + "isCollectiveName": false, + "name": "Rafael A Irizarry", + "orcid": null + }, + { + "ForeName": "Carl", + "LastName": "Kingsford", + "abbrevName": "Kingsford C", + "email": null, + "isCollectiveName": false, + "name": "Carl Kingsford", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth.4197", + "pmid": "28263959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Methods 14 2017", + "title": "Salmon provides fast and bias-aware quantification of transcript expression." + } + }, + { + "pmid": "28027327", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival. CONCLUSIONS: This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.", + "authors": { + "abbreviation": "Celine Lefebvre, Thomas Bachelot, Thomas Filleron, ..., Fabrice André", + "authorList": [ + { + "ForeName": "Celine", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Celine Lefebvre", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Bachelot", + "abbrevName": "Bachelot T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Bachelot", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Filleron", + "abbrevName": "Filleron T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Filleron", + "orcid": "0000-0003-0724-0659" + }, + { + "ForeName": "Marion", + "LastName": "Pedrero", + "abbrevName": "Pedrero M", + "email": null, + "isCollectiveName": false, + "name": "Marion Pedrero", + "orcid": null + }, + { + "ForeName": "Mario", + "LastName": "Campone", + "abbrevName": "Campone M", + "email": null, + "isCollectiveName": false, + "name": "Mario Campone", + "orcid": null + }, + { + "ForeName": "Jean-Charles", + "LastName": "Soria", + "abbrevName": "Soria JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Charles Soria", + "orcid": null + }, + { + "ForeName": "Christophe", + "LastName": "Massard", + "abbrevName": "Massard C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Massard", + "orcid": null + }, + { + "ForeName": "Christelle", + "LastName": "Lévy", + "abbrevName": "Lévy C", + "email": null, + "isCollectiveName": false, + "name": "Christelle Lévy", + "orcid": null + }, + { + "ForeName": "Monica", + "LastName": "Arnedos", + "abbrevName": "Arnedos M", + "email": null, + "isCollectiveName": false, + "name": "Monica Arnedos", + "orcid": null + }, + { + "ForeName": "Magali", + "LastName": "Lacroix-Triki", + "abbrevName": "Lacroix-Triki M", + "email": null, + "isCollectiveName": false, + "name": "Magali Lacroix-Triki", + "orcid": null + }, + { + "ForeName": "Julie", + "LastName": "Garrabey", + "abbrevName": "Garrabey J", + "email": null, + "isCollectiveName": false, + "name": "Julie Garrabey", + "orcid": null + }, + { + "ForeName": "Yannick", + "LastName": "Boursin", + "abbrevName": "Boursin Y", + "email": null, + "isCollectiveName": false, + "name": "Yannick Boursin", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Deloger", + "abbrevName": "Deloger M", + "email": null, + "isCollectiveName": false, + "name": "Marc Deloger", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Fu", + "abbrevName": "Fu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Fu", + "orcid": "0000-0002-1497-1794" + }, + { + "ForeName": "Frédéric", + "LastName": "Commo", + "abbrevName": "Commo F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Commo", + "orcid": null + }, + { + "ForeName": "Véronique", + "LastName": "Scott", + "abbrevName": "Scott V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Scott", + "orcid": null + }, + { + "ForeName": "Ludovic", + "LastName": "Lacroix", + "abbrevName": "Lacroix L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Lacroix", + "orcid": "0000-0003-2535-1010" + }, + { + "ForeName": "Maria", + "LastName": "Dieci", + "abbrevName": "Dieci MV", + "email": null, + "isCollectiveName": false, + "name": "Maria Vittoria Dieci", + "orcid": "0000-0002-3967-9861" + }, + { + "ForeName": "Maud", + "LastName": "Kamal", + "abbrevName": "Kamal M", + "email": null, + "isCollectiveName": false, + "name": "Maud Kamal", + "orcid": null + }, + { + "ForeName": "Véronique", + "LastName": "Diéras", + "abbrevName": "Diéras V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Diéras", + "orcid": null + }, + { + "ForeName": "Anthony", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Anthony Gonçalves", + "orcid": null + }, + { + "ForeName": "Jean-Marc", + "LastName": "Ferrerro", + "abbrevName": "Ferrerro JM", + "email": null, + "isCollectiveName": false, + "name": "Jean-Marc Ferrerro", + "orcid": "0000-0003-0069-3743" + }, + { + "ForeName": "Gilles", + "LastName": "Romieu", + "abbrevName": "Romieu G", + "email": null, + "isCollectiveName": false, + "name": "Gilles Romieu", + "orcid": null + }, + { + "ForeName": "Laurence", + "LastName": "Vanlemmens", + "abbrevName": "Vanlemmens L", + "email": null, + "isCollectiveName": false, + "name": "Laurence Vanlemmens", + "orcid": null + }, + { + "ForeName": "Marie-Ange", + "LastName": "Mouret Reynier", + "abbrevName": "Mouret Reynier MA", + "email": null, + "isCollectiveName": false, + "name": "Marie-Ange Mouret Reynier", + "orcid": null + }, + { + "ForeName": "Jean-Christophe", + "LastName": "Théry", + "abbrevName": "Théry JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Christophe Théry", + "orcid": null + }, + { + "ForeName": "Fanny", + "LastName": "Le Du", + "abbrevName": "Le Du F", + "email": null, + "isCollectiveName": false, + "name": "Fanny Le Du", + "orcid": null + }, + { + "ForeName": "Séverine", + "LastName": "Guiu", + "abbrevName": "Guiu S", + "email": null, + "isCollectiveName": false, + "name": "Séverine Guiu", + "orcid": null + }, + { + "ForeName": "Florence", + "LastName": "Dalenc", + "abbrevName": "Dalenc F", + "email": null, + "isCollectiveName": false, + "name": "Florence Dalenc", + "orcid": null + }, + { + "ForeName": "Gilles", + "LastName": "Clapisson", + "abbrevName": "Clapisson G", + "email": null, + "isCollectiveName": false, + "name": "Gilles Clapisson", + "orcid": "0000-0002-5725-519X" + }, + { + "ForeName": "Hervé", + "LastName": "Bonnefoi", + "abbrevName": "Bonnefoi H", + "email": null, + "isCollectiveName": false, + "name": "Hervé Bonnefoi", + "orcid": null + }, + { + "ForeName": "Marta", + "LastName": "Jimenez", + "abbrevName": "Jimenez M", + "email": null, + "isCollectiveName": false, + "name": "Marta Jimenez", + "orcid": null + }, + { + "ForeName": "Christophe", + "LastName": "Le Tourneau", + "abbrevName": "Le Tourneau C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Le Tourneau", + "orcid": null + }, + { + "ForeName": "Fabrice", + "LastName": "André", + "abbrevName": "André F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice André", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pmed.1002201", + "pmid": "28027327", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS Med 13 2016", + "title": "Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis." + } + }, + { + "pmid": "27368101", + "pubmed": { + "ISODate": "2016-06-30T00:00:00.000Z", + "abstract": "The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIFα prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1α accumulation. Therefore, EglN1 senses both oxygen and cysteine.", + "authors": { + "abbreviation": "Kimberly J Briggs, Peppi Koivunen, Shugeng Cao, ..., William G Kaelin", + "authorList": [ + { + "ForeName": "Kimberly", + "LastName": "Briggs", + "abbrevName": "Briggs KJ", + "email": null, + "isCollectiveName": false, + "name": "Kimberly J Briggs", + "orcid": null + }, + { + "ForeName": "Peppi", + "LastName": "Koivunen", + "abbrevName": "Koivunen P", + "email": null, + "isCollectiveName": false, + "name": "Peppi Koivunen", + "orcid": null + }, + { + "ForeName": "Shugeng", + "LastName": "Cao", + "abbrevName": "Cao S", + "email": null, + "isCollectiveName": false, + "name": "Shugeng Cao", + "orcid": null + }, + { + "ForeName": "Keriann", + "LastName": "Backus", + "abbrevName": "Backus KM", + "email": null, + "isCollectiveName": false, + "name": "Keriann M Backus", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Olenchock", + "abbrevName": "Olenchock BA", + "email": null, + "isCollectiveName": false, + "name": "Benjamin A Olenchock", + "orcid": null + }, + { + "ForeName": "Hetalben", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hetalben Patel", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + }, + { + "ForeName": "Sabina", + "LastName": "Signoretti", + "abbrevName": "Signoretti S", + "email": null, + "isCollectiveName": false, + "name": "Sabina Signoretti", + "orcid": null + }, + { + "ForeName": "Gary", + "LastName": "Gerfen", + "abbrevName": "Gerfen GJ", + "email": null, + "isCollectiveName": false, + "name": "Gary J Gerfen", + "orcid": null + }, + { + "ForeName": "Andrea", + "LastName": "Richardson", + "abbrevName": "Richardson AL", + "email": null, + "isCollectiveName": false, + "name": "Andrea L Richardson", + "orcid": null + }, + { + "ForeName": "Agnieszka", + "LastName": "Witkiewicz", + "abbrevName": "Witkiewicz AK", + "email": null, + "isCollectiveName": false, + "name": "Agnieszka K Witkiewicz", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Cravatt", + "abbrevName": "Cravatt BF", + "email": null, + "isCollectiveName": false, + "name": "Benjamin F Cravatt", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Clardy", + "abbrevName": "Clardy J", + "email": null, + "isCollectiveName": false, + "name": "Jon Clardy", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": "william_kaelin@dfci.harvard.edu", + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "William", + "LastName": "Kaelin", + "email": [ + "william_kaelin@dfci.harvard.edu" + ], + "name": "William G Kaelin" + } + ] + }, + "doi": "10.1016/j.cell.2016.05.042", + "pmid": "27368101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cell 166 2016", + "title": "Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine." + } + }, + { + "pmid": "27161491", + "pubmed": { + "ISODate": "2016-05-10T00:00:00.000Z", + "abstract": "The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.", + "authors": { + "abbreviation": "Bernard Pereira, Suet-Feung Chin, Oscar M Rueda, ..., Carlos Caldas", + "authorList": [ + { + "ForeName": "Bernard", + "LastName": "Pereira", + "abbrevName": "Pereira B", + "email": null, + "isCollectiveName": false, + "name": "Bernard Pereira", + "orcid": null + }, + { + "ForeName": "Suet-Feung", + "LastName": "Chin", + "abbrevName": "Chin SF", + "email": null, + "isCollectiveName": false, + "name": "Suet-Feung Chin", + "orcid": null + }, + { + "ForeName": "Oscar", + "LastName": "Rueda", + "abbrevName": "Rueda OM", + "email": null, + "isCollectiveName": false, + "name": "Oscar M Rueda", + "orcid": null + }, + { + "ForeName": "Hans-Kristian", + "LastName": "Vollan", + "abbrevName": "Vollan HK", + "email": null, + "isCollectiveName": false, + "name": "Hans-Kristian Moen Vollan", + "orcid": null + }, + { + "ForeName": "Elena", + "LastName": "Provenzano", + "abbrevName": "Provenzano E", + "email": null, + "isCollectiveName": false, + "name": "Elena Provenzano", + "orcid": null + }, + { + "ForeName": "Helen", + "LastName": "Bardwell", + "abbrevName": "Bardwell HA", + "email": null, + "isCollectiveName": false, + "name": "Helen A Bardwell", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Pugh", + "abbrevName": "Pugh M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Pugh", + "orcid": null + }, + { + "ForeName": "Linda", + "LastName": "Jones", + "abbrevName": "Jones L", + "email": null, + "isCollectiveName": false, + "name": "Linda Jones", + "orcid": null + }, + { + "ForeName": "Roslin", + "LastName": "Russell", + "abbrevName": "Russell R", + "email": null, + "isCollectiveName": false, + "name": "Roslin Russell", + "orcid": null + }, + { + "ForeName": "Stephen-John", + "LastName": "Sammut", + "abbrevName": "Sammut SJ", + "email": null, + "isCollectiveName": false, + "name": "Stephen-John Sammut", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Tsui", + "abbrevName": "Tsui DW", + "email": null, + "isCollectiveName": false, + "name": "Dana W Y Tsui", + "orcid": null + }, + { + "ForeName": "Bin", + "LastName": "Liu", + "abbrevName": "Liu B", + "email": null, + "isCollectiveName": false, + "name": "Bin Liu", + "orcid": null + }, + { + "ForeName": "Sarah-Jane", + "LastName": "Dawson", + "abbrevName": "Dawson SJ", + "email": null, + "isCollectiveName": false, + "name": "Sarah-Jane Dawson", + "orcid": null + }, + { + "ForeName": "Jean", + "LastName": "Abraham", + "abbrevName": "Abraham J", + "email": null, + "isCollectiveName": false, + "name": "Jean Abraham", + "orcid": null + }, + { + "ForeName": "Helen", + "LastName": "Northen", + "abbrevName": "Northen H", + "email": null, + "isCollectiveName": false, + "name": "Helen Northen", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Peden", + "abbrevName": "Peden JF", + "email": null, + "isCollectiveName": false, + "name": "John F Peden", + "orcid": null + }, + { + "ForeName": "Abhik", + "LastName": "Mukherjee", + "abbrevName": "Mukherjee A", + "email": null, + "isCollectiveName": false, + "name": "Abhik Mukherjee", + "orcid": null + }, + { + "ForeName": "Gulisa", + "LastName": "Turashvili", + "abbrevName": "Turashvili G", + "email": null, + "isCollectiveName": false, + "name": "Gulisa Turashvili", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Green", + "abbrevName": "Green AR", + "email": null, + "isCollectiveName": false, + "name": "Andrew R Green", + "orcid": null + }, + { + "ForeName": "Steve", + "LastName": "McKinney", + "abbrevName": "McKinney S", + "email": null, + "isCollectiveName": false, + "name": "Steve McKinney", + "orcid": "0000-0002-1611-0867" + }, + { + "ForeName": "Arusha", + "LastName": "Oloumi", + "abbrevName": "Oloumi A", + "email": null, + "isCollectiveName": false, + "name": "Arusha Oloumi", + "orcid": null + }, + { + "ForeName": "Sohrab", + "LastName": "Shah", + "abbrevName": "Shah S", + "email": null, + "isCollectiveName": false, + "name": "Sohrab Shah", + "orcid": "0000-0001-6402-523X" + }, + { + "ForeName": "Nitzan", + "LastName": "Rosenfeld", + "abbrevName": "Rosenfeld N", + "email": null, + "isCollectiveName": false, + "name": "Nitzan Rosenfeld", + "orcid": null + }, + { + "ForeName": "Leigh", + "LastName": "Murphy", + "abbrevName": "Murphy L", + "email": null, + "isCollectiveName": false, + "name": "Leigh Murphy", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Bentley", + "abbrevName": "Bentley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Bentley", + "orcid": null + }, + { + "ForeName": "Ian", + "LastName": "Ellis", + "abbrevName": "Ellis IO", + "email": null, + "isCollectiveName": false, + "name": "Ian O Ellis", + "orcid": null + }, + { + "ForeName": "Arnie", + "LastName": "Purushotham", + "abbrevName": "Purushotham A", + "email": null, + "isCollectiveName": false, + "name": "Arnie Purushotham", + "orcid": null + }, + { + "ForeName": "Sarah", + "LastName": "Pinder", + "abbrevName": "Pinder SE", + "email": null, + "isCollectiveName": false, + "name": "Sarah E Pinder", + "orcid": null + }, + { + "ForeName": "Anne-Lise", + "LastName": "Børresen-Dale", + "abbrevName": "Børresen-Dale AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Lise Børresen-Dale", + "orcid": null + }, + { + "ForeName": "Helena", + "LastName": "Earl", + "abbrevName": "Earl HM", + "email": null, + "isCollectiveName": false, + "name": "Helena M Earl", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Pharoah", + "abbrevName": "Pharoah PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Pharoah", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "Ross", + "abbrevName": "Ross MT", + "email": null, + "isCollectiveName": false, + "name": "Mark T Ross", + "orcid": null + }, + { + "ForeName": "Samuel", + "LastName": "Aparicio", + "abbrevName": "Aparicio S", + "email": null, + "isCollectiveName": false, + "name": "Samuel Aparicio", + "orcid": null + }, + { + "ForeName": "Carlos", + "LastName": "Caldas", + "abbrevName": "Caldas C", + "email": null, + "isCollectiveName": false, + "name": "Carlos Caldas", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11479", + "pmid": "27161491", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes." + } + }, + { + "pmid": "27079975", + "pubmed": { + "ISODate": "2016-07-08T00:00:00.000Z", + "abstract": "We present an update to our Galaxy-based web server for processing and visualizing deeply sequenced data. Its core tool set, deepTools, allows users to perform complete bioinformatic workflows ranging from quality controls and normalizations of aligned reads to integrative analyses, including clustering and visualization approaches. Since we first described our deepTools Galaxy server in 2014, we have implemented new solutions for many requests from the community and our users. Here, we introduce significant enhancements and new tools to further improve data visualization and interpretation. deepTools continue to be open to all users and freely available as a web service at deeptools.ie-freiburg.mpg.de The new deepTools2 suite can be easily deployed within any Galaxy framework via the toolshed repository, and we also provide source code for command line usage under Linux and Mac OS X. A public and documented API for access to deepTools functionality is also available.", + "authors": { + "abbreviation": "Fidel Ramírez, Devon P Ryan, Björn Grüning, ..., Thomas Manke", + "authorList": [ + { + "ForeName": "Fidel", + "LastName": "Ramírez", + "abbrevName": "Ramírez F", + "email": null, + "isCollectiveName": false, + "name": "Fidel Ramírez", + "orcid": null + }, + { + "ForeName": "Devon", + "LastName": "Ryan", + "abbrevName": "Ryan DP", + "email": null, + "isCollectiveName": false, + "name": "Devon P Ryan", + "orcid": null + }, + { + "ForeName": "Björn", + "LastName": "Grüning", + "abbrevName": "Grüning B", + "email": null, + "isCollectiveName": false, + "name": "Björn Grüning", + "orcid": "0000-0002-3079-6586" + }, + { + "ForeName": "Vivek", + "LastName": "Bhardwaj", + "abbrevName": "Bhardwaj V", + "email": null, + "isCollectiveName": false, + "name": "Vivek Bhardwaj", + "orcid": null + }, + { + "ForeName": "Fabian", + "LastName": "Kilpert", + "abbrevName": "Kilpert F", + "email": null, + "isCollectiveName": false, + "name": "Fabian Kilpert", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Richter", + "abbrevName": "Richter AS", + "email": null, + "isCollectiveName": false, + "name": "Andreas S Richter", + "orcid": "0000-0002-4166-0991" + }, + { + "ForeName": "Steffen", + "LastName": "Heyne", + "abbrevName": "Heyne S", + "email": null, + "isCollectiveName": false, + "name": "Steffen Heyne", + "orcid": null + }, + { + "ForeName": "Friederike", + "LastName": "Dündar", + "abbrevName": "Dündar F", + "email": null, + "isCollectiveName": false, + "name": "Friederike Dündar", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Manke", + "abbrevName": "Manke T", + "email": "manke@ie-freiburg.mpg.de", + "isCollectiveName": false, + "name": "Thomas Manke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Manke", + "email": [ + "manke@ie-freiburg.mpg.de" + ], + "name": "Thomas Manke" + } + ] + }, + "doi": "10.1093/nar/gkw257", + "pmid": "27079975", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 44 2016", + "title": "deepTools2: a next generation web server for deep-sequencing data analysis." + } + }, + { + "pmid": "26605738", + "pubmed": { + "ISODate": "2012-09-11T00:00:00.000Z", + "abstract": "MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Reference Interaction Site Model. Vibrational frequencies may be calculated using normal mode or quasi-harmonic analysis to approximate the solute entropy. Specific interactions can also be dissected using free energy decomposition or alanine scanning. A parallel implementation significantly speeds up the calculation by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calculations. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.", + "authors": { + "abbreviation": "Bill R Miller, T Dwight McGee, Jason M Swails, ..., Adrian E Roitberg", + "authorList": [ + { + "ForeName": "Bill", + "LastName": "Miller", + "abbrevName": "Miller BR", + "email": null, + "isCollectiveName": false, + "name": "Bill R Miller", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "McGee", + "abbrevName": "McGee TD", + "email": null, + "isCollectiveName": false, + "name": "T Dwight McGee", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "Swails", + "abbrevName": "Swails JM", + "email": null, + "isCollectiveName": false, + "name": "Jason M Swails", + "orcid": null + }, + { + "ForeName": "Nadine", + "LastName": "Homeyer", + "abbrevName": "Homeyer N", + "email": null, + "isCollectiveName": false, + "name": "Nadine Homeyer", + "orcid": null + }, + { + "ForeName": "Holger", + "LastName": "Gohlke", + "abbrevName": "Gohlke H", + "email": null, + "isCollectiveName": false, + "name": "Holger Gohlke", + "orcid": null + }, + { + "ForeName": "Adrian", + "LastName": "Roitberg", + "abbrevName": "Roitberg AE", + "email": null, + "isCollectiveName": false, + "name": "Adrian E Roitberg", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1021/ct300418h", + "pmid": "26605738", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Chem Theory Comput 8 2012", + "title": "MMPBSA.py: An Efficient Program for End-State Free Energy Calculations." + } + }, + { + "pmid": "26574453", + "pubmed": { + "ISODate": "2015-08-11T00:00:00.000Z", + "abstract": "Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.", + "authors": { + "abbreviation": "James A Maier, Carmenza Martinez, Koushik Kasavajhala, ..., Carlos Simmerling", + "authorList": [ + { + "ForeName": "James", + "LastName": "Maier", + "abbrevName": "Maier JA", + "email": null, + "isCollectiveName": false, + "name": "James A Maier", + "orcid": null + }, + { + "ForeName": "Carmenza", + "LastName": "Martinez", + "abbrevName": "Martinez C", + "email": null, + "isCollectiveName": false, + "name": "Carmenza Martinez", + "orcid": null + }, + { + "ForeName": "Koushik", + "LastName": "Kasavajhala", + "abbrevName": "Kasavajhala K", + "email": null, + "isCollectiveName": false, + "name": "Koushik Kasavajhala", + "orcid": null + }, + { + "ForeName": "Lauren", + "LastName": "Wickstrom", + "abbrevName": "Wickstrom L", + "email": null, + "isCollectiveName": false, + "name": "Lauren Wickstrom", + "orcid": null + }, + { + "ForeName": "Kevin", + "LastName": "Hauser", + "abbrevName": "Hauser KE", + "email": null, + "isCollectiveName": false, + "name": "Kevin E Hauser", + "orcid": null + }, + { + "ForeName": "Carlos", + "LastName": "Simmerling", + "abbrevName": "Simmerling C", + "email": null, + "isCollectiveName": false, + "name": "Carlos Simmerling", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.jctc.5b00255", + "pmid": "26574453", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Chem Theory Comput 11 2015", + "title": "ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB." + } + }, + { + "pmid": "26574392", + "pubmed": { + "ISODate": "2015-04-14T00:00:00.000Z", + "abstract": "Previous studies have shown that the method of hydrogen mass repartitioning (HMR) is a potentially useful tool for accelerating molecular dynamics (MD) simulations. By repartitioning the mass of heavy atoms into the bonded hydrogen atoms, it is possible to slow the highest-frequency motions of the macromolecule under study, thus allowing the time step of the simulation to be increased by up to a factor of 2. In this communication, we investigate further how this mass repartitioning allows the simulation time step to be increased in a stable fashion without significantly increasing discretization error. To this end, we ran a set of simulations with different time steps and mass distributions on a three-residue peptide to get a comprehensive view of the effect of mass repartitioning and time step increase on a system whose accessible phase space is fully explored in a relatively short amount of time. We next studied a 129-residue protein, hen egg white lysozyme (HEWL), to verify that the observed behavior extends to a larger, more-realistic, system. Results for the protein include structural comparisons from MD trajectories, as well as comparisons of pKa calculations via constant-pH MD. We also calculated a potential of mean force (PMF) of a dihedral rotation for the MTS [(1-oxyl-2,2,5,5-tetramethyl-pyrroline-3-methyl)methanethiosulfonate] spin label via umbrella sampling with a set of regular MD trajectories, as well as a set of mass-repartitioned trajectories with a time step of 4 fs. Since no significant difference in kinetics or thermodynamics is observed by the use of fast HMR trajectories, further evidence is provided that long-time-step HMR MD simulations are a viable tool for accelerating MD simulations for molecules of biochemical interest.", + "authors": { + "abbreviation": "Chad W Hopkins, Scott Le Grand, Ross C Walker, Adrian E Roitberg", + "authorList": [ + { + "ForeName": "Chad", + "LastName": "Hopkins", + "abbrevName": "Hopkins CW", + "email": null, + "isCollectiveName": false, + "name": "Chad W Hopkins", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Le Grand", + "abbrevName": "Le Grand S", + "email": null, + "isCollectiveName": false, + "name": "Scott Le Grand", + "orcid": null + }, + { + "ForeName": "Ross", + "LastName": "Walker", + "abbrevName": "Walker RC", + "email": null, + "isCollectiveName": false, + "name": "Ross C Walker", + "orcid": null + }, + { + "ForeName": "Adrian", + "LastName": "Roitberg", + "abbrevName": "Roitberg AE", + "email": null, + "isCollectiveName": false, + "name": "Adrian E Roitberg", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1021/ct5010406", + "pmid": "26574392", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Chem Theory Comput 11 2015", + "title": "Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning." + } + }, + { + "pmid": "26569599", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ∼ 140 μs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/.", + "authors": { + "abbreviation": "Ivan Ivani, Pablo D Dans, Agnes Noy, ..., Modesto Orozco", + "authorList": [ + { + "ForeName": "Ivan", + "LastName": "Ivani", + "abbrevName": "Ivani I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Ivani", + "orcid": null + }, + { + "ForeName": "Pablo", + "LastName": "Dans", + "abbrevName": "Dans PD", + "email": null, + "isCollectiveName": false, + "name": "Pablo D Dans", + "orcid": "0000-0002-5927-372X" + }, + { + "ForeName": "Agnes", + "LastName": "Noy", + "abbrevName": "Noy A", + "email": null, + "isCollectiveName": false, + "name": "Agnes Noy", + "orcid": null + }, + { + "ForeName": "Alberto", + "LastName": "Pérez", + "abbrevName": "Pérez A", + "email": null, + "isCollectiveName": false, + "name": "Alberto Pérez", + "orcid": null + }, + { + "ForeName": "Ignacio", + "LastName": "Faustino", + "abbrevName": "Faustino I", + "email": null, + "isCollectiveName": false, + "name": "Ignacio Faustino", + "orcid": null + }, + { + "ForeName": "Adam", + "LastName": "Hospital", + "abbrevName": "Hospital A", + "email": null, + "isCollectiveName": false, + "name": "Adam Hospital", + "orcid": null + }, + { + "ForeName": "Jürgen", + "LastName": "Walther", + "abbrevName": "Walther J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Walther", + "orcid": null + }, + { + "ForeName": "Pau", + "LastName": "Andrio", + "abbrevName": "Andrio P", + "email": null, + "isCollectiveName": false, + "name": "Pau Andrio", + "orcid": null + }, + { + "ForeName": "Ramon", + "LastName": "Goñi", + "abbrevName": "Goñi R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Goñi", + "orcid": null + }, + { + "ForeName": "Alexandra", + "LastName": "Balaceanu", + "abbrevName": "Balaceanu A", + "email": null, + "isCollectiveName": false, + "name": "Alexandra Balaceanu", + "orcid": null + }, + { + "ForeName": "Guillem", + "LastName": "Portella", + "abbrevName": "Portella G", + "email": null, + "isCollectiveName": false, + "name": "Guillem Portella", + "orcid": null + }, + { + "ForeName": "Federica", + "LastName": "Battistini", + "abbrevName": "Battistini F", + "email": null, + "isCollectiveName": false, + "name": "Federica Battistini", + "orcid": null + }, + { + "ForeName": "Josep", + "LastName": "Gelpí", + "abbrevName": "Gelpí JL", + "email": null, + "isCollectiveName": false, + "name": "Josep Lluis Gelpí", + "orcid": "0000-0002-0566-7723" + }, + { + "ForeName": "Carlos", + "LastName": "González", + "abbrevName": "González C", + "email": null, + "isCollectiveName": false, + "name": "Carlos González", + "orcid": "0000-0001-8796-1282" + }, + { + "ForeName": "Michele", + "LastName": "Vendruscolo", + "abbrevName": "Vendruscolo M", + "email": null, + "isCollectiveName": false, + "name": "Michele Vendruscolo", + "orcid": null + }, + { + "ForeName": "Charles", + "LastName": "Laughton", + "abbrevName": "Laughton CA", + "email": null, + "isCollectiveName": false, + "name": "Charles A Laughton", + "orcid": null + }, + { + "ForeName": "Sarah", + "LastName": "Harris", + "abbrevName": "Harris SA", + "email": null, + "isCollectiveName": false, + "name": "Sarah A Harris", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Case", + "abbrevName": "Case DA", + "email": null, + "isCollectiveName": false, + "name": "David A Case", + "orcid": null + }, + { + "ForeName": "Modesto", + "LastName": "Orozco", + "abbrevName": "Orozco M", + "email": null, + "isCollectiveName": false, + "name": "Modesto Orozco", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth.3658", + "pmid": "26569599", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Methods 13 2016", + "title": "Parmbsc1: a refined force field for DNA simulations." + } + }, + { + "pmid": "26451490", + "pubmed": { + "ISODate": "2015-10-08T00:00:00.000Z", + "abstract": "Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.", + "authors": { + "abbreviation": "Giovanni Ciriello, Michael L Gatza, Andrew H Beck, ..., Charles M Perou", + "authorList": [ + { + "ForeName": "Giovanni", + "LastName": "Ciriello", + "abbrevName": "Ciriello G", + "email": null, + "isCollectiveName": false, + "name": "Giovanni Ciriello", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Gatza", + "abbrevName": "Gatza ML", + "email": null, + "isCollectiveName": false, + "name": "Michael L Gatza", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Beck", + "abbrevName": "Beck AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Beck", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Wilkerson", + "abbrevName": "Wilkerson MD", + "email": null, + "isCollectiveName": false, + "name": "Matthew D Wilkerson", + "orcid": null + }, + { + "ForeName": "Suhn", + "LastName": "Rhie", + "abbrevName": "Rhie SK", + "email": null, + "isCollectiveName": false, + "name": "Suhn K Rhie", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Pastore", + "abbrevName": "Pastore A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Pastore", + "orcid": null + }, + { + "ForeName": "Hailei", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hailei Zhang", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "McLellan", + "abbrevName": "McLellan M", + "email": null, + "isCollectiveName": false, + "name": "Michael McLellan", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Yau", + "abbrevName": "Yau C", + "email": null, + "isCollectiveName": false, + "name": "Christina Yau", + "orcid": null + }, + { + "ForeName": "Cyriac", + "LastName": "Kandoth", + "abbrevName": "Kandoth C", + "email": null, + "isCollectiveName": false, + "name": "Cyriac Kandoth", + "orcid": null + }, + { + "ForeName": "Reanne", + "LastName": "Bowlby", + "abbrevName": "Bowlby R", + "email": null, + "isCollectiveName": false, + "name": "Reanne Bowlby", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Shen", + "abbrevName": "Shen H", + "email": null, + "isCollectiveName": false, + "name": "Hui Shen", + "orcid": null + }, + { + "ForeName": "Sikander", + "LastName": "Hayat", + "abbrevName": "Hayat S", + "email": null, + "isCollectiveName": false, + "name": "Sikander Hayat", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Fieldhouse", + "abbrevName": "Fieldhouse R", + "email": null, + "isCollectiveName": false, + "name": "Robert Fieldhouse", + "orcid": null + }, + { + "ForeName": "Susan", + "LastName": "Lester", + "abbrevName": "Lester SC", + "email": null, + "isCollectiveName": false, + "name": "Susan C Lester", + "orcid": null + }, + { + "ForeName": "Gary", + "LastName": "Tse", + "abbrevName": "Tse GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M K Tse", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Factor", + "abbrevName": "Factor RE", + "email": null, + "isCollectiveName": false, + "name": "Rachel E Factor", + "orcid": null + }, + { + "ForeName": "Laura", + "LastName": "Collins", + "abbrevName": "Collins LC", + "email": null, + "isCollectiveName": false, + "name": "Laura C Collins", + "orcid": null + }, + { + "ForeName": "Kimberly", + "LastName": "Allison", + "abbrevName": "Allison KH", + "email": null, + "isCollectiveName": false, + "name": "Kimberly H Allison", + "orcid": null + }, + { + "ForeName": "Yunn-Yi", + "LastName": "Chen", + "abbrevName": "Chen YY", + "email": null, + "isCollectiveName": false, + "name": "Yunn-Yi Chen", + "orcid": null + }, + { + "ForeName": "Kristin", + "LastName": "Jensen", + "abbrevName": "Jensen K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Jensen", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Johnson", + "abbrevName": "Johnson NB", + "email": null, + "isCollectiveName": false, + "name": "Nicole B Johnson", + "orcid": null + }, + { + "ForeName": "Steffi", + "LastName": "Oesterreich", + "abbrevName": "Oesterreich S", + "email": null, + "isCollectiveName": false, + "name": "Steffi Oesterreich", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Mills", + "abbrevName": "Mills GB", + "email": null, + "isCollectiveName": false, + "name": "Gordon B Mills", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Cherniack", + "abbrevName": "Cherniack AD", + "email": null, + "isCollectiveName": false, + "name": "Andrew D Cherniack", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Robertson", + "abbrevName": "Robertson G", + "email": null, + "isCollectiveName": false, + "name": "Gordon Robertson", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Benz", + "abbrevName": "Benz C", + "email": null, + "isCollectiveName": false, + "name": "Christopher Benz", + "orcid": null + }, + { + "ForeName": "Chris", + "LastName": "Sander", + "abbrevName": "Sander C", + "email": null, + "isCollectiveName": false, + "name": "Chris Sander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Laird", + "abbrevName": "Laird PW", + "email": null, + "isCollectiveName": false, + "name": "Peter W Laird", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Hoadley", + "abbrevName": "Hoadley KA", + "email": null, + "isCollectiveName": false, + "name": "Katherine A Hoadley", + "orcid": null + }, + { + "ForeName": "Tari", + "LastName": "King", + "abbrevName": "King TA", + "email": null, + "isCollectiveName": false, + "name": "Tari A King", + "orcid": null + }, + { + "ForeName": null, + "LastName": null, + "abbrevName": "TCGA Research Network", + "email": null, + "isCollectiveName": true, + "name": "TCGA Research Network", + "orcid": null + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": "cperou@med.unc.edu", + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Charles", + "LastName": "Perou", + "email": [ + "cperou@med.unc.edu" + ], + "name": "Charles M Perou" + } + ] + }, + "doi": "10.1016/j.cell.2015.09.033", + "pmid": "26451490", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 163 2015", + "title": "Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer." + } + }, + { + "pmid": "25516281", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html webcite.", + "authors": { + "abbreviation": "Michael I Love, Wolfgang Huber, Simon Anders", + "authorList": [ + { + "ForeName": "Michael", + "LastName": "Love", + "abbrevName": "Love MI", + "email": null, + "isCollectiveName": false, + "name": "Michael I Love", + "orcid": null + }, + { + "ForeName": "Wolfgang", + "LastName": "Huber", + "abbrevName": "Huber W", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang Huber", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Anders", + "abbrevName": "Anders S", + "email": null, + "isCollectiveName": false, + "name": "Simon Anders", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1186/s13059-014-0550-8", + "pmid": "25516281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genome Biol 15 2014", + "title": "Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2." + } + }, + { + "pmid": "25473899", + "pubmed": { + "ISODate": "2015-01-20T00:00:00.000Z", + "abstract": "We previously reported the tumor suppressor function of Zinc-fingers and homeoboxes 2 (ZHX2) in hepatocellular carcinoma (HCC). Other studies indicate the association of increased ZHX2 expression with improved response to high dose chemotherapy in multiple myeloma. Here, we aim to test whether increased ZHX2 levels in HCC cells repress multidrug resistance 1(MDR1) expression resulting in increased sensitivity to chemotherapeutic drugs. We showed evidence that increased ZHX2 levels correlated with reduced MDR1 expression and enhanced the cytotoxicity of CDDP and ADM in different HCC cell lines. Consistently, elevated ZHX2 significantly reduced ADM efflux in HepG2 cells and greatly increased the CDDP-mediated suppression of liver tumor growth in vivo. Furthermore, immunohistochemical staining demonstrated the inverse correlation of ZHX2 and MDR1 expression in HCC tissues. Luciferase report assay showed that ZHX2 repressed the MDR1 promoter activity, while knockdown of NF-YA or mutating the NF-Y binding site eliminated this ZHX2-mediated repression of MDR1 transcription. Co-IP and ChIP assay further suggested that ZHX2 interacted with NF-YA and reduced NF-Y binding to the MDR1 promoter. Taken together, we clarify that ZHX2 represses NF-Y-mediated activation of MDR1 transcription and, in doing so, enhances the effects of chemotherapeutics in HCC cells both in vitro and in vivo.", + "authors": { + "abbreviation": "Hongxin Ma, Xuetian Yue, Lifen Gao, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Hongxin", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Ma", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Wenjiang", + "LastName": "Yan", + "abbrevName": "Yan W", + "email": null, + "isCollectiveName": false, + "name": "Wenjiang Yan", + "orcid": null + }, + { + "ForeName": "Zhenyu", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenyu Zhang", + "orcid": null + }, + { + "ForeName": "Haixia", + "LastName": "Shan", + "abbrevName": "Shan H", + "email": null, + "isCollectiveName": false, + "name": "Haixia Shan", + "orcid": null + }, + { + "ForeName": "Hualin", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hualin Zhang", + "orcid": null + }, + { + "ForeName": "Brett", + "LastName": "Spear", + "abbrevName": "Spear BT", + "email": null, + "isCollectiveName": false, + "name": "Brett T Spear", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.2832", + "pmid": "25473899", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncotarget 6 2015", + "title": "ZHX2 enhances the cytotoxicity of chemotherapeutic drugs in liver tumor cells by repressing MDR1 via interfering with NF-YA." + } + }, + { + "pmid": "24990963", + "pubmed": { + "ISODate": "2014-07-01T00:00:00.000Z", + "abstract": "The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.", + "authors": { + "abbreviation": "Xingnan Zheng, Bo Zhai, Peppi Koivunen, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Xingnan", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xingnan Zheng", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Zhai", + "abbrevName": "Zhai B", + "email": null, + "isCollectiveName": false, + "name": "Bo Zhai", + "orcid": null + }, + { + "ForeName": "Peppi", + "LastName": "Koivunen", + "abbrevName": "Koivunen P", + "email": null, + "isCollectiveName": false, + "name": "Peppi Koivunen", + "orcid": null + }, + { + "ForeName": "Sandra", + "LastName": "Shin", + "abbrevName": "Shin SJ", + "email": null, + "isCollectiveName": false, + "name": "Sandra J Shin", + "orcid": null + }, + { + "ForeName": "Gang", + "LastName": "Lu", + "abbrevName": "Lu G", + "email": null, + "isCollectiveName": false, + "name": "Gang Lu", + "orcid": null + }, + { + "ForeName": "Jiayun", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jiayun Liu", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Geisen", + "abbrevName": "Geisen C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Geisen", + "orcid": null + }, + { + "ForeName": "Abhishek", + "LastName": "Chakraborty", + "abbrevName": "Chakraborty AA", + "email": null, + "isCollectiveName": false, + "name": "Abhishek A Chakraborty", + "orcid": null + }, + { + "ForeName": "Javid", + "LastName": "Moslehi", + "abbrevName": "Moslehi JJ", + "email": null, + "isCollectiveName": false, + "name": "Javid J Moslehi", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Smalley", + "abbrevName": "Smalley DM", + "email": null, + "isCollectiveName": false, + "name": "David M Smalley", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Wei", + "abbrevName": "Wei X", + "email": null, + "isCollectiveName": false, + "name": "Xin Wei", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Zhengming", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zhengming Chen", + "orcid": null + }, + { + "ForeName": "Justine", + "LastName": "Beres", + "abbrevName": "Beres JM", + "email": null, + "isCollectiveName": false, + "name": "Justine M Beres", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": null + }, + { + "ForeName": "Jen", + "LastName": "Tsao", + "abbrevName": "Tsao JL", + "email": null, + "isCollectiveName": false, + "name": "Jen Lan Tsao", + "orcid": null + }, + { + "ForeName": "Mitchell", + "LastName": "Brenner", + "abbrevName": "Brenner MC", + "email": null, + "isCollectiveName": false, + "name": "Mitchell C Brenner", + "orcid": null + }, + { + "ForeName": "Yuqing", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Zhang", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Ronald", + "LastName": "DePinho", + "abbrevName": "DePinho RA", + "email": null, + "isCollectiveName": false, + "name": "Ronald A DePinho", + "orcid": null + }, + { + "ForeName": "Jihye", + "LastName": "Paik", + "abbrevName": "Paik J", + "email": null, + "isCollectiveName": false, + "name": "Jihye Paik", + "orcid": null + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.242131.114", + "pmid": "24990963", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 28 2014", + "title": "Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase." + } + }, + { + "pmid": "24885402", + "pubmed": { + "ISODate": "2014-05-02T00:00:00.000Z", + "abstract": "BACKGROUND: The precise nature of how cell type specific chromatin structures at enhancer sites affect gene expression is largely unknown. Here we identified cell type specific enhancers coupled with gene expression in two different types of breast epithelial cells, HMEC (normal breast epithelial cells) and MDAMB231 (triple negative breast cancer cell line). RESULTS: Enhancers were defined by modified neighboring histones [using chromatin immunoprecipitation followed by sequencing (ChIP-seq)] and nucleosome depletion [using formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq)]. Histone modifications at enhancers were related to the expression levels of nearby genes up to 750 kb away. These expression levels were correlated with enhancer status (poised or active), defined by surrounding histone marks. Furthermore, about fifty percent of poised and active enhancers contained nucleosome-depleted regions. We also identified response element motifs enriched at these enhancer sites that revealed key transcription factors (e.g. TP63) likely involved in regulating breast epithelial enhancer-mediated gene expression. By utilizing expression data, potential target genes of more than 600 active enhancers were identified. These genes were involved in proteolysis, epidermis development, cell adhesion, mitosis, cell cycle, and DNA replication. CONCLUSIONS: These findings facilitate the understanding of epigenetic regulation specifically, such as the relationships between regulatory elements and gene expression and generally, how breast epithelial cellular phenotypes are determined by cell type specific enhancers.", + "authors": { + "abbreviation": "Suhn Kyong Rhie, Dennis J Hazelett, Simon G Coetzee, ..., Gerhard A Coetzee", + "authorList": [ + { + "ForeName": "Suhn", + "LastName": "Rhie", + "abbrevName": "Rhie SK", + "email": null, + "isCollectiveName": false, + "name": "Suhn Kyong Rhie", + "orcid": null + }, + { + "ForeName": "Dennis", + "LastName": "Hazelett", + "abbrevName": "Hazelett DJ", + "email": null, + "isCollectiveName": false, + "name": "Dennis J Hazelett", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Coetzee", + "abbrevName": "Coetzee SG", + "email": null, + "isCollectiveName": false, + "name": "Simon G Coetzee", + "orcid": null + }, + { + "ForeName": "Chunli", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Chunli Yan", + "orcid": null + }, + { + "ForeName": "Houtan", + "LastName": "Noushmehr", + "abbrevName": "Noushmehr H", + "email": null, + "isCollectiveName": false, + "name": "Houtan Noushmehr", + "orcid": null + }, + { + "ForeName": "Gerhard", + "LastName": "Coetzee", + "abbrevName": "Coetzee GA", + "email": "coetzee@usc.edu", + "isCollectiveName": false, + "name": "Gerhard A Coetzee", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Gerhard", + "LastName": "Coetzee", + "email": [ + "coetzee@usc.edu" + ], + "name": "Gerhard A Coetzee" + } + ] + }, + "doi": "10.1186/1471-2164-15-331", + "pmid": "24885402", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Genomics 15 2014", + "title": "Nucleosome positioning and histone modifications define relationships between regulatory elements and nearby gene expression in breast epithelial cells." + } + }, + { + "pmid": "24614317", + "pubmed": { + "ISODate": "2014-04-01T00:00:00.000Z", + "abstract": "Cellular development, morphology and function are governed by precise patterns of gene expression. These are established by the coordinated action of genomic regulatory elements known as enhancers or cis-regulatory modules. More than 30 years after the initial discovery of enhancers, many of their properties have been elucidated; however, despite major efforts, we only have an incomplete picture of enhancers in animal genomes. In this Review, we discuss how properties of enhancer sequences and chromatin are used to predict enhancers in genome-wide studies. We also cover recently developed high-throughput methods that allow the direct testing and identification of enhancers on the basis of their activity. Finally, we discuss recent technological advances and current challenges in the field of regulatory genomics.", + "authors": { + "abbreviation": "Daria Shlyueva, Gerald Stampfel, Alexander Stark", + "authorList": [ + { + "ForeName": "Daria", + "LastName": "Shlyueva", + "abbrevName": "Shlyueva D", + "email": null, + "isCollectiveName": false, + "name": "Daria Shlyueva", + "orcid": null + }, + { + "ForeName": "Gerald", + "LastName": "Stampfel", + "abbrevName": "Stampfel G", + "email": null, + "isCollectiveName": false, + "name": "Gerald Stampfel", + "orcid": null + }, + { + "ForeName": "Alexander", + "LastName": "Stark", + "abbrevName": "Stark A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Stark", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nrg3682", + "pmid": "24614317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Genet 15 2014", + "title": "Transcriptional enhancers: from properties to genome-wide predictions." + } + }, + { + "pmid": "23792809", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.", + "authors": { + "abbreviation": "Lei Wang, Jianjun Chang, Diana Varghese, ..., Elisabeth D Martinez", + "authorList": [ + { + "ForeName": "Lei", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Lei Wang", + "orcid": null + }, + { + "ForeName": "Jianjun", + "LastName": "Chang", + "abbrevName": "Chang J", + "email": null, + "isCollectiveName": false, + "name": "Jianjun Chang", + "orcid": null + }, + { + "ForeName": "Diana", + "LastName": "Varghese", + "abbrevName": "Varghese D", + "email": null, + "isCollectiveName": false, + "name": "Diana Varghese", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Dellinger", + "abbrevName": "Dellinger M", + "email": null, + "isCollectiveName": false, + "name": "Michael Dellinger", + "orcid": null + }, + { + "ForeName": "Subodh", + "LastName": "Kumar", + "abbrevName": "Kumar S", + "email": null, + "isCollectiveName": false, + "name": "Subodh Kumar", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Best", + "abbrevName": "Best AM", + "email": null, + "isCollectiveName": false, + "name": "Anne M Best", + "orcid": null + }, + { + "ForeName": "Julio", + "LastName": "Ruiz", + "abbrevName": "Ruiz J", + "email": null, + "isCollectiveName": false, + "name": "Julio Ruiz", + "orcid": null + }, + { + "ForeName": "Richard", + "LastName": "Bruick", + "abbrevName": "Bruick R", + "email": null, + "isCollectiveName": false, + "name": "Richard Bruick", + "orcid": null + }, + { + "ForeName": "Samuel", + "LastName": "Peña-Llopis", + "abbrevName": "Peña-Llopis S", + "email": null, + "isCollectiveName": false, + "name": "Samuel Peña-Llopis", + "orcid": null + }, + { + "ForeName": "Junjie", + "LastName": "Xu", + "abbrevName": "Xu J", + "email": null, + "isCollectiveName": false, + "name": "Junjie Xu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Babinski", + "abbrevName": "Babinski DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Babinski", + "orcid": null + }, + { + "ForeName": "Doug", + "LastName": "Frantz", + "abbrevName": "Frantz DE", + "email": null, + "isCollectiveName": false, + "name": "Doug E Frantz", + "orcid": null + }, + { + "ForeName": "Rolf", + "LastName": "Brekken", + "abbrevName": "Brekken RA", + "email": null, + "isCollectiveName": false, + "name": "Rolf A Brekken", + "orcid": null + }, + { + "ForeName": "Amy", + "LastName": "Quinn", + "abbrevName": "Quinn AM", + "email": null, + "isCollectiveName": false, + "name": "Amy M Quinn", + "orcid": null + }, + { + "ForeName": "Anton", + "LastName": "Simeonov", + "abbrevName": "Simeonov A", + "email": null, + "isCollectiveName": false, + "name": "Anton Simeonov", + "orcid": null + }, + { + "ForeName": "Johnny", + "LastName": "Easmon", + "abbrevName": "Easmon J", + "email": null, + "isCollectiveName": false, + "name": "Johnny Easmon", + "orcid": null + }, + { + "ForeName": "Elisabeth", + "LastName": "Martinez", + "abbrevName": "Martinez ED", + "email": null, + "isCollectiveName": false, + "name": "Elisabeth D Martinez", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms3035", + "pmid": "23792809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Nat Commun 4 2013", + "title": "A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth." + } + }, + { + "pmid": "23550210", + "pubmed": { + "ISODate": "2013-04-02T00:00:00.000Z", + "abstract": "The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.", + "authors": { + "abbreviation": "Jianjiong Gao, Bülent Arman Aksoy, Ugur Dogrusoz, ..., Nikolaus Schultz", + "authorList": [ + { + "ForeName": "Jianjiong", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": null, + "isCollectiveName": false, + "name": "Jianjiong Gao", + "orcid": null + }, + { + "ForeName": "Bülent", + "LastName": "Aksoy", + "abbrevName": "Aksoy BA", + "email": null, + "isCollectiveName": false, + "name": "Bülent Arman Aksoy", + "orcid": null + }, + { + "ForeName": "Ugur", + "LastName": "Dogrusoz", + "abbrevName": "Dogrusoz U", + "email": null, + "isCollectiveName": false, + "name": "Ugur Dogrusoz", + "orcid": null + }, + { + "ForeName": "Gideon", + "LastName": "Dresdner", + "abbrevName": "Dresdner G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Dresdner", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Gross", + "abbrevName": "Gross B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Gross", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sumer", + "abbrevName": "Sumer SO", + "email": null, + "isCollectiveName": false, + "name": "S Onur Sumer", + "orcid": null + }, + { + "ForeName": "Yichao", + "LastName": "Sun", + "abbrevName": "Sun Y", + "email": null, + "isCollectiveName": false, + "name": "Yichao Sun", + "orcid": null + }, + { + "ForeName": "Anders", + "LastName": "Jacobsen", + "abbrevName": "Jacobsen A", + "email": null, + "isCollectiveName": false, + "name": "Anders Jacobsen", + "orcid": null + }, + { + "ForeName": "Rileen", + "LastName": "Sinha", + "abbrevName": "Sinha R", + "email": null, + "isCollectiveName": false, + "name": "Rileen Sinha", + "orcid": null + }, + { + "ForeName": "Erik", + "LastName": "Larsson", + "abbrevName": "Larsson E", + "email": null, + "isCollectiveName": false, + "name": "Erik Larsson", + "orcid": null + }, + { + "ForeName": "Ethan", + "LastName": "Cerami", + "abbrevName": "Cerami E", + "email": null, + "isCollectiveName": false, + "name": "Ethan Cerami", + "orcid": null + }, + { + "ForeName": "Chris", + "LastName": "Sander", + "abbrevName": "Sander C", + "email": null, + "isCollectiveName": false, + "name": "Chris Sander", + "orcid": null + }, + { + "ForeName": "Nikolaus", + "LastName": "Schultz", + "abbrevName": "Schultz N", + "email": null, + "isCollectiveName": false, + "name": "Nikolaus Schultz", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/scisignal.2004088", + "pmid": "23550210", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Signal 6 2013", + "title": "Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal." + } + }, + { + "pmid": "23455378", + "pubmed": { + "ISODate": "2013-04-01T00:00:00.000Z", + "abstract": "Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested clinically. This analysis supports the contention that understanding modes of resistance to both chemotherapy and molecularly targeted therapies may be very useful in selecting those drugs of each class that will have complementing mechanisms of sensitivity and thereby represent reasonable combination therapies.", + "authors": { + "abbreviation": "Kenta Masui, Beatrice Gini, Jill Wykosky, ..., Webster K Cavenee", + "authorList": [ + { + "ForeName": "Kenta", + "LastName": "Masui", + "abbrevName": "Masui K", + "email": null, + "isCollectiveName": false, + "name": "Kenta Masui", + "orcid": null + }, + { + "ForeName": "Beatrice", + "LastName": "Gini", + "abbrevName": "Gini B", + "email": null, + "isCollectiveName": false, + "name": "Beatrice Gini", + "orcid": null + }, + { + "ForeName": "Jill", + "LastName": "Wykosky", + "abbrevName": "Wykosky J", + "email": null, + "isCollectiveName": false, + "name": "Jill Wykosky", + "orcid": null + }, + { + "ForeName": "Ciro", + "LastName": "Zanca", + "abbrevName": "Zanca C", + "email": null, + "isCollectiveName": false, + "name": "Ciro Zanca", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Mischel", + "abbrevName": "Mischel PS", + "email": null, + "isCollectiveName": false, + "name": "Paul S Mischel", + "orcid": null + }, + { + "ForeName": "Frank", + "LastName": "Furnari", + "abbrevName": "Furnari FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Furnari", + "orcid": null + }, + { + "ForeName": "Webster", + "LastName": "Cavenee", + "abbrevName": "Cavenee WK", + "email": null, + "isCollectiveName": false, + "name": "Webster K Cavenee", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1093/carcin/bgt086", + "pmid": "23455378", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Carcinogenesis 34 2013", + "title": "A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatments." + } + }, + { + "pmid": "23104886", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "MOTIVATION: Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. RESULTS: To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. AVAILABILITY AND IMPLEMENTATION: STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.", + "authors": { + "abbreviation": "Alexander Dobin, Carrie A Davis, Felix Schlesinger, ..., Thomas R Gingeras", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Dobin", + "abbrevName": "Dobin A", + "email": "dobin@cshl.edu", + "isCollectiveName": false, + "name": "Alexander Dobin", + "orcid": null + }, + { + "ForeName": "Carrie", + "LastName": "Davis", + "abbrevName": "Davis CA", + "email": null, + "isCollectiveName": false, + "name": "Carrie A Davis", + "orcid": null + }, + { + "ForeName": "Felix", + "LastName": "Schlesinger", + "abbrevName": "Schlesinger F", + "email": null, + "isCollectiveName": false, + "name": "Felix Schlesinger", + "orcid": null + }, + { + "ForeName": "Jorg", + "LastName": "Drenkow", + "abbrevName": "Drenkow J", + "email": null, + "isCollectiveName": false, + "name": "Jorg Drenkow", + "orcid": null + }, + { + "ForeName": "Chris", + "LastName": "Zaleski", + "abbrevName": "Zaleski C", + "email": null, + "isCollectiveName": false, + "name": "Chris Zaleski", + "orcid": null + }, + { + "ForeName": "Sonali", + "LastName": "Jha", + "abbrevName": "Jha S", + "email": null, + "isCollectiveName": false, + "name": "Sonali Jha", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Batut", + "abbrevName": "Batut P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Batut", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "Chaisson", + "abbrevName": "Chaisson M", + "email": null, + "isCollectiveName": false, + "name": "Mark Chaisson", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Gingeras", + "abbrevName": "Gingeras TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Gingeras", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alexander", + "LastName": "Dobin", + "email": [ + "dobin@cshl.edu" + ], + "name": "Alexander Dobin" + } + ] + }, + "doi": "10.1093/bioinformatics/bts635", + "pmid": "23104886", + "pubTypes": [ + { + "UI": "D023362", + "value": "Evaluation Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Bioinformatics 29 2013", + "title": "STAR: ultrafast universal RNA-seq aligner." + } + }, + { + "pmid": "23000897", + "pubmed": { + "ISODate": "2012-10-04T00:00:00.000Z", + "abstract": "We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.", + "authors": { + "abbreviation": "Cancer Genome Atlas Network", + "authorList": [ + { + "ForeName": null, + "LastName": null, + "abbrevName": "Cancer Genome Atlas Network", + "email": null, + "isCollectiveName": true, + "name": "Cancer Genome Atlas Network", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature11412", + "pmid": "23000897", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Nature 490 2012", + "title": "Comprehensive molecular portraits of human breast tumours." + } + }, + { + "pmid": "22522925", + "pubmed": { + "ISODate": "2012-04-18T00:00:00.000Z", + "abstract": "The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.", + "authors": { + "abbreviation": "Christina Curtis, Sohrab P Shah, Suet-Feung Chin, ..., Samuel Aparicio", + "authorList": [ + { + "ForeName": "Christina", + "LastName": "Curtis", + "abbrevName": "Curtis C", + "email": null, + "isCollectiveName": false, + "name": "Christina Curtis", + "orcid": null + }, + { + "ForeName": "Sohrab", + "LastName": "Shah", + "abbrevName": "Shah SP", + "email": null, + "isCollectiveName": false, + "name": "Sohrab P Shah", + "orcid": null + }, + { + "ForeName": "Suet-Feung", + "LastName": "Chin", + "abbrevName": "Chin SF", + "email": null, + "isCollectiveName": false, + "name": "Suet-Feung Chin", + "orcid": null + }, + { + "ForeName": "Gulisa", + "LastName": "Turashvili", + "abbrevName": "Turashvili G", + "email": null, + "isCollectiveName": false, + "name": "Gulisa Turashvili", + "orcid": null + }, + { + "ForeName": "Oscar", + "LastName": "Rueda", + "abbrevName": "Rueda OM", + "email": null, + "isCollectiveName": false, + "name": "Oscar M Rueda", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "Dunning", + "abbrevName": "Dunning MJ", + "email": null, + "isCollectiveName": false, + "name": "Mark J Dunning", + "orcid": null + }, + { + "ForeName": "Doug", + "LastName": "Speed", + "abbrevName": "Speed D", + "email": null, + "isCollectiveName": false, + "name": "Doug Speed", + "orcid": null + }, + { + "ForeName": "Andy", + "LastName": "Lynch", + "abbrevName": "Lynch AG", + "email": null, + "isCollectiveName": false, + "name": "Andy G Lynch", + "orcid": null + }, + { + "ForeName": "Shamith", + "LastName": "Samarajiwa", + "abbrevName": "Samarajiwa S", + "email": null, + "isCollectiveName": false, + "name": "Shamith Samarajiwa", + "orcid": null + }, + { + "ForeName": "Yinyin", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yinyin Yuan", + "orcid": null + }, + { + "ForeName": "Stefan", + "LastName": "Gräf", + "abbrevName": "Gräf S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Gräf", + "orcid": null + }, + { + "ForeName": "Gavin", + "LastName": "Ha", + "abbrevName": "Ha G", + "email": null, + "isCollectiveName": false, + "name": "Gavin Ha", + "orcid": null + }, + { + "ForeName": "Gholamreza", + "LastName": "Haffari", + "abbrevName": "Haffari G", + "email": null, + "isCollectiveName": false, + "name": "Gholamreza Haffari", + "orcid": null + }, + { + "ForeName": "Ali", + "LastName": "Bashashati", + "abbrevName": "Bashashati A", + "email": null, + "isCollectiveName": false, + "name": "Ali Bashashati", + "orcid": null + }, + { + "ForeName": "Roslin", + "LastName": "Russell", + "abbrevName": "Russell R", + "email": null, + "isCollectiveName": false, + "name": "Roslin Russell", + "orcid": null + }, + { + "ForeName": "Steven", + "LastName": "McKinney", + "abbrevName": "McKinney S", + "email": null, + "isCollectiveName": false, + "name": "Steven McKinney", + "orcid": null + }, + { + "ForeName": null, + "LastName": null, + "abbrevName": "METABRIC Group", + "email": null, + "isCollectiveName": true, + "name": "METABRIC Group", + "orcid": null + }, + { + "ForeName": "Anita", + "LastName": "Langerød", + "abbrevName": "Langerød A", + "email": null, + "isCollectiveName": false, + "name": "Anita Langerød", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Green", + "abbrevName": "Green A", + "email": null, + "isCollectiveName": false, + "name": "Andrew Green", + "orcid": null + }, + { + "ForeName": "Elena", + "LastName": "Provenzano", + "abbrevName": "Provenzano E", + "email": null, + "isCollectiveName": false, + "name": "Elena Provenzano", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Wishart", + "abbrevName": "Wishart G", + "email": null, + "isCollectiveName": false, + "name": "Gordon Wishart", + "orcid": null + }, + { + "ForeName": "Sarah", + "LastName": "Pinder", + "abbrevName": "Pinder S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Pinder", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Watson", + "abbrevName": "Watson P", + "email": null, + "isCollectiveName": false, + "name": "Peter Watson", + "orcid": null + }, + { + "ForeName": "Florian", + "LastName": "Markowetz", + "abbrevName": "Markowetz F", + "email": null, + "isCollectiveName": false, + "name": "Florian Markowetz", + "orcid": null + }, + { + "ForeName": "Leigh", + "LastName": "Murphy", + "abbrevName": "Murphy L", + "email": null, + "isCollectiveName": false, + "name": "Leigh Murphy", + "orcid": null + }, + { + "ForeName": "Ian", + "LastName": "Ellis", + "abbrevName": "Ellis I", + "email": null, + "isCollectiveName": false, + "name": "Ian Ellis", + "orcid": null + }, + { + "ForeName": "Arnie", + "LastName": "Purushotham", + "abbrevName": "Purushotham A", + "email": null, + "isCollectiveName": false, + "name": "Arnie Purushotham", + "orcid": null + }, + { + "ForeName": "Anne-Lise", + "LastName": "Børresen-Dale", + "abbrevName": "Børresen-Dale AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Lise Børresen-Dale", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Brenton", + "abbrevName": "Brenton JD", + "email": null, + "isCollectiveName": false, + "name": "James D Brenton", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Tavaré", + "abbrevName": "Tavaré S", + "email": null, + "isCollectiveName": false, + "name": "Simon Tavaré", + "orcid": null + }, + { + "ForeName": "Carlos", + "LastName": "Caldas", + "abbrevName": "Caldas C", + "email": null, + "isCollectiveName": false, + "name": "Carlos Caldas", + "orcid": null + }, + { + "ForeName": "Samuel", + "LastName": "Aparicio", + "abbrevName": "Aparicio S", + "email": null, + "isCollectiveName": false, + "name": "Samuel Aparicio", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature10983", + "pmid": "22522925", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 486 2012", + "title": "The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups." + } + }, + { + "pmid": "22406477", + "pubmed": { + "ISODate": "2012-06-01T00:00:00.000Z", + "abstract": "BACKGROUND & AIMS: Zinc-fingers and homeoboxes 2 (ZHX2) represses transcription of several genes associated with liver cancer. However, little is known about the role of ZHX2 in the development of hepatocellular carcinoma (HCC). We investigated the mechanisms by which ZHX2 might affect proliferation of HCC cells. METHODS: We overexpressed and knocked down ZHX2 in HCC cells and analyzed the effects on proliferation, colony formation, and the cell cycle. We also analyzed the effects of ZHX2 overexpression in growth of HepG2.2.15 tumor xenografts in nude mice. Chromatin immunoprecipitation and luciferase reporter assays were used to measure binding of ZHX2 target promoters. Levels of ZHX2 in HCC samples were evaluated by immunohistochemistry. RESULTS: ZHX2 overexpression significantly reduced proliferation of HCC cells and growth of tumor xenografts in mice; it led to G1 arrest and reduced levels of Cyclins A and E in HCC cell lines. ZHX2 bound to promoter regions of CCNA2 (which encodes Cyclin A) and CCNE1 (which encodes Cyclin E) and inhibited their transcription. Knockdown of Cyclin A or Cyclin E reduced the increased proliferation mediated by ZHX2 knockdown. Nuclear localization of ZHX2 was required for it to inhibit proliferation of HCC cells in culture and in mice. Nuclear localization of ZHX2 was reduced in human HCC samples, even in small tumors (diameter, <5 cm), compared with adjacent nontumor tissues. Moreover, reduced nuclear levels of ZHX2 correlated with reduced survival times of patients, high levels of tumor microvascularization, and hepatocyte proliferation. CONCLUSIONS: ZHX2 inhibits HCC cell proliferation by preventing expression of Cyclins A and E, and reduces growth of xenograft tumors in mice. Loss of nuclear ZHX2 might be an early step in the development of HCC.", + "authors": { + "abbreviation": "Xuetian Yue, Zhenyu Zhang, Xiaohong Liang, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Zhenyu", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenyu Zhang", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaoning", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoning Zhang", + "orcid": null + }, + { + "ForeName": "Di", + "LastName": "Zhao", + "abbrevName": "Zhao D", + "email": null, + "isCollectiveName": false, + "name": "Di Zhao", + "orcid": null + }, + { + "ForeName": "Xiao", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xiao Liu", + "orcid": null + }, + { + "ForeName": "Hongxin", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Ma", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Guo", + "abbrevName": "Guo M", + "email": null, + "isCollectiveName": false, + "name": "Min Guo", + "orcid": null + }, + { + "ForeName": "Brett", + "LastName": "Spear", + "abbrevName": "Spear BT", + "email": null, + "isCollectiveName": false, + "name": "Brett T Spear", + "orcid": null + }, + { + "ForeName": "Yaoqin", + "LastName": "Gong", + "abbrevName": "Gong Y", + "email": null, + "isCollectiveName": false, + "name": "Yaoqin Gong", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1053/j.gastro.2012.02.049", + "pmid": "22406477", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Gastroenterology 142 2012", + "title": "Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of Cyclins A and E." + } + }, + { + "pmid": "22304911", + "pubmed": { + "ISODate": "2012-02-03T00:00:00.000Z", + "abstract": "Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes.", + "authors": { + "abbreviation": "Gregg L Semenza", + "authorList": [ + { + "ForeName": "Gregg", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": "gsemenza@jhmi.edu", + "isCollectiveName": false, + "name": "Gregg L Semenza", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Gregg", + "LastName": "Semenza", + "email": [ + "gsemenza@jhmi.edu" + ], + "name": "Gregg L Semenza" + } + ] + }, + "doi": "10.1016/j.cell.2012.01.021", + "pmid": "22304911", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell 148 2012", + "title": "Hypoxia-inducible factors in physiology and medicine." + } + }, + { + "pmid": "22078940", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Recently, we identified a novel chromosomal rearrangement in Hodgkin lymphoma (HL), t(4;8)(q27;q24), which targets homeobox gene ZHX2 at the recurrent breakpoint 8q24. This aberration deletes the far upstream region of ZHX2 and results in silenced transcription pinpointing loss of activatory elements. Here, we have looked for potential binding sites within this deleted region to analyze the transcriptional deregulation of this tumor suppressor gene in B-cell malignancies. SiRNA-mediated knockdown and reporter gene analyses identified two transcription factors, homeodomain protein MSX1 and bZIP protein XBP1, directly regulating ZHX2 expression. Furthermore, MSX1-cofactor histone H1C mediated repression of ZHX2 and showed enhanced expression levels in cell line L-1236. As demonstrated by fluorescence in situ hybridization and genomic array analysis, the gene loci of MSX1 at 4p16 and H1C at 6p22 were rearranged in several HL cell lines, correlating with their altered expression activity. The expression of XBP1 was reduced in 6/7 HL cell lines as compared to primary hematopoietic cells. Taken together, our results demonstrate multiple mechanisms decreasing expression of tumor suppressor gene ZHX2 in HL cell lines: loss of enhancing binding sites, reduced expression of activators MSX1 and XBP1, and overexpression of MSX1-corepressor H1C. Moreover, chromosomal deregulations of genes involved in this regulative network highlight their role in development and malignancy of B-cells.", + "authors": { + "abbreviation": "Stefan Nagel, Björn Schneider, Corinna Meyer, ..., Roderick A F Macleod", + "authorList": [ + { + "ForeName": "Stefan", + "LastName": "Nagel", + "abbrevName": "Nagel S", + "email": "sna@dsmz.de", + "isCollectiveName": false, + "name": "Stefan Nagel", + "orcid": null + }, + { + "ForeName": "Björn", + "LastName": "Schneider", + "abbrevName": "Schneider B", + "email": null, + "isCollectiveName": false, + "name": "Björn Schneider", + "orcid": null + }, + { + "ForeName": "Corinna", + "LastName": "Meyer", + "abbrevName": "Meyer C", + "email": null, + "isCollectiveName": false, + "name": "Corinna Meyer", + "orcid": null + }, + { + "ForeName": "Maren", + "LastName": "Kaufmann", + "abbrevName": "Kaufmann M", + "email": null, + "isCollectiveName": false, + "name": "Maren Kaufmann", + "orcid": null + }, + { + "ForeName": "Hans", + "LastName": "Drexler", + "abbrevName": "Drexler HG", + "email": null, + "isCollectiveName": false, + "name": "Hans G Drexler", + "orcid": null + }, + { + "ForeName": "Roderick", + "LastName": "Macleod", + "abbrevName": "Macleod RA", + "email": null, + "isCollectiveName": false, + "name": "Roderick A F Macleod", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Stefan", + "LastName": "Nagel", + "email": [ + "sna@dsmz.de" + ], + "name": "Stefan Nagel" + } + ] + }, + "doi": "10.1016/j.leukres.2011.10.019", + "pmid": "22078940", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Leuk Res 36 2012", + "title": "Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma." + } + }, + { + "pmid": "21987443", + "pubmed": { + "ISODate": "2011-12-01T00:00:00.000Z", + "abstract": "Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.", + "authors": { + "abbreviation": "Stefan Nagel, Björn Schneider, Andreas Rosenwald, ..., Roderick A F MacLeod", + "authorList": [ + { + "ForeName": "Stefan", + "LastName": "Nagel", + "abbrevName": "Nagel S", + "email": "sna@dsmz.de", + "isCollectiveName": false, + "name": "Stefan Nagel", + "orcid": null + }, + { + "ForeName": "Björn", + "LastName": "Schneider", + "abbrevName": "Schneider B", + "email": null, + "isCollectiveName": false, + "name": "Björn Schneider", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Rosenwald", + "abbrevName": "Rosenwald A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Rosenwald", + "orcid": null + }, + { + "ForeName": "Corinna", + "LastName": "Meyer", + "abbrevName": "Meyer C", + "email": null, + "isCollectiveName": false, + "name": "Corinna Meyer", + "orcid": null + }, + { + "ForeName": "Maren", + "LastName": "Kaufmann", + "abbrevName": "Kaufmann M", + "email": null, + "isCollectiveName": false, + "name": "Maren Kaufmann", + "orcid": null + }, + { + "ForeName": "Hans", + "LastName": "Drexler", + "abbrevName": "Drexler HG", + "email": null, + "isCollectiveName": false, + "name": "Hans G Drexler", + "orcid": null + }, + { + "ForeName": "Roderick", + "LastName": "MacLeod", + "abbrevName": "MacLeod RA", + "email": null, + "isCollectiveName": false, + "name": "Roderick A F MacLeod", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Stefan", + "LastName": "Nagel", + "email": [ + "sna@dsmz.de" + ], + "name": "Stefan Nagel" + } + ] + }, + "doi": "10.1002/gcc.20920", + "pmid": "21987443", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Genes Chromosomes Cancer 50 2011", + "title": "t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2." + } + }, + { + "pmid": "20509910", + "pubmed": { + "ISODate": "2010-05-28T00:00:00.000Z", + "abstract": "BACKGROUND: Zhx1 to 3 (zinc-fingers and homeoboxes) form a set of paralogous genes encoding multi-domain proteins. ZHX proteins consist of two zinc fingers followed by five homeodomains. ZHXs have biological roles in cell cycle control by acting as co-repressors of the transcriptional regulator Nuclear Factor Y. As part of a structural genomics project we have expressed single and multi-domain fragments of the different human ZHX genes for use in structure determination. RESULTS: A total of 30 single and multiple domain ZHX1-3 constructs selected from bioinformatics protocols were screened for soluble expression in E. coli using high throughput methodologies. Two homeodomains were crystallized leading to structures for ZHX1 HD4 and ZHX2 HD2. ZHX1 HD4, although closest matched to homeodomains from 'homez' and 'engrailed', showed structural differences, notably an additional C-terminal helix (helix V) which wrapped over helix I thereby making extensive contacts. Although ZHX2 HD2-3 was successfully expressed and purified, proteolysis occurred during crystallization yielding crystals of just HD2. The structure of ZHX2 HD2 showed an unusual open conformation with helix I undergoing 'domain-swapping' to form a homodimer. CONCLUSIONS: Although multiple-domain constructs of ZHX1 selected by bioinformatics studies could be expressed solubly, only single homeodomains yielded crystals. The crystal structure of ZHX1 HD4 showed additional hydrophobic interactions relative to many known homeodomains via extensive contacts formed by the novel C-terminal helix V with, in particular, helix I. Additionally, the replacement of some charged covariant residues (which are commonly observed to form salt bridges in non-homeotherms such as the Drosophila 'engrailed' homeodomain), by apolar residues further increases hydrophobic contacts within ZHX1 HD4, and potentially stability, relative to engrailed homeodomain. ZHX1 HD4 helix V points away from the normally observed DNA major groove binding site on homeodomains and thus would not obstruct the putative binding of nucleic acid. In contrast, for ZHX2 HD2 the observed altered conformation involving rearrangement of helix I, relative to the canonical homeodomain fold, disrupts the normal DNA binding site, although protein-protein binding is possible as observed in homodimer formation.", + "authors": { + "abbreviation": "Louise E Bird, Jingshan Ren, Joanne E Nettleship, ..., David K Stammers", + "authorList": [ + { + "ForeName": "Louise", + "LastName": "Bird", + "abbrevName": "Bird LE", + "email": null, + "isCollectiveName": false, + "name": "Louise E Bird", + "orcid": null + }, + { + "ForeName": "Jingshan", + "LastName": "Ren", + "abbrevName": "Ren J", + "email": null, + "isCollectiveName": false, + "name": "Jingshan Ren", + "orcid": null + }, + { + "ForeName": "Joanne", + "LastName": "Nettleship", + "abbrevName": "Nettleship JE", + "email": null, + "isCollectiveName": false, + "name": "Joanne E Nettleship", + "orcid": null + }, + { + "ForeName": "Gert", + "LastName": "Folkers", + "abbrevName": "Folkers GE", + "email": null, + "isCollectiveName": false, + "name": "Gert E Folkers", + "orcid": null + }, + { + "ForeName": "Raymond", + "LastName": "Owens", + "abbrevName": "Owens RJ", + "email": null, + "isCollectiveName": false, + "name": "Raymond J Owens", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Stammers", + "abbrevName": "Stammers DK", + "email": null, + "isCollectiveName": false, + "name": "David K Stammers", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1186/1472-6807-10-13", + "pmid": "20509910", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Struct Biol 10 2010", + "title": "Novel structural features in two ZHX homeodomains derived from a systematic study of single and multiple domains." + } + }, + { + "pmid": "20110278", + "pubmed": { + "ISODate": "2010-03-15T00:00:00.000Z", + "abstract": "MOTIVATION: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing web-based methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. RESULTS: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. AVAILABILITY AND IMPLEMENTATION: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at http://code.google.com/p/bedtools CONTACT: aaronquinlan@gmail.com; imh4y@virginia.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.", + "authors": { + "abbreviation": "Aaron R Quinlan, Ira M Hall", + "authorList": [ + { + "ForeName": "Aaron", + "LastName": "Quinlan", + "abbrevName": "Quinlan AR", + "email": "aaronquinlan@gmail.com", + "isCollectiveName": false, + "name": "Aaron R Quinlan", + "orcid": null + }, + { + "ForeName": "Ira", + "LastName": "Hall", + "abbrevName": "Hall IM", + "email": null, + "isCollectiveName": false, + "name": "Ira M Hall", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Aaron", + "LastName": "Quinlan", + "email": [ + "aaronquinlan@gmail.com" + ], + "name": "Aaron R Quinlan" + } + ] + }, + "doi": "10.1093/bioinformatics/btq033", + "pmid": "20110278", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Bioinformatics 26 2010", + "title": "BEDTools: a flexible suite of utilities for comparing genomic features." + } + }, + { + "pmid": "20020197", + "pubmed": { + "ISODate": "2010-10-01T00:00:00.000Z", + "abstract": "Validating prognostic or predictive candidate genes in appropriately powered breast cancer cohorts are of utmost interest. Our aim was to develop an online tool to draw survival plots, which can be used to assess the relevance of the expression levels of various genes on the clinical outcome both in untreated and treated breast cancer patients. A background database was established using gene expression data and survival information of 1,809 patients downloaded from GEO (Affymetrix HGU133A and HGU133+2 microarrays). The median relapse free survival is 6.43 years, 968/1,231 patients are estrogen-receptor (ER) positive, and 190/1,369 are lymph-node positive. After quality control and normalization only probes present on both Affymetrix platforms were retained (n = 22,277). In order to analyze the prognostic value of a particular gene, the cohorts are divided into two groups according to the median (or upper/lower quartile) expression of the gene. The two groups can be compared in terms of relapse free survival, overall survival, and distant metastasis free survival. A survival curve is displayed, and the hazard ratio with 95% confidence intervals and logrank P value are calculated and displayed. Additionally, three subgroups of patients can be assessed: systematically untreated patients, endocrine-treated ER positive patients, and patients with a distribution of clinical characteristics representative of those seen in general clinical practice in the US. Web address: www.kmplot.com . We used this integrative data analysis tool to confirm the prognostic power of the proliferation-related genes TOP2A and TOP2B, MKI67, CCND2, CCND3, CCNDE2, as well as CDKN1A, and TK2. We also validated the capability of microarrays to determine estrogen receptor status in 1,231 patients. The tool is highly valuable for the preliminary assessment of biomarkers, especially for research groups with limited bioinformatic resources.", + "authors": { + "abbreviation": "Balazs Györffy, Andras Lanczky, Aron C Eklund, ..., Zoltan Szallasi", + "authorList": [ + { + "ForeName": "Balazs", + "LastName": "Györffy", + "abbrevName": "Györffy B", + "email": "zsalab2@yahoo.com", + "isCollectiveName": false, + "name": "Balazs Györffy", + "orcid": null + }, + { + "ForeName": "Andras", + "LastName": "Lanczky", + "abbrevName": "Lanczky A", + "email": null, + "isCollectiveName": false, + "name": "Andras Lanczky", + "orcid": null + }, + { + "ForeName": "Aron", + "LastName": "Eklund", + "abbrevName": "Eklund AC", + "email": null, + "isCollectiveName": false, + "name": "Aron C Eklund", + "orcid": null + }, + { + "ForeName": "Carsten", + "LastName": "Denkert", + "abbrevName": "Denkert C", + "email": null, + "isCollectiveName": false, + "name": "Carsten Denkert", + "orcid": null + }, + { + "ForeName": "Jan", + "LastName": "Budczies", + "abbrevName": "Budczies J", + "email": null, + "isCollectiveName": false, + "name": "Jan Budczies", + "orcid": null + }, + { + "ForeName": "Qiyuan", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qiyuan Li", + "orcid": null + }, + { + "ForeName": "Zoltan", + "LastName": "Szallasi", + "abbrevName": "Szallasi Z", + "email": null, + "isCollectiveName": false, + "name": "Zoltan Szallasi", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Balazs", + "LastName": "Györffy", + "email": [ + "zsalab2@yahoo.com" + ], + "name": "Balazs Györffy" + } + ] + }, + "doi": "10.1007/s10549-009-0674-9", + "pmid": "20020197", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 123 2010", + "title": "An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients." + } + }, + { + "pmid": "19946328", + "pubmed": { + "ISODate": "2010-02-04T00:00:00.000Z", + "abstract": "Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.", + "authors": { + "abbreviation": "G L Semenza", + "authorList": [ + { + "ForeName": "G", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": "gsemenza@jhmi.edu", + "isCollectiveName": false, + "name": "G L Semenza", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Semenza", + "email": [ + "gsemenza@jhmi.edu" + ], + "name": "G L Semenza" + } + ] + }, + "doi": "10.1038/onc.2009.441", + "pmid": "19946328", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Oncogene 29 2010", + "title": "Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics." + } + }, + { + "pmid": "19840953", + "pubmed": { + "ISODate": "2010-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Patients with breast cancer brain metastasis are a heterogeneous group in relation to tumor biology and outcome. MATERIALS AND METHODS: The group of 222 breast cancer patients with brain metastasis was divided into three biological subgroups. The propensity of biological subtypes for metastases to the brain and survivals depending on biological subtype, recursive partitioning analysis of Radiation Therapy Oncology Group (RPA RTOG) prognostic class and the use of systemic treatment after whole-brain radiotherapy were assessed. RESULTS: The rate of patients with triple-negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal breast cancer with brain metastases was 28%, 53% and 19%, respectively. Median survival from brain metastases in triple-negative, HER2-positive and luminal subtype was 3.7, 9 and 15 months, respectively. Median survival from brain metastases in RPA RTOG prognostic class I, II and III was 15, 11 and 3 months, respectively. In the luminal and in the triple-negative subtype, systemic therapy prolonged survival from 3 to 14 months and from 3 to 4 months, respectively. In HER2-positive subtype, median survival without further treatment, after chemotherapy and after chemotherapy with targeted therapy were 3, 8 and 11 months, respectively. CONCLUSIONS: HER2-positive and triple-negative breast cancers have special predilection for metastases to the brain. Survival from brain metastases depended on performance status and the use of systemic treatment.", + "authors": { + "abbreviation": "A Niwińska, M Murawska, K Pogoda", + "authorList": [ + { + "ForeName": "A", + "LastName": "Niwińska", + "abbrevName": "Niwińska A", + "email": "alphaonetau@poczta.onet.pl", + "isCollectiveName": false, + "name": "A Niwińska", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Murawska", + "abbrevName": "Murawska M", + "email": null, + "isCollectiveName": false, + "name": "M Murawska", + "orcid": null + }, + { + "ForeName": "K", + "LastName": "Pogoda", + "abbrevName": "Pogoda K", + "email": null, + "isCollectiveName": false, + "name": "K Pogoda", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "A", + "LastName": "Niwińska", + "email": [ + "alphaonetau@poczta.onet.pl" + ], + "name": "A Niwińska" + } + ] + }, + "doi": "10.1093/annonc/mdp407", + "pmid": "19840953", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Ann Oncol 21 2010", + "title": "Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT)." + } + }, + { + "pmid": "19757835", + "pubmed": { + "ISODate": "2009-10-08T00:00:00.000Z", + "abstract": "The dynamic and energetic properties of the alkali and halide ions were calculated using molecular dynamics (MD) and free energy simulations with various different water and ion force fields including our recently developed water-model-specific ion parameters. The properties calculated were activity coefficients, diffusion coefficients, residence times of atomic pairs, association constants, and solubility. Through calculation of these properties, we can assess the validity and range of applicability of the simple pair potential models and better understand their limitations. Due to extreme computational demands, the activity coefficients were only calculated for a subset of the models. The results qualitatively agree with experiment. Calculated diffusion coefficients and residence times between cation-anion, water-cation, and water-anion showed differences depending on the choice of water and ion force field used. The calculated solubilities of the alkali-halide salts were generally lower than the true solubility of the salts. However, for both the TIP4P(EW) and SPC/E water-model-specific ion parameters, solubility was reasonably well-reproduced. Finally, the correlations among the various properties led to the following conclusions: (1) The reliability of the ion force fields is significantly affected by the specific choice of water model. (2) Ion-ion interactions are very important to accurately simulate the properties, especially solubility. (3) The SPC/E and TIP4P(EW) water-model-specific ion force fields are preferred for simulation in high salt environments compared to the other ion force fields.", + "authors": { + "abbreviation": "In Suk Joung, Thomas E Cheatham", + "authorList": [ + { + "ForeName": "In", + "LastName": "Joung", + "abbrevName": "Joung IS", + "email": null, + "isCollectiveName": false, + "name": "In Suk Joung", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Cheatham", + "abbrevName": "Cheatham TE", + "email": null, + "isCollectiveName": false, + "name": "Thomas E Cheatham", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1021/jp902584c", + "pmid": "19757835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Phys Chem B 113 2009", + "title": "Molecular dynamics simulations of the dynamic and energetic properties of alkali and halide ions using water-model-specific ion parameters." + } + }, + { + "pmid": "19643597", + "pubmed": { + "ISODate": "2009-11-01T00:00:00.000Z", + "abstract": "PURPOSE: Evaluation of the influence of immunohistochemically defined breast cancer (BC) subtypes and other risk factors on the development of cerebral metastases (CM). METHODS: Exploratory analysis of a hospital-based prospective tumour registry including all patients with primary BC treated in our EUSOMA breast unit between 1998 and 2006. RESULTS: The study cohort contained 2441 patients, including 284 patients (11.6%) with triple-negative (oestrogen receptor (ER), progesterone receptor (PR) and HER2-negative) and 245 patients (10.1%) with HER2-overexpressing BC subtypes. Overall, 80 patients (3.3%) developed CM within a median follow-up period of 47 months, 19 (23.8%) of them with triple-negative and 19 (23.8%) with HER2-positive tumours. Therefore, 6.7% of all patients with triple-negative and 7.8% of patients with HER2-positive breast cancer developed CM. Multivariate analysis indicated that the highest risk for CM was triple-negative breast cancer. Further independent risk factors were: HER2-overexpression, early onset BC (age<50 years), and large tumour size (pT3/4). Among those patients developing CM, triple-negative BC showed the shortest interval between primary diagnosis and occurrence of CM with a median of 22 months, compared to 30 and 63.5 months in HER2-positive and ER+/HER2- BC, respectively. Survival after occurrence of CM did not differ among the subtypes. CONCLUSION: Patients with triple-negative or HER2-positive BC have a higher risk for CM compared with patients bearing the ER+/HER2- phenotype and develop CM earlier in the course of disease. A risk profile for CM might help adjust surveillance in high risk populations and identify patients with a need for new treatment strategies.", + "authors": { + "abbreviation": "Florian Heitz, Philipp Harter, Hans-Joachim Lueck, ..., Andreas du Bois", + "authorList": [ + { + "ForeName": "Florian", + "LastName": "Heitz", + "abbrevName": "Heitz F", + "email": "florian.heitz@gmx.net", + "isCollectiveName": false, + "name": "Florian Heitz", + "orcid": null + }, + { + "ForeName": "Philipp", + "LastName": "Harter", + "abbrevName": "Harter P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Harter", + "orcid": null + }, + { + "ForeName": "Hans-Joachim", + "LastName": "Lueck", + "abbrevName": "Lueck HJ", + "email": null, + "isCollectiveName": false, + "name": "Hans-Joachim Lueck", + "orcid": null + }, + { + "ForeName": "Annette", + "LastName": "Fissler-Eckhoff", + "abbrevName": "Fissler-Eckhoff A", + "email": null, + "isCollectiveName": false, + "name": "Annette Fissler-Eckhoff", + "orcid": null + }, + { + "ForeName": "Fatemeh", + "LastName": "Lorenz-Salehi", + "abbrevName": "Lorenz-Salehi F", + "email": null, + "isCollectiveName": false, + "name": "Fatemeh Lorenz-Salehi", + "orcid": null + }, + { + "ForeName": "Stefanie", + "LastName": "Scheil-Bertram", + "abbrevName": "Scheil-Bertram S", + "email": null, + "isCollectiveName": false, + "name": "Stefanie Scheil-Bertram", + "orcid": null + }, + { + "ForeName": "Alexander", + "LastName": "Traut", + "abbrevName": "Traut A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Traut", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "du Bois", + "abbrevName": "du Bois A", + "email": null, + "isCollectiveName": false, + "name": "Andreas du Bois", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Florian", + "LastName": "Heitz", + "email": [ + "florian.heitz@gmx.net" + ], + "name": "Florian Heitz" + } + ] + }, + "doi": "10.1016/j.ejca.2009.06.027", + "pmid": "19643597", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Eur J Cancer 45 2009", + "title": "Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases." + } + }, + { + "pmid": "19596646", + "pubmed": { + "ISODate": "2009-06-01T00:00:00.000Z", + "abstract": "Of the estimated 1 million cases of breast cancer diagnosed annually worldwide, it is estimated that over 170,000 will harbor the triple-negative (estrogen receptor/progesterone receptor/HER2-negative) phenotype. Most, though not all, triple-negative breast cancers will be basal-like on gene expression micorarrays. The basal-like molecular subtype exhibits a unique molecular profile and set of risk factors, aggressive and early pattern of metastasis, limited treatment options, and poor prognosis. Large population-based studies have identified a higher proportion of triple-negative breast tumors among premenopausal African American women, and a suggestion that increased parity, younger age at first-term pregnancy, shorter duration of breast feeding, and elevated hip-to-waist ratio might be particular risk factors. When BRCA1 mutation carriers develop breast cancer, it is usually basal-like; given the central role of BRCA1 in DNA repair, this could have profound therapeutic implications. When diagnosed, triple-negative breast cancers illustrate preferential relapse in visceral organs, including the central nervous system. Although initial response to chemotherapy might be more profound, relapse is early and common among triple-negative breast cancers compared with luminal breast cancers. The armamentarium of \"targeted therapeutics\" for triple-negative breast cancer is evolving and includes strategies to inhibit angiogenesis, epidermal growth factor receptor, and other kinases. Finally, the positive association between triple-negative breast cancer and BRCA mutations makes inhibition of poly(adenosine diphosphate-ribose) polymerase-1 an attractive therapeutic strategy that is in active study.", + "authors": { + "abbreviation": "Carey K Anders, Lisa A Carey", + "authorList": [ + { + "ForeName": "Carey", + "LastName": "Anders", + "abbrevName": "Anders CK", + "email": null, + "isCollectiveName": false, + "name": "Carey K Anders", + "orcid": null + }, + { + "ForeName": "Lisa", + "LastName": "Carey", + "abbrevName": "Carey LA", + "email": null, + "isCollectiveName": false, + "name": "Lisa A Carey", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3816/CBC.2009.s.008", + "pmid": "19596646", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Breast Cancer 9 Suppl 2 2009", + "title": "Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer." + } + }, + { + "pmid": "19033387", + "pubmed": { + "ISODate": "2008-12-15T00:00:00.000Z", + "abstract": "The ADP-ribosylation factor 6 (Arf6) GTPase functions as a key regulator of endocytic trafficking, participating in clathrin-independent endocytosis in most cell types. Unexpectedly, we found that siRNA-mediated depletion of clathrin or of adaptor protein 2 (AP-2)-complex subunits alters trafficking of Arf6 pathway cargo proteins, such as major histocompatibility complex class I (MHCI) and beta1 integrin. Internalization of these cargoes from the plasma membrane was not affected in cells depleted of clathrin, but was modestly delayed in cells lacking AP-2. Furthermore, depletion of clathrin or AP-2 altered the intracellular distribution of MHCI and beta1 integrin, inducing clustering in a perinuclear region. Despite this altered localization in both depleted populations, enhanced lysosomal targeting of MHCI was observed uniquely in cells that lack AP-2. Total levels of MHCI were modestly but consistently reduced in AP-2-depleted cells, and restored by the lysosomal inhibitor bafilomycin A. Furthermore, the half-life of surface-derived MHCI was reduced in AP-2-depleted cells. Consistent with enhanced degradative sorting, colocalization of Arf6 cargo with the late endosome and lysosome markers CD63 and Lamp1 was increased in cells depleted of AP-2 but not clathrin. These studies indicate a role for AP-2 in maintaining normal post-endocytic trafficking through the Arf6-regulated, non-clathrin pathway, and reveal pervasive effects of clathrin and AP-2 depletion on the endosomal and lysosomal system.", + "authors": { + "abbreviation": "Alan W Lau, Margaret M Chou", + "authorList": [ + { + "ForeName": "Alan", + "LastName": "Lau", + "abbrevName": "Lau AW", + "email": null, + "isCollectiveName": false, + "name": "Alan W Lau", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Chou", + "abbrevName": "Chou MM", + "email": null, + "isCollectiveName": false, + "name": "Margaret M Chou", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.033522", + "pmid": "19033387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Sci 121 2008", + "title": "The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway." + } + }, + { + "pmid": "18833576", + "pubmed": { + "ISODate": "2008-11-15T00:00:00.000Z", + "abstract": "BACKGROUND: The purpose of the current study was to characterize the outcomes of patients with metastatic triple-negative breast cancers, including the risk and clinical consequences of central nervous system (CNS) recurrence. METHODS: Using pharmacy and pathology records, a study group of 116 patients who were treated for metastatic triple-negative breast cancer at Dana-Farber Cancer Institute between January 2000 and June 2006 was identified. RESULTS: The median survival from time of metastatic diagnosis was 13.3 months. Sixteen patients (14%) were diagnosed with CNS involvement at the time of initial metastatic diagnosis; overall, 46% of patients were diagnosed with CNS metastases before death. The median survival after a diagnosis of CNS metastasis was 4.9 months. The age-adjusted and race-adjusted rate of death for patients whose first presentation included a CNS metastasis was 3.4 times (95% confidence interval, 1.9-6.1 times) that of patients without a CNS lesion at the time of first metastatic presentation. Of the 53 patients who developed brain metastases, only 3 patients were judged to have stable or responsive systemic disease in the face of progressive CNS disease at the last follow-up before death. CONCLUSIONS: Triple-negative breast cancer is associated with poor survival after recurrence. CNS recurrence is common, but death as a direct consequence of CNS progression in the setting of controlled systemic disease is uncommon. Thus, it does not appear that the high rate of CNS involvement is because of a sanctuary effect, but rather is due to the lack of effective therapies in general for this aggressive subtype of breast cancer. New treatment strategies are needed.", + "authors": { + "abbreviation": "Nancy U Lin, Elizabeth Claus, Jessica Sohl, ..., Eric P Winer", + "authorList": [ + { + "ForeName": "Nancy", + "LastName": "Lin", + "abbrevName": "Lin NU", + "email": "nlin@partners.org", + "isCollectiveName": false, + "name": "Nancy U Lin", + "orcid": null + }, + { + "ForeName": "Elizabeth", + "LastName": "Claus", + "abbrevName": "Claus E", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth Claus", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Sohl", + "abbrevName": "Sohl J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Sohl", + "orcid": null + }, + { + "ForeName": "Abdul", + "LastName": "Razzak", + "abbrevName": "Razzak AR", + "email": null, + "isCollectiveName": false, + "name": "Abdul R Razzak", + "orcid": null + }, + { + "ForeName": "Amal", + "LastName": "Arnaout", + "abbrevName": "Arnaout A", + "email": null, + "isCollectiveName": false, + "name": "Amal Arnaout", + "orcid": null + }, + { + "ForeName": "Eric", + "LastName": "Winer", + "abbrevName": "Winer EP", + "email": null, + "isCollectiveName": false, + "name": "Eric P Winer", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Nancy", + "LastName": "Lin", + "email": [ + "nlin@partners.org" + ], + "name": "Nancy U Lin" + } + ] + }, + "doi": "10.1002/cncr.23930", + "pmid": "18833576", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer 113 2008", + "title": "Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases." + } + }, + { + "pmid": "18798982", + "pubmed": { + "ISODate": "2008-01-01T00:00:00.000Z", + "abstract": "We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.", + "authors": { + "abbreviation": "Yong Zhang, Tao Liu, Clifford A Meyer, ..., X Shirley Liu", + "authorList": [ + { + "ForeName": "Yong", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Zhang", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Liu", + "abbrevName": "Liu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Liu", + "orcid": null + }, + { + "ForeName": "Clifford", + "LastName": "Meyer", + "abbrevName": "Meyer CA", + "email": null, + "isCollectiveName": false, + "name": "Clifford A Meyer", + "orcid": null + }, + { + "ForeName": "Jérôme", + "LastName": "Eeckhoute", + "abbrevName": "Eeckhoute J", + "email": null, + "isCollectiveName": false, + "name": "Jérôme Eeckhoute", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Johnson", + "abbrevName": "Johnson DS", + "email": null, + "isCollectiveName": false, + "name": "David S Johnson", + "orcid": null + }, + { + "ForeName": "Bradley", + "LastName": "Bernstein", + "abbrevName": "Bernstein BE", + "email": null, + "isCollectiveName": false, + "name": "Bradley E Bernstein", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Nusbaum", + "abbrevName": "Nusbaum C", + "email": null, + "isCollectiveName": false, + "name": "Chad Nusbaum", + "orcid": null + }, + { + "ForeName": "Richard", + "LastName": "Myers", + "abbrevName": "Myers RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Myers", + "orcid": null + }, + { + "ForeName": "Myles", + "LastName": "Brown", + "abbrevName": "Brown M", + "email": null, + "isCollectiveName": false, + "name": "Myles Brown", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Li", + "abbrevName": "Li W", + "email": null, + "isCollectiveName": false, + "name": "Wei Li", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XS", + "email": null, + "isCollectiveName": false, + "name": "X Shirley Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1186/gb-2008-9-9-r137", + "pmid": "18798982", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genome Biol 9 2008", + "title": "Model-based analysis of ChIP-Seq (MACS)." + } + }, + { + "pmid": "18353163", + "pubmed": { + "ISODate": "2008-04-01T00:00:00.000Z", + "abstract": "RAN, ZHX2 and RCBTB2 (CHC1L) expression was evaluated by quantitative real time reverse transcription polymerase chain reaction in plasma cells from 85 monoclonal gammopathies: 58 symptomatic multiple myeloma (MM) (52 untreated, six relapsed), eight smouldering MM, five monoclonal gammopathy of undetermined significance, four plasma cell leukaemias and 10 myeloid cell lines. ZHX2 was weakly expressed in high-risk/proliferative disease compared to low-risk or indolent disease. High ZHX2 expression was associated with better response and longer survival after high-dose therapy. RCBTB2 expression was weaker in hyperdiploid versus non-hyperdiploid cases while RAN was more expressed in symptomatic MM and cell lines.", + "authors": { + "abbreviation": "A Armellini, M E Sarasquete, R García-Sanz, ..., J F San Miguel", + "authorList": [ + { + "ForeName": "A", + "LastName": "Armellini", + "abbrevName": "Armellini A", + "email": null, + "isCollectiveName": false, + "name": "A Armellini", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Sarasquete", + "abbrevName": "Sarasquete ME", + "email": null, + "isCollectiveName": false, + "name": "M E Sarasquete", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "García-Sanz", + "abbrevName": "García-Sanz R", + "email": null, + "isCollectiveName": false, + "name": "R García-Sanz", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Chillón", + "abbrevName": "Chillón MC", + "email": null, + "isCollectiveName": false, + "name": "M C Chillón", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Balanzategui", + "abbrevName": "Balanzategui A", + "email": null, + "isCollectiveName": false, + "name": "A Balanzategui", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Alcoceba", + "abbrevName": "Alcoceba M", + "email": null, + "isCollectiveName": false, + "name": "M Alcoceba", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Fuertes", + "abbrevName": "Fuertes M", + "email": null, + "isCollectiveName": false, + "name": "M Fuertes", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "López", + "abbrevName": "López R", + "email": null, + "isCollectiveName": false, + "name": "R López", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Hernández", + "abbrevName": "Hernández JM", + "email": null, + "isCollectiveName": false, + "name": "J M Hernández", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Fernández-Calvo", + "abbrevName": "Fernández-Calvo J", + "email": null, + "isCollectiveName": false, + "name": "J Fernández-Calvo", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Sierra", + "abbrevName": "Sierra M", + "email": null, + "isCollectiveName": false, + "name": "M Sierra", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Megido", + "abbrevName": "Megido M", + "email": null, + "isCollectiveName": false, + "name": "M Megido", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Orfão", + "abbrevName": "Orfão A", + "email": null, + "isCollectiveName": false, + "name": "A Orfão", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez NC", + "email": null, + "isCollectiveName": false, + "name": "N C Gutiérrez", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "González", + "abbrevName": "González M", + "email": null, + "isCollectiveName": false, + "name": "M González", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "San Miguel", + "abbrevName": "San Miguel JF", + "email": null, + "isCollectiveName": false, + "name": "J F San Miguel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2141.2007.06956.x", + "pmid": "18353163", + "pubTypes": [ + { + "UI": "D016430", + "value": "Clinical Trial" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Haematol 141 2008", + "title": "Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma." + } + }, + { + "pmid": "17908964", + "pubmed": { + "ISODate": "2007-10-01T00:00:00.000Z", + "abstract": "PURPOSE: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers. EXPERIMENTAL DESIGN: To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24. RESULTS: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA-mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed. CONCLUSIONS: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.", + "authors": { + "abbreviation": "Yinghui Guan, Wen-Lin Kuo, Jackie L Stilwell, ..., Joe W Gray", + "authorList": [ + { + "ForeName": "Yinghui", + "LastName": "Guan", + "abbrevName": "Guan Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghui Guan", + "orcid": null + }, + { + "ForeName": "Wen-Lin", + "LastName": "Kuo", + "abbrevName": "Kuo WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-Lin Kuo", + "orcid": null + }, + { + "ForeName": "Jackie", + "LastName": "Stilwell", + "abbrevName": "Stilwell JL", + "email": null, + "isCollectiveName": false, + "name": "Jackie L Stilwell", + "orcid": null + }, + { + "ForeName": "Hirokuni", + "LastName": "Takano", + "abbrevName": "Takano H", + "email": null, + "isCollectiveName": false, + "name": "Hirokuni Takano", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Lapuk", + "abbrevName": "Lapuk AV", + "email": null, + "isCollectiveName": false, + "name": "Anna V Lapuk", + "orcid": null + }, + { + "ForeName": "Jane", + "LastName": "Fridlyand", + "abbrevName": "Fridlyand J", + "email": null, + "isCollectiveName": false, + "name": "Jane Fridlyand", + "orcid": null + }, + { + "ForeName": "Jian-Hua", + "LastName": "Mao", + "abbrevName": "Mao JH", + "email": null, + "isCollectiveName": false, + "name": "Jian-Hua Mao", + "orcid": null + }, + { + "ForeName": "Mamie", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Mamie Yu", + "orcid": null + }, + { + "ForeName": "Melinda", + "LastName": "Miller", + "abbrevName": "Miller MA", + "email": null, + "isCollectiveName": false, + "name": "Melinda A Miller", + "orcid": null + }, + { + "ForeName": "Jennifer", + "LastName": "Santos", + "abbrevName": "Santos JL", + "email": null, + "isCollectiveName": false, + "name": "Jennifer L Santos", + "orcid": null + }, + { + "ForeName": "Steve", + "LastName": "Kalloger", + "abbrevName": "Kalloger SE", + "email": null, + "isCollectiveName": false, + "name": "Steve E Kalloger", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Carlson", + "abbrevName": "Carlson JW", + "email": null, + "isCollectiveName": false, + "name": "Joseph W Carlson", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Ginzinger", + "abbrevName": "Ginzinger DG", + "email": null, + "isCollectiveName": false, + "name": "David G Ginzinger", + "orcid": null + }, + { + "ForeName": "Susan", + "LastName": "Celniker", + "abbrevName": "Celniker SE", + "email": null, + "isCollectiveName": false, + "name": "Susan E Celniker", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Mills", + "abbrevName": "Mills GB", + "email": null, + "isCollectiveName": false, + "name": "Gordon B Mills", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Huntsman", + "abbrevName": "Huntsman DG", + "email": null, + "isCollectiveName": false, + "name": "David G Huntsman", + "orcid": null + }, + { + "ForeName": "Joe", + "LastName": "Gray", + "abbrevName": "Gray JW", + "email": null, + "isCollectiveName": false, + "name": "Joe W Gray", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/1078-0432.CCR-06-2882", + "pmid": "17908964", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Clin Cancer Res 13 2007", + "title": "Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer." + } + }, + { + "pmid": "17488841", + "pubmed": { + "ISODate": "2007-07-01T00:00:00.000Z", + "abstract": "Real-world observable physical and chemical characteristics are increasingly being calculated from the 3D structures of biomolecules. Methods for calculating pK(a) values, binding constants of ligands, and changes in protein stability are readily available, but often the limiting step in computational biology is the conversion of PDB structures into formats ready for use with biomolecular simulation software. The continued sophistication and integration of biomolecular simulation methods for systems- and genome-wide studies requires a fast, robust, physically realistic and standardized protocol for preparing macromolecular structures for biophysical algorithms. As described previously, the PDB2PQR web server addresses this need for electrostatic field calculations (Dolinsky et al., Nucleic Acids Research, 32, W665-W667, 2004). Here we report the significantly expanded PDB2PQR that includes the following features: robust standalone command line support, improved pK(a) estimation via the PROPKA framework, ligand parameterization via PEOE_PB charge methodology, expanded set of force fields and easily incorporated user-defined parameters via XML input files, and improvement of atom addition and optimization code. These features are available through a new web interface (http://pdb2pqr.sourceforge.net/), which offers users a wide range of options for PDB file conversion, modification and parameterization.", + "authors": { + "abbreviation": "Todd J Dolinsky, Paul Czodrowski, Hui Li, ..., Nathan A Baker", + "authorList": [ + { + "ForeName": "Todd", + "LastName": "Dolinsky", + "abbrevName": "Dolinsky TJ", + "email": null, + "isCollectiveName": false, + "name": "Todd J Dolinsky", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Czodrowski", + "abbrevName": "Czodrowski P", + "email": null, + "isCollectiveName": false, + "name": "Paul Czodrowski", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Hui Li", + "orcid": null + }, + { + "ForeName": "Jens", + "LastName": "Nielsen", + "abbrevName": "Nielsen JE", + "email": null, + "isCollectiveName": false, + "name": "Jens E Nielsen", + "orcid": null + }, + { + "ForeName": "Jan", + "LastName": "Jensen", + "abbrevName": "Jensen JH", + "email": null, + "isCollectiveName": false, + "name": "Jan H Jensen", + "orcid": null + }, + { + "ForeName": "Gerhard", + "LastName": "Klebe", + "abbrevName": "Klebe G", + "email": null, + "isCollectiveName": false, + "name": "Gerhard Klebe", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Baker", + "abbrevName": "Baker NA", + "email": null, + "isCollectiveName": false, + "name": "Nathan A Baker", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1093/nar/gkm276", + "pmid": "17488841", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Nucleic Acids Res 35 2007", + "title": "PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations." + } + }, + { + "pmid": "17447851", + "pubmed": { + "ISODate": "2007-01-01T00:00:00.000Z", + "abstract": "Zinc-fingers and homeoboxes 2 (ZHX2) is a novel transcriptional repressor. ZHX2 protein expression and its clinicopathological significance in hepatocellular carcinoma (HCC) remain largely unknown. The aim of this study was to analyze ZHX2 protein expression in a range of liver tissues obtained from cholangitis, cirrhosis, adjacent non-tumorous tissues, primary HCC tissues, and matched metastatic lesions by using Tissue microarray (TMA) technology and compare our findings with clinicopathological parameters. ZHX2 protein expression was detected only in HCC tissues. ZHX2 expression was associated with clinical stage of the disease. The rate of ZHX2 expression was approximately twice as high in stage III-IV (31.25%) compared with stage I-II (16.5%). These results demonstrated that ZHX2 protein may take part in hepatocellular carcinogenesis and HCC progression. In addition, ZHX2 expression in primary lesions with metastasis was significantly higher than without metastasis. ZHX2 expression in metastatic lesions (45.5%) was as approximately twice as higher than that in primary lesions (24.2%) from the same patient. According to these results, ZHX2 was associated with metastasis in HCC.", + "authors": { + "abbreviation": "S Hu, M Zhang, Z Lv, ..., J Wen", + "authorList": [ + { + "ForeName": "S", + "LastName": "Hu", + "abbrevName": "Hu S", + "email": null, + "isCollectiveName": false, + "name": "S Hu", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "M Zhang", + "orcid": null + }, + { + "ForeName": "Z", + "LastName": "Lv", + "abbrevName": "Lv Z", + "email": null, + "isCollectiveName": false, + "name": "Z Lv", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bi", + "abbrevName": "Bi J", + "email": null, + "isCollectiveName": false, + "name": "J Bi", + "orcid": null + }, + { + "ForeName": "Y", + "LastName": "Dong", + "abbrevName": "Dong Y", + "email": null, + "isCollectiveName": false, + "name": "Y Dong", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Wen", + "abbrevName": "Wen J", + "email": null, + "isCollectiveName": false, + "name": "J Wen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "17447851", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Neoplasma 54 2007", + "title": "Expression of zinc-fingers and homeoboxes 2 in hepatocellular carcinogenesis: a tissue microarray and clinicopathological analysis." + } + }, + { + "pmid": "15626755", + "pubmed": { + "ISODate": "2005-01-11T00:00:00.000Z", + "abstract": "The alpha-fetoprotein (AFP) and H19 genes are transcribed at high levels in the mammalian fetal liver but are rapidly repressed postnatally. This repression in the liver is controlled, at least in part, by the Afr1 gene. Afr1 was defined >25 years ago when BALB/cJ mice were found to have 5- to 20-fold higher adult serum AFP levels compared with all other mouse strains; subsequent studies showed that this elevation was due to higher Afp expression in the liver. H19, which has become a model for genomic imprinting, was identified initially in a screen for Afr1-regulated genes. The BALB/cJ allele (Afr1(b)) is recessive to the wild-type allele (Afr1(a)), consistent with the idea that Afr1 functions as a repressor. By high-resolution mapping, we identified a gene that maps to the Afr1 interval on chromosome 15 and encodes a putative zinc fingers and homeoboxes (ZHX) protein. In BALB/cJ mice, this gene contains a murine endogenous retrovirus within its first intron and produces predominantly an aberrant transcript that no longer encodes a functional protein. Liver-specific overexpression of a Zhx2 transgene restores wild-type H19 repression on a BALB/cJ background, confirming that this gene is responsible for hereditary persistence of Afp and H19 in the livers of BALB/cJ mice. Thus we have identified a genetically defined transcription factor that is involved in developmental gene silencing in mammals. We present a model to explain the liver-specific phenotype in BALB/cJ mice, even though Afr1 is a ubiquitously expressed gene.", + "authors": { + "abbreviation": "Sudhir Perincheri, R W Cameron Dingle, Martha L Peterson, Brett T Spear", + "authorList": [ + { + "ForeName": "Sudhir", + "LastName": "Perincheri", + "abbrevName": "Perincheri S", + "email": null, + "isCollectiveName": false, + "name": "Sudhir Perincheri", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Dingle", + "abbrevName": "Dingle RW", + "email": null, + "isCollectiveName": false, + "name": "R W Cameron Dingle", + "orcid": null + }, + { + "ForeName": "Martha", + "LastName": "Peterson", + "abbrevName": "Peterson ML", + "email": null, + "isCollectiveName": false, + "name": "Martha L Peterson", + "orcid": null + }, + { + "ForeName": "Brett", + "LastName": "Spear", + "abbrevName": "Spear BT", + "email": null, + "isCollectiveName": false, + "name": "Brett T Spear", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0408555102", + "pmid": "15626755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 102 2005", + "title": "Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene." + } + }, + { + "pmid": "15247232", + "pubmed": { + "ISODate": "2004-09-10T00:00:00.000Z", + "abstract": "Hypoxia-inducible factor (HIF) is a transcriptional regulator that plays a key role in many aspects of oxygen homeostasis. The heterodimeric HIF complex is regulated by proteolysis of its alpha-subunits, following oxygen-dependent hydroxylation of specific prolyl residues. Although three HIF prolyl hydroxylases, PHD1, PHD2, and PHD3, have been identified that have the potential to catalyze this reaction, the contribution of each isoform to the physiological regulation of HIF remains uncertain. Here we show using suppression by small interference RNA that each of the three PHD isoforms contributes in a non-redundant manner to the regulation of both HIF-1alpha and HIF-2alpha subunits and that the contribution of each PHD under particular culture conditions is strongly dependent on the abundance of the enzyme. Thus in different cell types, isoform-specific patterns of PHD induction by hypoxia and estrogen alter both the relative abundance of the PHDs and their relative contribution to the regulation of HIF. In addition, the PHDs manifest specificity for different prolyl hydroxylation sites within each HIF-alpha subunit, and a degree of selectively between HIF-1alpha and HIF-2alpha isoforms, indicating that differential PHD inhibition has the potential to selectively alter the characteristics of HIF activation.", + "authors": { + "abbreviation": "Rebecca J Appelhoff, Ya-Min Tian, Raju R Raval, ..., Jonathan M Gleadle", + "authorList": [ + { + "ForeName": "Rebecca", + "LastName": "Appelhoff", + "abbrevName": "Appelhoff RJ", + "email": null, + "isCollectiveName": false, + "name": "Rebecca J Appelhoff", + "orcid": null + }, + { + "ForeName": "Ya-Min", + "LastName": "Tian", + "abbrevName": "Tian YM", + "email": null, + "isCollectiveName": false, + "name": "Ya-Min Tian", + "orcid": null + }, + { + "ForeName": "Raju", + "LastName": "Raval", + "abbrevName": "Raval RR", + "email": null, + "isCollectiveName": false, + "name": "Raju R Raval", + "orcid": null + }, + { + "ForeName": "Helen", + "LastName": "Turley", + "abbrevName": "Turley H", + "email": null, + "isCollectiveName": false, + "name": "Helen Turley", + "orcid": null + }, + { + "ForeName": "Adrian", + "LastName": "Harris", + "abbrevName": "Harris AL", + "email": null, + "isCollectiveName": false, + "name": "Adrian L Harris", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Pugh", + "abbrevName": "Pugh CW", + "email": null, + "isCollectiveName": false, + "name": "Christopher W Pugh", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Ratcliffe", + "abbrevName": "Ratcliffe PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Ratcliffe", + "orcid": null + }, + { + "ForeName": "Jonathan", + "LastName": "Gleadle", + "abbrevName": "Gleadle JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gleadle", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M406026200", + "pmid": "15247232", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor." + } + }, + { + "pmid": "15170446", + "pubmed": { + "ISODate": "2004-06-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "J Martin Brown, William R Wilson", + "authorList": [ + { + "ForeName": "J", + "LastName": "Brown", + "abbrevName": "Brown JM", + "email": "mbrown@stanford.edu", + "isCollectiveName": false, + "name": "J Martin Brown", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Wilson", + "abbrevName": "Wilson WR", + "email": null, + "isCollectiveName": false, + "name": "William R Wilson", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "J", + "LastName": "Brown", + "email": [ + "mbrown@stanford.edu" + ], + "name": "J Martin Brown" + } + ] + }, + "doi": "10.1038/nrc1367", + "pmid": "15170446", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Cancer 4 2004", + "title": "Exploiting tumour hypoxia in cancer treatment." + } + }, + { + "pmid": "13106296", + "pubmed": { + "ISODate": "1953-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "L H GRAY, A D CONGER, M EBERT, ..., O C SCOTT", + "authorList": [ + { + "ForeName": "L", + "LastName": "GRAY", + "abbrevName": "GRAY LH", + "email": null, + "isCollectiveName": false, + "name": "L H GRAY", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "CONGER", + "abbrevName": "CONGER AD", + "email": null, + "isCollectiveName": false, + "name": "A D CONGER", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "EBERT", + "abbrevName": "EBERT M", + "email": null, + "isCollectiveName": false, + "name": "M EBERT", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "HORNSEY", + "abbrevName": "HORNSEY S", + "email": null, + "isCollectiveName": false, + "name": "S HORNSEY", + "orcid": null + }, + { + "ForeName": "O", + "LastName": "SCOTT", + "abbrevName": "SCOTT OC", + "email": null, + "isCollectiveName": false, + "name": "O C SCOTT", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1259/0007-1285-26-312-638", + "pmid": "13106296", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Br J Radiol 26 1953", + "title": "The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy." + } + }, + { + "pmid": "12741956", + "pubmed": { + "ISODate": "2003-08-01T00:00:00.000Z", + "abstract": "Zinc-fingers and homeoboxes (ZHX) 1 is a transcription factor that interacts with the activation domain of the A subunit of nuclear factor-Y (NF-YA). Using a yeast two-hybrid system, a novel ubiquitous transcription factor ZHX2 as a ZHX1-interacting protein was cloned. ZHX2 consists of 837 amino acid residues and contains two zinc-finger motifs and five homeodomains (HDs) as well as ZHX1. The mRNA is expressed among various tissues. ZHX2 not only forms a heterodimer with ZHX1, but also forms a homodimer. Moreover, ZHX2 interacts with the activation domain of NF-YA. Further analysis revealed that ZHX2 is a transcriptional repressor that is localized in the nuclei. Since ZHX2 shares a number of properties in common with ZHX1, we conclude that all these come under the ZHX family. The minimal functional domains of ZHX2 were then characterized. The dimerization domain with both ZHX1 and ZHX2 is the region containing HD1, the domain that interacts with NF-YA is the HD1 to HD2 region, the repressor domain is the HD1 to a proline-rich region. Lastly, using an immunoprecipitation assay, we showed that ZHX2 intrinsically interacts with NF-YA in HEK-293 cells and that ZHX2 represses the promoter activity of the cdc25C gene stimulated by NF-Y in Drosophila Schneider line 2 cells. Thus the ZHX family of proteins may participate in the expression of a number of NF-Y-regulated genes via a more organized transcription network.", + "authors": { + "abbreviation": "Hiroko Kawata, Kazuya Yamada, Zhangfei Shou, ..., Kaoru Miyamoto", + "authorList": [ + { + "ForeName": "Hiroko", + "LastName": "Kawata", + "abbrevName": "Kawata H", + "email": null, + "isCollectiveName": false, + "name": "Hiroko Kawata", + "orcid": null + }, + { + "ForeName": "Kazuya", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kazuya Yamada", + "orcid": null + }, + { + "ForeName": "Zhangfei", + "LastName": "Shou", + "abbrevName": "Shou Z", + "email": null, + "isCollectiveName": false, + "name": "Zhangfei Shou", + "orcid": null + }, + { + "ForeName": "Tetsuya", + "LastName": "Mizutani", + "abbrevName": "Mizutani T", + "email": null, + "isCollectiveName": false, + "name": "Tetsuya Mizutani", + "orcid": null + }, + { + "ForeName": "Takashi", + "LastName": "Yazawa", + "abbrevName": "Yazawa T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Yazawa", + "orcid": null + }, + { + "ForeName": "Miki", + "LastName": "Yoshino", + "abbrevName": "Yoshino M", + "email": null, + "isCollectiveName": false, + "name": "Miki Yoshino", + "orcid": null + }, + { + "ForeName": "Toshio", + "LastName": "Sekiguchi", + "abbrevName": "Sekiguchi T", + "email": null, + "isCollectiveName": false, + "name": "Toshio Sekiguchi", + "orcid": null + }, + { + "ForeName": "Takashi", + "LastName": "Kajitani", + "abbrevName": "Kajitani T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Kajitani", + "orcid": null + }, + { + "ForeName": "Kaoru", + "LastName": "Miyamoto", + "abbrevName": "Miyamoto K", + "email": null, + "isCollectiveName": false, + "name": "Kaoru Miyamoto", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1042/BJ20030171", + "pmid": "12741956", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 373 2003", + "title": "Zinc-fingers and homeoboxes (ZHX) 2, a novel member of the ZHX family, functions as a transcriptional repressor." + } + }, + { + "pmid": "11583619", + "pubmed": { + "ISODate": "2001-09-01T00:00:00.000Z", + "abstract": "Two crystal structures of Oct-1 POU domain bound to DNA provide a rationale for differential, conformation-dependent recruitment of transcription cofactors. The POU-homeo and POU-specific subdomains of Oct-1 contain two different nonoverlapping pairs of surface patches that are capable of forming unrelated protein-protein interfaces. Members of the POU factor family contain one or two conserved sequence motifs in the interface that are known to be phosphorylated, as noted for Oct-1 and Pit-1. Modeling of Oct-4 reveals the unique case where the same conserved sequence is located in both interfaces. Our studies provide the basis for two distinct dimeric POU factor arrangements that are dictated by the architecture of each DNA response element. We suggest interface swapping in dimers could be a general mechanism of modulating the activity of transcription factors.", + "authors": { + "abbreviation": "A Reményi, A Tomilin, E Pohl, ..., M Wilmanns", + "authorList": [ + { + "ForeName": "A", + "LastName": "Reményi", + "abbrevName": "Reményi A", + "email": null, + "isCollectiveName": false, + "name": "A Reményi", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Tomilin", + "abbrevName": "Tomilin A", + "email": null, + "isCollectiveName": false, + "name": "A Tomilin", + "orcid": null + }, + { + "ForeName": "E", + "LastName": "Pohl", + "abbrevName": "Pohl E", + "email": null, + "isCollectiveName": false, + "name": "E Pohl", + "orcid": null + }, + { + "ForeName": "K", + "LastName": "Lins", + "abbrevName": "Lins K", + "email": null, + "isCollectiveName": false, + "name": "K Lins", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Philippsen", + "abbrevName": "Philippsen A", + "email": null, + "isCollectiveName": false, + "name": "A Philippsen", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Reinbold", + "abbrevName": "Reinbold R", + "email": null, + "isCollectiveName": false, + "name": "R Reinbold", + "orcid": null + }, + { + "ForeName": "H", + "LastName": "Schöler", + "abbrevName": "Schöler HR", + "email": null, + "isCollectiveName": false, + "name": "H R Schöler", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Wilmanns", + "abbrevName": "Wilmanns M", + "email": null, + "isCollectiveName": false, + "name": "M Wilmanns", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/s1097-2765(01)00336-7", + "pmid": "11583619", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 8 2001", + "title": "Differential dimer activities of the transcription factor Oct-1 by DNA-induced interface swapping." + } + }, + { + "pmid": "11292862", + "pubmed": { + "ISODate": "2001-04-20T00:00:00.000Z", + "abstract": "HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.", + "authors": { + "abbreviation": "M Ivan, K Kondo, H Yang, ..., W G Kaelin", + "authorList": [ + { + "ForeName": "M", + "LastName": "Ivan", + "abbrevName": "Ivan M", + "email": null, + "isCollectiveName": false, + "name": "M Ivan", + "orcid": null + }, + { + "ForeName": "K", + "LastName": "Kondo", + "abbrevName": "Kondo K", + "email": null, + "isCollectiveName": false, + "name": "K Kondo", + "orcid": null + }, + { + "ForeName": "H", + "LastName": "Yang", + "abbrevName": "Yang H", + "email": null, + "isCollectiveName": false, + "name": "H Yang", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Kim", + "abbrevName": "Kim W", + "email": null, + "isCollectiveName": false, + "name": "W Kim", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Valiando", + "abbrevName": "Valiando J", + "email": null, + "isCollectiveName": false, + "name": "J Valiando", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Ohh", + "abbrevName": "Ohh M", + "email": null, + "isCollectiveName": false, + "name": "M Ohh", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Salic", + "abbrevName": "Salic A", + "email": null, + "isCollectiveName": false, + "name": "A Salic", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Asara", + "abbrevName": "Asara JM", + "email": null, + "isCollectiveName": false, + "name": "J M Asara", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lane", + "abbrevName": "Lane WS", + "email": null, + "isCollectiveName": false, + "name": "W S Lane", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "W G Kaelin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1059817", + "pmid": "11292862", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Science 292 2001", + "title": "HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing." + } + }, + { + "pmid": "11292861", + "pubmed": { + "ISODate": "2001-04-20T00:00:00.000Z", + "abstract": "Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.", + "authors": { + "abbreviation": "P Jaakkola, D R Mole, Y M Tian, ..., P J Ratcliffe", + "authorList": [ + { + "ForeName": "P", + "LastName": "Jaakkola", + "abbrevName": "Jaakkola P", + "email": null, + "isCollectiveName": false, + "name": "P Jaakkola", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Mole", + "abbrevName": "Mole DR", + "email": null, + "isCollectiveName": false, + "name": "D R Mole", + "orcid": null + }, + { + "ForeName": "Y", + "LastName": "Tian", + "abbrevName": "Tian YM", + "email": null, + "isCollectiveName": false, + "name": "Y M Tian", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Wilson", + "abbrevName": "Wilson MI", + "email": null, + "isCollectiveName": false, + "name": "M I Wilson", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Gielbert", + "abbrevName": "Gielbert J", + "email": null, + "isCollectiveName": false, + "name": "J Gielbert", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Gaskell", + "abbrevName": "Gaskell SJ", + "email": null, + "isCollectiveName": false, + "name": "S J Gaskell", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "von Kriegsheim", + "abbrevName": "von Kriegsheim A", + "email": null, + "isCollectiveName": false, + "name": "A von Kriegsheim", + "orcid": null + }, + { + "ForeName": "H", + "LastName": "Hebestreit", + "abbrevName": "Hebestreit HF", + "email": null, + "isCollectiveName": false, + "name": "H F Hebestreit", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Mukherji", + "abbrevName": "Mukherji M", + "email": null, + "isCollectiveName": false, + "name": "M Mukherji", + "orcid": null + }, + { + "ForeName": "C", + "LastName": "Schofield", + "abbrevName": "Schofield CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Schofield", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Maxwell", + "abbrevName": "Maxwell PH", + "email": null, + "isCollectiveName": false, + "name": "P H Maxwell", + "orcid": null + }, + { + "ForeName": "C", + "LastName": "Pugh", + "abbrevName": "Pugh CW", + "email": null, + "isCollectiveName": false, + "name": "C W Pugh", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Ratcliffe", + "abbrevName": "Ratcliffe PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Ratcliffe", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1059796", + "pmid": "11292861", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 292 2001", + "title": "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation." + } + }, + { + "pmid": "11181778", + "pubmed": { + "ISODate": "2001-02-21T00:00:00.000Z", + "abstract": "BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated whether the level of HIF-1 alpha is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. METHODS: Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1 alpha protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1 alpha and these biomarkers were tested statistically. All statistical tests are two-sided. RESULTS: The frequency of HIF-1 alpha-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, chi(2) test for trend) as follows: normal breast tissue (0 specimens with > or = 1% HIF-1 alpha-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1 alpha were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density. HIF-1alpha showed a borderline association with HER-2/neu but no association with p53. CONCLUSIONS: The level of HIF-1 alpha increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 alpha are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.", + "authors": { + "abbreviation": "R Bos, H Zhong, C F Hanrahan, ..., E van der Wall", + "authorList": [ + { + "ForeName": "R", + "LastName": "Bos", + "abbrevName": "Bos R", + "email": null, + "isCollectiveName": false, + "name": "R Bos", + "orcid": null + }, + { + "ForeName": "H", + "LastName": "Zhong", + "abbrevName": "Zhong H", + "email": null, + "isCollectiveName": false, + "name": "H Zhong", + "orcid": null + }, + { + "ForeName": "C", + "LastName": "Hanrahan", + "abbrevName": "Hanrahan CF", + "email": null, + "isCollectiveName": false, + "name": "C F Hanrahan", + "orcid": null + }, + { + "ForeName": "E", + "LastName": "Mommers", + "abbrevName": "Mommers EC", + "email": null, + "isCollectiveName": false, + "name": "E C Mommers", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": null, + "isCollectiveName": false, + "name": "G L Semenza", + "orcid": null + }, + { + "ForeName": "H", + "LastName": "Pinedo", + "abbrevName": "Pinedo HM", + "email": null, + "isCollectiveName": false, + "name": "H M Pinedo", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Abeloff", + "abbrevName": "Abeloff MD", + "email": null, + "isCollectiveName": false, + "name": "M D Abeloff", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Simons", + "abbrevName": "Simons JW", + "email": null, + "isCollectiveName": false, + "name": "J W Simons", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "van Diest", + "abbrevName": "van Diest PJ", + "email": null, + "isCollectiveName": false, + "name": "P J van Diest", + "orcid": null + }, + { + "ForeName": "E", + "LastName": "van der Wall", + "abbrevName": "van der Wall E", + "email": null, + "isCollectiveName": false, + "name": "E van der Wall", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1093/jnci/93.4.309", + "pmid": "11181778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Natl Cancer Inst 93 2001", + "title": "Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis." + } + }, + { + "pmid": "10671482", + "pubmed": { + "ISODate": "2000-02-18T00:00:00.000Z", + "abstract": "We have identified Cox20p, a 23.8-kDa protein of the mitochondrial inner membrane that is involved in the biogenesis of the yeast cytochrome oxidase complex. Cytochrome oxidase subunit 2 (Cox2p) accumulates as a precursor in cox20 mutants, suggesting a defect in biogenesis of this mitochondrially encoded protein. The inability of cox20 mutants to process the subunit 2 precursor (pCox2p) is not due to impaired export of the protein across the inner membrane or to an inactive Imp1p/Imp2p peptidase. Rather, Cox20p specifically binds the newly synthesized pCox2p, a step required to present the exported pCox2p as a substrate to the Imp1p peptidase. All of the endogenous pCox2p accumulated in an Deltaimp1 mutant, and a small fraction of Cox2p in wild type yeast, is detected in a complex with Cox20p. Following maturation Cox2p remained associated with Cox20p, prior to assembling into the cytochrome oxidase complex. We propose that Cox20p acts as a membrane-bound chaperone necessary for cleavage of pCox2p and for interaction of the mature protein with other subunits of cytochrome oxidase in a later step of the assembly process.", + "authors": { + "abbreviation": "K Hell, A Tzagoloff, W Neupert, R A Stuart", + "authorList": [ + { + "ForeName": "K", + "LastName": "Hell", + "abbrevName": "Hell K", + "email": null, + "isCollectiveName": false, + "name": "K Hell", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Tzagoloff", + "abbrevName": "Tzagoloff A", + "email": null, + "isCollectiveName": false, + "name": "A Tzagoloff", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Neupert", + "abbrevName": "Neupert W", + "email": null, + "isCollectiveName": false, + "name": "W Neupert", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Stuart", + "abbrevName": "Stuart RA", + "email": null, + "isCollectiveName": false, + "name": "R A Stuart", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.275.7.4571", + "pmid": "10671482", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 275 2000", + "title": "Identification of Cox20p, a novel protein involved in the maturation and assembly of cytochrome oxidase subunit 2." + } + }, + { + "pmid": "10592235", + "pubmed": { + "ISODate": "2000-01-01T00:00:00.000Z", + "abstract": "The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.", + "authors": { + "abbreviation": "H M Berman, J Westbrook, Z Feng, ..., P E Bourne", + "authorList": [ + { + "ForeName": "H", + "LastName": "Berman", + "abbrevName": "Berman HM", + "email": "berman@rcsb.rutgers.edu", + "isCollectiveName": false, + "name": "H M Berman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Westbrook", + "abbrevName": "Westbrook J", + "email": null, + "isCollectiveName": false, + "name": "J Westbrook", + "orcid": null + }, + { + "ForeName": "Z", + "LastName": "Feng", + "abbrevName": "Feng Z", + "email": null, + "isCollectiveName": false, + "name": "Z Feng", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Gilliland", + "abbrevName": "Gilliland G", + "email": null, + "isCollectiveName": false, + "name": "G Gilliland", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Bhat", + "abbrevName": "Bhat TN", + "email": null, + "isCollectiveName": false, + "name": "T N Bhat", + "orcid": null + }, + { + "ForeName": "H", + "LastName": "Weissig", + "abbrevName": "Weissig H", + "email": null, + "isCollectiveName": false, + "name": "H Weissig", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Shindyalov", + "abbrevName": "Shindyalov IN", + "email": null, + "isCollectiveName": false, + "name": "I N Shindyalov", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Bourne", + "abbrevName": "Bourne PE", + "email": null, + "isCollectiveName": false, + "name": "P E Bourne", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "H", + "LastName": "Berman", + "email": [ + "berman@rcsb.rutgers.edu" + ], + "name": "H M Berman" + } + ] + }, + "doi": "10.1093/nar/28.1.235", + "pmid": "10592235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nucleic Acids Res 28 2000", + "title": "The Protein Data Bank." + } + }, + { + "pmid": "10195279", + "pubmed": { + "ISODate": "1999-02-01T00:00:00.000Z", + "abstract": "Sequence alignments unambiguously distinguish between protein pairs of similar and non-similar structure when the pairwise sequence identity is high (>40% for long alignments). The signal gets blurred in the twilight zone of 20-35% sequence identity. Here, more than a million sequence alignments were analysed between protein pairs of known structures to re-define a line distinguishing between true and false positives for low levels of similarity. Four results stood out. (i) The transition from the safe zone of sequence alignment into the twilight zone is described by an explosion of false negatives. More than 95% of all pairs detected in the twilight zone had different structures. More precisely, above a cut-off roughly corresponding to 30% sequence identity, 90% of the pairs were homologous; below 25% less than 10% were. (ii) Whether or not sequence homology implied structural identity depended crucially on the alignment length. For example, if 10 residues were similar in an alignment of length 16 (>60%), structural similarity could not be inferred. (iii) The 'more similar than identical' rule (discarding all pairs for which percentage similarity was lower than percentage identity) reduced false positives significantly. (iv) Using intermediate sequences for finding links between more distant families was almost as successful: pairs were predicted to be homologous when the respective sequence families had proteins in common. All findings are applicable to automatic database searches.", + "authors": { + "abbreviation": "B Rost", + "authorList": [ + { + "ForeName": "B", + "LastName": "Rost", + "abbrevName": "Rost B", + "email": null, + "isCollectiveName": false, + "name": "B Rost", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1093/protein/12.2.85", + "pmid": "10195279", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Protein Eng 12 1999", + "title": "Twilight zone of protein sequence alignments." + } + }, + { + "pmid": "9490409", + "pubmed": { + "ISODate": "1998-02-12T00:00:00.000Z", + "abstract": "The structure of a complex containing the homeodomain repressor protein MATalpha2 and the MADS-box transcription factor MCM1 bound to DNA has been determined by X-ray crystallography at 2.25 A resolution. It reveals the protein-protein interactions responsible for cooperative binding of MATalpha2 and MCM1 to DNA. The otherwise flexible amino-terminal extension of the MATalpha2 homeodomain forms a beta-hairpin that grips the MCM1 surface through parallel beta-strand hydrogen bonds and close-packed, predominantly hydrophobic, side chains. DNA bending induced by MCM1 brings the two proteins closer together, facilitating their interaction. An unusual feature of the complex is that an eight-amino-acid sequence adopts an alpha-helical conformation in one of two copies of the MATalpha2 monomer and a beta-strand conformation in the other. This 'chameleon' sequence of MATalpha2 may be important for recognizing natural operator sites.", + "authors": { + "abbreviation": "S Tan, T J Richmond", + "authorList": [ + { + "ForeName": "S", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "S Tan", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Richmond", + "abbrevName": "Richmond TJ", + "email": null, + "isCollectiveName": false, + "name": "T J Richmond", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/35563", + "pmid": "9490409", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 391 1998", + "title": "Crystal structure of the yeast MATalpha2/MCM1/DNA ternary complex." + } + }, + { + "pmid": "9154919", + "pubmed": { + "ISODate": "1997-05-06T00:00:00.000Z", + "abstract": "The interactions responsible for the nucleotide sequence-specific binding of the vnd/NK-2 homeodomain of Drosophila melanogaster to its consensus DNA binding site have been identified. A three-dimensional structure of the vnd/NK-2 homeodomain-DNA complex is presented, with emphasis on the structure of regions of observed protein-DNA contacts. This structure is based on protein-DNA distance restraints derived from NMR data, along with homology modeling, solvated molecular dynamics, and results from methylation and ethylation interference experiments. Helix III of the homeodomain binds in the major groove of the DNA and the N-terminal arm binds in the minor groove, in analogy with other homeodomain-DNA complexes whose structures have been reported. The vnd/NK-2 homeodomain recognizes the unusual DNA consensus sequence 5'-CAAGTG-3'. The roles in sequence specificity and strength of binding of individual amino acid residues that make contact with the DNA are described. We show, based primarily on the observed protein-DNA contacts, that the interaction of Y54 with the DNA is the major determinant of this uncommon nucleotide binding specificity in the vnd/NK-2 homeodomain-DNA complex.", + "authors": { + "abbreviation": "J M Gruschus, D H Tsao, L H Wang, ..., J A Ferretti", + "authorList": [ + { + "ForeName": "J", + "LastName": "Gruschus", + "abbrevName": "Gruschus JM", + "email": null, + "isCollectiveName": false, + "name": "J M Gruschus", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Tsao", + "abbrevName": "Tsao DH", + "email": null, + "isCollectiveName": false, + "name": "D H Tsao", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Wang", + "abbrevName": "Wang LH", + "email": null, + "isCollectiveName": false, + "name": "L H Wang", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Nirenberg", + "abbrevName": "Nirenberg M", + "email": null, + "isCollectiveName": false, + "name": "M Nirenberg", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Ferretti", + "abbrevName": "Ferretti JA", + "email": null, + "isCollectiveName": false, + "name": "J A Ferretti", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1021/bi9620060", + "pmid": "9154919", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochemistry 36 1997", + "title": "Interactions of the vnd/NK-2 homeodomain with DNA by nuclear magnetic resonance spectroscopy: basis of binding specificity." + } + }, + { + "pmid": "7490328", + "pubmed": { + "ISODate": "1995-09-01T00:00:00.000Z", + "abstract": "Immunohistochemistry is increasingly used in the assessment of markers for breast cancer prognosis. Semiquantitation is frequently desirable but, other than by the use of image analysis, the approaches currently in use are cumbersome. The most common method used is the H-score which takes into consideration the staining intensity in conjunction with the percentage of cells staining positively in breast carcinoma tissue. A \"quickscore\" has been developed which dispenses with the need to count individual cells. The quantitative biochemical Abbott enzyme immunoassay (EIA) and the Dako immunohistochemical assay (IHA) incorporating a semiquantitative H-score, have been used as standards against which the IHA quickscore for the semiquantitation of oestrogen receptor expression was tested. A good correlation was found between the quickscore and the EIA, which was as good as that between the H-score and EIA. The quickscore is a valid approach and there is no advantage in using the more rigorous H-score. A positive cut off quickscore of > or = 3 has been suggested.", + "authors": { + "abbreviation": "S Detre, G Saclani Jotti, M Dowsett", + "authorList": [ + { + "ForeName": "S", + "LastName": "Detre", + "abbrevName": "Detre S", + "email": null, + "isCollectiveName": false, + "name": "S Detre", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Saclani Jotti", + "abbrevName": "Saclani Jotti G", + "email": null, + "isCollectiveName": false, + "name": "G Saclani Jotti", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Dowsett", + "abbrevName": "Dowsett M", + "email": null, + "isCollectiveName": false, + "name": "M Dowsett", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1136/jcp.48.9.876", + "pmid": "7490328", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Pathol 48 1995", + "title": "A \"quickscore\" method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas." + } + } + ], + "relatedPapers": [ + { + "pmid": "36037364", + "pubmed": { + "ISODate": "2022-09-06T00:00:00.000Z", + "abstract": "Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.", + "authors": { + "abbreviation": "Haibiao Xie, Jin Zhou, Xijuan Liu, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Haibiao", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haibiao Xie", + "orcid": "0000-0001-6729-8479" + }, + { + "ForeName": "Jin", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zhou", + "orcid": null + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Yawei", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yawei Xu", + "orcid": null + }, + { + "ForeName": "Austin", + "LastName": "Hepperla", + "abbrevName": "Hepperla AJ", + "email": null, + "isCollectiveName": false, + "name": "Austin J Hepperla", + "orcid": "0000-0002-0107-2001" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Tao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Yao", + "abbrevName": "Yao H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Yao", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": "0000-0002-9073-3835" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Gong", + "abbrevName": "Gong K", + "email": null, + "isCollectiveName": false, + "name": "Kan Gong", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119854119", + "pmid": "36037364", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer." + } + }, + { + "pmid": "24670641", + "pubmed": { + "ISODate": "2014-04-03T00:00:00.000Z", + "abstract": "Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Xi Chen, Dimitrios Iliopoulos, Qing Zhang, ..., Laurie H Glimcher", + "authorList": [ + { + "ForeName": "Xi", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xi Chen", + "orcid": null + }, + { + "ForeName": "Dimitrios", + "LastName": "Iliopoulos", + "abbrevName": "Iliopoulos D", + "email": null, + "isCollectiveName": false, + "name": "Dimitrios Iliopoulos", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + }, + { + "ForeName": "Qianzi", + "LastName": "Tang", + "abbrevName": "Tang Q", + "email": null, + "isCollectiveName": false, + "name": "Qianzi Tang", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Greenblatt", + "abbrevName": "Greenblatt MB", + "email": null, + "isCollectiveName": false, + "name": "Matthew B Greenblatt", + "orcid": null + }, + { + "ForeName": "Maria", + "LastName": "Hatziapostolou", + "abbrevName": "Hatziapostolou M", + "email": null, + "isCollectiveName": false, + "name": "Maria Hatziapostolou", + "orcid": null + }, + { + "ForeName": "Elgene", + "LastName": "Lim", + "abbrevName": "Lim E", + "email": null, + "isCollectiveName": false, + "name": "Elgene Lim", + "orcid": null + }, + { + "ForeName": "Wai", + "LastName": "Tam", + "abbrevName": "Tam WL", + "email": null, + "isCollectiveName": false, + "name": "Wai Leong Tam", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ni", + "abbrevName": "Ni M", + "email": null, + "isCollectiveName": false, + "name": "Min Ni", + "orcid": null + }, + { + "ForeName": "Yiwen", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yiwen Chen", + "orcid": null + }, + { + "ForeName": "Junhua", + "LastName": "Mai", + "abbrevName": "Mai J", + "email": null, + "isCollectiveName": false, + "name": "Junhua Mai", + "orcid": null + }, + { + "ForeName": "Haifa", + "LastName": "Shen", + "abbrevName": "Shen H", + "email": null, + "isCollectiveName": false, + "name": "Haifa Shen", + "orcid": null + }, + { + "ForeName": "Dorothy", + "LastName": "Hu", + "abbrevName": "Hu DZ", + "email": null, + "isCollectiveName": false, + "name": "Dorothy Z Hu", + "orcid": null + }, + { + "ForeName": "Stanley", + "LastName": "Adoro", + "abbrevName": "Adoro S", + "email": null, + "isCollectiveName": false, + "name": "Stanley Adoro", + "orcid": null + }, + { + "ForeName": "Bella", + "LastName": "Hu", + "abbrevName": "Hu B", + "email": null, + "isCollectiveName": false, + "name": "Bella Hu", + "orcid": null + }, + { + "ForeName": "Minkyung", + "LastName": "Song", + "abbrevName": "Song M", + "email": null, + "isCollectiveName": false, + "name": "Minkyung Song", + "orcid": null + }, + { + "ForeName": "Chen", + "LastName": "Tan", + "abbrevName": "Tan C", + "email": null, + "isCollectiveName": false, + "name": "Chen Tan", + "orcid": null + }, + { + "ForeName": "Melissa", + "LastName": "Landis", + "abbrevName": "Landis MD", + "email": null, + "isCollectiveName": false, + "name": "Melissa D Landis", + "orcid": null + }, + { + "ForeName": "Mauro", + "LastName": "Ferrari", + "abbrevName": "Ferrari M", + "email": null, + "isCollectiveName": false, + "name": "Mauro Ferrari", + "orcid": null + }, + { + "ForeName": "Sandra", + "LastName": "Shin", + "abbrevName": "Shin SJ", + "email": null, + "isCollectiveName": false, + "name": "Sandra J Shin", + "orcid": null + }, + { + "ForeName": "Myles", + "LastName": "Brown", + "abbrevName": "Brown M", + "email": null, + "isCollectiveName": false, + "name": "Myles Brown", + "orcid": null + }, + { + "ForeName": "Jenny", + "LastName": "Chang", + "abbrevName": "Chang JC", + "email": null, + "isCollectiveName": false, + "name": "Jenny C Chang", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XS", + "email": null, + "isCollectiveName": false, + "name": "X Shirley Liu", + "orcid": null + }, + { + "ForeName": "Laurie", + "LastName": "Glimcher", + "abbrevName": "Glimcher LH", + "email": null, + "isCollectiveName": false, + "name": "Laurie H Glimcher", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13119", + "pmid": "24670641", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 508 2014", + "title": "XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway." + } + }, + { + "pmid": "31529195", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype. Extended periods of lactation protect against breast cancer development, but the mechanisms underlying this protection are unknown. We examined the effects of the milk protein alpha-casein over expression in the triple negative MDA-MB-231 breast cancer cell line. The effects of recombinant alpha-casein added exogenously to MDA-MB-231 breast cancer cells, and immortalised human fibroblasts were also investigated. We used transcriptional reporters to understand the signalling pathways downstream of alpha-casein in breast cancer cells and these fibroblasts that were activated by breast cancer cells. To extend our findings to the clinical setting, we analysed public gene expression datasets to further understand the relevance of these signalling pathways in triple negative breast cancer cells and patient samples. Finally, we used small molecular inhibitors to target relevant pathways and highlight these as potential candidates for the treatment of TN breast cancer. High levels of alpha-casein gene expression were predictive of good prognosis across 263 TNBC patient tumour samples. Alpha-casein over expression or exogenous addition reduces cancer stem cell (CSC) activity. HIF-1alpha was identified to be a key downstream target of alpha-casein, in both breast cancer cells and activated fibroblasts, and STAT transcription factors to be upstream of HIF-1alpha. Interestingly, HIF-1alpha is regulated by STAT3 in breast cancer cells, but STAT1 is the regulator of HIF-1alpha in activated fibroblasts. In analysis of 573 TNBC patient samples, alpha-casein expression, inversely correlated to HIF-1alpha, STAT3 and STAT1. STAT1 and STAT3 inhibitors target HIF-1alpha signalling in activated fibroblasts and MDA-MB-231 breast cancer cells respectively, and also abrogate CSC activities. Our findings provide an explanation for the protective effects of lactation in TNBC. Clinical data correlates high alpha-casein expression with increased recurrence-free survival in TNBC patients. Mechanistically, alpha-casein reduces breast cancer stem cell activity in vitro, and STAT3 and STAT1 were identified as regulators of pro-tumorigenic HIF-1alpha signalling in breast cancer cells and fibroblasts respectively.", + "authors": { + "abbreviation": "Kirsten E L Garner, Nathan J Hull, Andrew H Sims, ..., Robert B Clarke", + "authorList": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "abbrevName": "Garner KEL", + "email": "Kirsten.garner@manchester.ac.uk", + "isCollectiveName": false, + "name": "Kirsten E L Garner", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Hull", + "abbrevName": "Hull NJ", + "email": null, + "isCollectiveName": false, + "name": "Nathan J Hull", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Lamb", + "abbrevName": "Lamb R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lamb", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Clarke", + "abbrevName": "Clarke RB", + "email": null, + "isCollectiveName": false, + "name": "Robert B Clarke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "email": [ + "Kirsten.garner@manchester.ac.uk" + ], + "name": "Kirsten E L Garner" + } + ] + }, + "doi": "10.1007/s10911-019-09435-1", + "pmid": "31529195", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mammary Gland Biol Neoplasia 24 2019", + "title": "The Milk Protein Alpha-Casein Suppresses Triple Negative Breast Cancer Stem Cell Activity Via STAT and HIF-1alpha Signalling Pathways in Breast Cancer Cells and Fibroblasts." + } + }, + { + "pmid": "35867755", + "pubmed": { + "ISODate": "2022-07-12T00:00:00.000Z", + "abstract": "Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Zhaoping Qiu, Weijie Guo, Bo Dong, ..., Yadi Wu", + "authorList": [ + { + "ForeName": "Zhaoping", + "LastName": "Qiu", + "abbrevName": "Qiu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaoping Qiu", + "orcid": null + }, + { + "ForeName": "Weijie", + "LastName": "Guo", + "abbrevName": "Guo W", + "email": null, + "isCollectiveName": false, + "name": "Weijie Guo", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bo Dong", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Wang", + "orcid": null + }, + { + "ForeName": "Pan", + "LastName": "Deng", + "abbrevName": "Deng P", + "email": null, + "isCollectiveName": false, + "name": "Pan Deng", + "orcid": "0000-0003-2974-7389" + }, + { + "ForeName": "Chi", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Chi Wang", + "orcid": null + }, + { + "ForeName": "Jinpeng", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jinpeng Liu", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + }, + { + "ForeName": "Rudolf", + "LastName": "Grosschedl", + "abbrevName": "Grosschedl R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Grosschedl", + "orcid": null + }, + { + "ForeName": "Zhiyong", + "LastName": "Yu", + "abbrevName": "Yu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyong Yu", + "orcid": null + }, + { + "ForeName": "Jiong", + "LastName": "Deng", + "abbrevName": "Deng J", + "email": null, + "isCollectiveName": false, + "name": "Jiong Deng", + "orcid": null + }, + { + "ForeName": "Yadi", + "LastName": "Wu", + "abbrevName": "Wu Y", + "email": null, + "isCollectiveName": false, + "name": "Yadi Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119518119", + "pmid": "35867755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "EBF1 promotes triple-negative breast cancer progression by surveillance of the HIF1α pathway." + } + }, + { + "pmid": "36228375", + "pubmed": { + "ISODate": "2022-12-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly aggressive and hypoxic compared with other subtypes. The role of hypoxia inducible factor 1α (HIF-1α) as a key hypoxic transcription factor in oncogenic processes has been extensively studied. Recently, it has been shown that HIF-1α regulates the complex biological processes of TNBC, such as glycolysis, angiogenesis, invasion and metastasis, breast cancer stem cells (BCSCs) enrichment, and immune escape, to promote TNBC survival and development through the activation of downstream target genes. In addition, inflammatory mediators, oxygen levels, noncoding RNAs, complex signaling regulatory networks, epigenetic regulators are involved in the upstream regulatory expression of HIF-1α. However, further studies are needed to determine the potential and future directions of targeting HIF-1α in TNBC. This article discusses the expression of the HIF-1α transcription factor in TNBC. We also explored the mechanism by which HIF-1α drives TNBC progression. The potential significance of targeting HIF-1α for immunotherapy, chemotherapy, anti-angiogenic therapy, and photodynamic therapy is discussed. The intrinsic mechanism, existing problems and future directions of targeting HIF-1α are also studied.", + "authors": { + "abbreviation": "Qi Liu, Chengcheng Guan, Cui Liu, ..., Changgang Sun", + "authorList": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": "2020110892@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Qi Liu", + "orcid": null + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "abbrevName": "Guan C", + "email": "2020110896@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Chengcheng Guan", + "orcid": null + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": "2019101062@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Cui Liu", + "orcid": null + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "abbrevName": "Li H", + "email": "2019101020@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Huayao Li", + "orcid": null + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "2020111256@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Jibiao Wu", + "orcid": null + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "abbrevName": "Sun C", + "email": "zyxyscg@wfmc.edu.cn", + "isCollectiveName": false, + "name": "Changgang Sun", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "email": [ + "2020110892@sdutcm.edu.cn" + ], + "name": "Qi Liu" + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "email": [ + "2020110896@sdutcm.edu.cn" + ], + "name": "Chengcheng Guan" + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "email": [ + "2019101062@sdutcm.edu.cn" + ], + "name": "Cui Liu" + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "email": [ + "2019101020@sdutcm.edu.cn" + ], + "name": "Huayao Li" + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "email": [ + "2020111256@sdutcm.edu.cn" + ], + "name": "Jibiao Wu" + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "email": [ + "zyxyscg@wfmc.edu.cn" + ], + "name": "Changgang Sun" + } + ] + }, + "doi": "10.1016/j.biopha.2022.113861", + "pmid": "36228375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biomed Pharmacother 156 2022", + "title": "Targeting hypoxia-inducible factor-1alpha: A new strategy for triple-negative breast cancer therapy." + } + }, + { + "pmid": "30026228", + "pubmed": { + "ISODate": "2018-07-20T00:00:00.000Z", + "abstract": "Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.", + "authors": { + "abbreviation": "Jing Zhang, Tao Wu, Jeremy Simon, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": "0000-0001-6438-9113" + }, + { + "ForeName": "Tao", + "LastName": "Wu", + "abbrevName": "Wu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wu", + "orcid": "0000-0001-5380-3905" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon J", + "email": null, + "isCollectiveName": false, + "name": "Jeremy Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": "0000-0002-3961-9009" + }, + { + "ForeName": "Ryoichi", + "LastName": "Saito", + "abbrevName": "Saito R", + "email": null, + "isCollectiveName": false, + "name": "Ryoichi Saito", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Xian-De", + "LastName": "Liu", + "abbrevName": "Liu XD", + "email": null, + "isCollectiveName": false, + "name": "Xian-De Liu", + "orcid": "0000-0002-9639-0458" + }, + { + "ForeName": "Eric", + "LastName": "Jonasch", + "abbrevName": "Jonasch E", + "email": null, + "isCollectiveName": false, + "name": "Eric Jonasch", + "orcid": "0000-0003-0943-2806" + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Xiaosai", + "LastName": "Yao", + "abbrevName": "Yao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaosai Yao", + "orcid": "0000-0001-9729-0726" + }, + { + "ForeName": "Bin", + "LastName": "Teh", + "abbrevName": "Teh BT", + "email": null, + "isCollectiveName": false, + "name": "Bin Tean Teh", + "orcid": "0000-0003-1514-1124" + }, + { + "ForeName": "Patrick", + "LastName": "Tan", + "abbrevName": "Tan P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Tan", + "orcid": null + }, + { + "ForeName": "Xingnan", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xingnan Zheng", + "orcid": "0000-0003-3034-4421" + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": "0000-0001-5337-4901" + }, + { + "ForeName": "Cortney", + "LastName": "Lawrence", + "abbrevName": "Lawrence C", + "email": null, + "isCollectiveName": false, + "name": "Cortney Lawrence", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Fan", + "abbrevName": "Fan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Fan", + "orcid": "0000-0003-3842-2391" + }, + { + "ForeName": "Jiang", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiang Geng", + "orcid": "0000-0002-7202-2167" + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Kai", + "LastName": "Hong", + "abbrevName": "Hong K", + "email": null, + "isCollectiveName": false, + "name": "Kai Hong", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Joel", + "LastName": "Parker", + "abbrevName": "Parker JS", + "email": null, + "isCollectiveName": false, + "name": "Joel S Parker", + "orcid": "0000-0003-2080-6901" + }, + { + "ForeName": "J", + "LastName": "Auman", + "abbrevName": "Auman JT", + "email": null, + "isCollectiveName": false, + "name": "J Todd Auman", + "orcid": "0000-0002-9328-8829" + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "W", + "LastName": "Rathmell", + "abbrevName": "Rathmell WK", + "email": null, + "isCollectiveName": false, + "name": "W Kimryn Rathmell", + "orcid": "0000-0002-4984-0225" + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Kirschner", + "abbrevName": "Kirschner MW", + "email": null, + "isCollectiveName": false, + "name": "Marc W Kirschner", + "orcid": "0000-0001-6540-6130" + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": "0000-0002-0574-4856" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": "0000-0003-1246-1333" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "qing_zhang@med.unc.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "qing_zhang@med.unc.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1126/science.aap8411", + "pmid": "30026228", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 361 2018", + "title": "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma." + } + }, + { + "pmid": "32770671", + "pubmed": { + "ISODate": "2020-12-01T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.", + "authors": { + "abbreviation": "Xiangguo Yu, Qinghai Lin, Zhuanchang Wu, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Yankun", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yankun Zhang", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Songbai", + "LastName": "Zhao", + "abbrevName": "Zhao S", + "email": null, + "isCollectiveName": false, + "name": "Songbai Zhao", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Chaojia", + "LastName": "Chen", + "abbrevName": "Chen C", + "email": null, + "isCollectiveName": false, + "name": "Chaojia Chen", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Chunyang", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunyang Li", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": "0000-0002-8121-4718" + } + ], + "contacts": [] + }, + "doi": "10.1002/path.5530", + "pmid": "32770671", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Pathol 252 2020", + "title": "ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p." + } + }, + { + "pmid": "32778144", + "pubmed": { + "ISODate": "2020-08-10T00:00:00.000Z", + "abstract": "BACKGROUND: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. METHODS: In order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation. RESULTS: We first determined that IL-1β expression correlates with the levels of HIF-1α as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1α, GPER and the IL-1β/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1β that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1β released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs. CONCLUSIONS: Our data shed new light on the role of hypoxia in the activation of the IL-1β/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.", + "authors": { + "abbreviation": "Rosamaria Lappano, Marianna Talia, Francesca Cirillo, ..., Marcello Maggiolini", + "authorList": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "abbrevName": "Lappano R", + "email": "rosamaria.lappano@unical.it", + "isCollectiveName": false, + "name": "Rosamaria Lappano", + "orcid": null + }, + { + "ForeName": "Marianna", + "LastName": "Talia", + "abbrevName": "Talia M", + "email": null, + "isCollectiveName": false, + "name": "Marianna Talia", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Cirillo", + "abbrevName": "Cirillo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Cirillo", + "orcid": null + }, + { + "ForeName": "Damiano", + "LastName": "Rigiracciolo", + "abbrevName": "Rigiracciolo DC", + "email": null, + "isCollectiveName": false, + "name": "Damiano Cosimo Rigiracciolo", + "orcid": null + }, + { + "ForeName": "Domenica", + "LastName": "Scordamaglia", + "abbrevName": "Scordamaglia D", + "email": null, + "isCollectiveName": false, + "name": "Domenica Scordamaglia", + "orcid": null + }, + { + "ForeName": "Rita", + "LastName": "Guzzi", + "abbrevName": "Guzzi R", + "email": null, + "isCollectiveName": false, + "name": "Rita Guzzi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Miglietta", + "abbrevName": "Miglietta AM", + "email": null, + "isCollectiveName": false, + "name": "Anna Maria Miglietta", + "orcid": null + }, + { + "ForeName": "Ernestina", + "LastName": "De Francesco", + "abbrevName": "De Francesco EM", + "email": null, + "isCollectiveName": false, + "name": "Ernestina Marianna De Francesco", + "orcid": null + }, + { + "ForeName": "Antonino", + "LastName": "Belfiore", + "abbrevName": "Belfiore A", + "email": null, + "isCollectiveName": false, + "name": "Antonino Belfiore", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "abbrevName": "Maggiolini M", + "email": "marcello.maggiolini@unical.it", + "isCollectiveName": false, + "name": "Marcello Maggiolini", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "email": [ + "rosamaria.lappano@unical.it" + ], + "name": "Rosamaria Lappano" + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "email": [ + "marcello.maggiolini@unical.it" + ], + "name": "Marcello Maggiolini" + } + ] + }, + "doi": "10.1186/s13046-020-01667-y", + "pmid": "32778144", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Exp Clin Cancer Res 39 2020", + "title": "The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)." + } + }, + { + "pmid": "25195714", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Glypican 3 (GPC3) has been paid particular attention owing to its potential as diagnosis marker for hepatocellular carcinoma (HCC). Identifying the mechanisms regulating the reactivation of GPC3 in HCC appears to be clinically meaningful. Previous study identified zinc-fingers and homeoboxes 2 (ZHX2) as transcriptional factor responsible for postnatal repression of GPC3 in mice. Here, in this study, we provided the first evidence that down regulated ZHX2 is responsible for GPC3 reactivation in HCC. First, inverse correlation of ZHX2 with GPC3 expression was shown in cultured liver cell lines. Second, ZHX2 overexpression significantly decreased GPC3 expression, while ZHX2 knockdown effectively increased GPC3 level in different HCC cell lines. Consistently, dual luciferase and ChIP assay showed that ZHX2 dose-dependently suppressed GPC3 promoter activity by binding with the core promoter. More importantly, immunohistochemical staining demonstrated the inverse correlation between nuclear ZHX2 with GPC3 expression in HCC tissues. Further in vitro analysis showed that nuclear translocation was crucial for ZHX2 mediated repression on GPC3 transcription. Taken together, our results prove that ZHX2 suppresses GPC3 transcription by binding with its core promoter and reduced nucleic ZHX2 expression may be involved in GPC3 reactivation in HCC.", + "authors": { + "abbreviation": "Fang Luan, Peng Liu, Hongxin Ma, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Fang", + "LastName": "Luan", + "abbrevName": "Luan F", + "email": null, + "isCollectiveName": false, + "name": "Fang Luan", + "orcid": null + }, + { + "ForeName": "Peng", + "LastName": "Liu", + "abbrevName": "Liu P", + "email": null, + "isCollectiveName": false, + "name": "Peng Liu", + "orcid": null + }, + { + "ForeName": "Hongxin", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Ma", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Liu", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.biocel.2014.08.021", + "pmid": "25195714", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Biochem Cell Biol 55 2014", + "title": "Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma." + } + }, + { + "pmid": "32382017", + "pubmed": { + "ISODate": "2020-05-07T00:00:00.000Z", + "abstract": "Zinc fingers and homeoboxes 2 (ZHX2) was found as a novel VHL substrate target, and acted as an oncogenic driver in ccRCC. However, the detailed mechanism of ZHX2 in ccRCC development remains elusive, and no research has focused on studying ZHX2 in drug resistance yet. A tissue microarray with 358 ccRCC samples was used to determine the expression of ZHX2 in ccRCC patients. VHL-deficient cell line 786-O and VHL-normal cell line CAKI-1 was used for lineage reprogramming by transfecting with lentivirus. The in vitro and in vivo experiments were performed with these new cell lines to determine the mechanism of ZHX2 in ccRCC development and drug resistance. Immunohistochemistry analysis showed that ZHX2 was not highly expressed in ccRCC tumor tissues, only 33.2% (119/358) patients have high ZHX2 expression. However, high ZHX2 was significantly associated with advanced Fuhrman grade (p = 0.004), and proved to be an independent prognosis factor for progression-free survival (p = 0.0003), while there is no significant correlation with overall survival. We further discovered that ZHX2 overexpression could increase VEGF secretion and transcriptional activate the MEK/ERK1/2 and promote its downstream targets. We also found ZHX2 overexpression induce Sunitinib resistance though activating autophagy and the combination treatment of Sunitinib and Chloroquine could significantly rescue the phenomenon. In summary, these results indicate that ZHX2 drivers cell growth, migration though increase VEGF expression, and transcriptional activate MEK/ERK1/2 signaling pathway, and could induce Sunitinib resistance by regulating self-protective autophagy, these may provide new insight in advanced ccRCC treatment.", + "authors": { + "abbreviation": "Liangsong Zhu, Rong Ding, Hao Yan, ..., Zongming Lin", + "authorList": [ + { + "ForeName": "Liangsong", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liangsong Zhu", + "orcid": null + }, + { + "ForeName": "Rong", + "LastName": "Ding", + "abbrevName": "Ding R", + "email": null, + "isCollectiveName": false, + "name": "Rong Ding", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Yan", + "abbrevName": "Yan H", + "email": null, + "isCollectiveName": false, + "name": "Hao Yan", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "med-zhangjin@vip.sina.com", + "isCollectiveName": false, + "name": "Jin Zhang", + "orcid": null + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "abbrevName": "Lin Z", + "email": "lin.zongming@zs-hospital.sh.cn", + "isCollectiveName": false, + "name": "Zongming Lin", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jin", + "LastName": "Zhang", + "email": [ + "med-zhangjin@vip.sina.com" + ], + "name": "Jin Zhang" + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "email": [ + "lin.zongming@zs-hospital.sh.cn" + ], + "name": "Zongming Lin" + } + ] + }, + "doi": "10.1038/s41419-020-2541-x", + "pmid": "32382017", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 11 2020", + "title": "ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma." + } + }, + { + "pmid": "28054302", + "pubmed": { + "ISODate": "2017-04-01T00:00:00.000Z", + "abstract": "PURPOSE: Despite advances that have been made in systemic chemotherapy, the prognosis of advanced triple-negative breast cancer (TNBC) patients is still poor. The identification of key factors governing TNBC development is considered imperative for the development of novel effective therapeutic approaches. Previously, it has been reported that microRNA (miR)-761 may act as either a tumor suppressor or as an oncogene in different types of cancer. Here, we aimed at assessing the biological role of this miRNA in TNBC. METHODS: First, we measured the expression of miR-761 in primary breast cancer tissues and breast cancer-derived cell lines using qRT-PCR. Subsequently, over-expression and silencing experiments were performed to determine the role of miR-761 in TNBC cell proliferation, colony formation, migration and invasion in vitro. The in vivo role of miR-761 in TNBC growth and metastasis was determined in mouse models. Bioinformatics analyses, dual-luciferase reporter assays, Western blot analyses and rescue experiments were performed to identify miR-761 target gene(s). RESULTS: We found that miR-761 was up-regulated in primary breast cancer tissues and its derived cell lines and, particularly, in TNBC tissues and cell lines. We also found that exogenous miR-761 over-expression augmented in vitro TNBC cell proliferation, colony formation, migration and invasion, whereas miR-761 down-regulation impaired these features. In vivo, we found that miR-761 over-expression facilitated TNBC growth and lung metastasis. Mechanistically, miR-761 was found to negatively regulate the expression of tripartite motif-containing 29 (TRIM29) in TNBC cells by binding to the 3'-untranslated region of its mRNA. In conformity with these results, a significant negative correlation between miR-761 expression and TRIM29 protein expression was noted in primary TNBC tissues (r = -0.452, p = 0.0126). We also found that exogenous TRIM29 over-expression reversed the proliferative and invasive capacities of TNBC cells. CONCLUSIONS: Our data indicate that miR-761 acts as an oncogene in TNBC. This mode of action can, at least partially, be ascribed to the down-regulation of its target TRIM29. We suggest that miR-761 may serve as a promising therapeutic target for TNBC.", + "authors": { + "abbreviation": "Guang-Cheng Guo, Jia-Xiang Wang, Ming-Li Han, ..., Lin Li", + "authorList": [ + { + "ForeName": "Guang-Cheng", + "LastName": "Guo", + "abbrevName": "Guo GC", + "email": null, + "isCollectiveName": false, + "name": "Guang-Cheng Guo", + "orcid": null + }, + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "abbrevName": "Wang JX", + "email": "ggc503@126.com", + "isCollectiveName": false, + "name": "Jia-Xiang Wang", + "orcid": null + }, + { + "ForeName": "Ming-Li", + "LastName": "Han", + "abbrevName": "Han ML", + "email": null, + "isCollectiveName": false, + "name": "Ming-Li Han", + "orcid": null + }, + { + "ForeName": "Lian-Ping", + "LastName": "Zhang", + "abbrevName": "Zhang LP", + "email": null, + "isCollectiveName": false, + "name": "Lian-Ping Zhang", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Lin Li", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "email": [ + "ggc503@126.com" + ], + "name": "Jia-Xiang Wang" + } + ] + }, + "doi": "10.1007/s13402-016-0312-6", + "pmid": "28054302", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Oncol (Dordr) 40 2017", + "title": "microRNA-761 induces aggressive phenotypes in triple-negative breast cancer cells by repressing TRIM29 expression." + } + }, + { + "pmid": "26825173", + "pubmed": { + "ISODate": "2016-03-15T00:00:00.000Z", + "abstract": "Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.", + "authors": { + "abbreviation": "Tarah M Regan Anderson, Shi Hong Ma, Ganesh V Raj, ..., Carol A Lange", + "authorList": [ + { + "ForeName": "Tarah", + "LastName": "Regan Anderson", + "abbrevName": "Regan Anderson TM", + "email": null, + "isCollectiveName": false, + "name": "Tarah M Regan Anderson", + "orcid": null + }, + { + "ForeName": "Shi", + "LastName": "Ma", + "abbrevName": "Ma SH", + "email": null, + "isCollectiveName": false, + "name": "Shi Hong Ma", + "orcid": null + }, + { + "ForeName": "Ganesh", + "LastName": "Raj", + "abbrevName": "Raj GV", + "email": null, + "isCollectiveName": false, + "name": "Ganesh V Raj", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Cidlowski", + "abbrevName": "Cidlowski JA", + "email": null, + "isCollectiveName": false, + "name": "John A Cidlowski", + "orcid": null + }, + { + "ForeName": "Taylor", + "LastName": "Helle", + "abbrevName": "Helle TM", + "email": null, + "isCollectiveName": false, + "name": "Taylor M Helle", + "orcid": null + }, + { + "ForeName": "Todd", + "LastName": "Knutson", + "abbrevName": "Knutson TP", + "email": null, + "isCollectiveName": false, + "name": "Todd P Knutson", + "orcid": null + }, + { + "ForeName": "Raisa", + "LastName": "Krutilina", + "abbrevName": "Krutilina RI", + "email": null, + "isCollectiveName": false, + "name": "Raisa I Krutilina", + "orcid": null + }, + { + "ForeName": "Tiffany", + "LastName": "Seagroves", + "abbrevName": "Seagroves TN", + "email": null, + "isCollectiveName": false, + "name": "Tiffany N Seagroves", + "orcid": null + }, + { + "ForeName": "Carol", + "LastName": "Lange", + "abbrevName": "Lange CA", + "email": "lange047@umn.edu", + "isCollectiveName": false, + "name": "Carol A Lange", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Carol", + "LastName": "Lange", + "email": [ + "lange047@umn.edu" + ], + "name": "Carol A Lange" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-2510", + "pmid": "26825173", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "27184798", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer.", + "authors": { + "abbreviation": "Min-Sun Jin, Hyebin Lee, In Ae Park, ..., Han Suk Ryu", + "authorList": [ + { + "ForeName": "Min-Sun", + "LastName": "Jin", + "abbrevName": "Jin MS", + "email": null, + "isCollectiveName": false, + "name": "Min-Sun Jin", + "orcid": null + }, + { + "ForeName": "Hyebin", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "Hyebin Lee", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Park", + "abbrevName": "Park IA", + "email": null, + "isCollectiveName": false, + "name": "In Ae Park", + "orcid": null + }, + { + "ForeName": "Yul", + "LastName": "Chung", + "abbrevName": "Chung YR", + "email": null, + "isCollectiveName": false, + "name": "Yul Ri Chung", + "orcid": null + }, + { + "ForeName": "Seock-Ah", + "LastName": "Im", + "abbrevName": "Im SA", + "email": null, + "isCollectiveName": false, + "name": "Seock-Ah Im", + "orcid": null + }, + { + "ForeName": "Kyung-Hun", + "LastName": "Lee", + "abbrevName": "Lee KH", + "email": null, + "isCollectiveName": false, + "name": "Kyung-Hun Lee", + "orcid": null + }, + { + "ForeName": "Hyeong-Gon", + "LastName": "Moon", + "abbrevName": "Moon HG", + "email": null, + "isCollectiveName": false, + "name": "Hyeong-Gon Moon", + "orcid": null + }, + { + "ForeName": "Wonshik", + "LastName": "Han", + "abbrevName": "Han W", + "email": null, + "isCollectiveName": false, + "name": "Wonshik Han", + "orcid": null + }, + { + "ForeName": "Kyubo", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyubo Kim", + "orcid": null + }, + { + "ForeName": "Tae-Yong", + "LastName": "Kim", + "abbrevName": "Kim TY", + "email": null, + "isCollectiveName": false, + "name": "Tae-Yong Kim", + "orcid": null + }, + { + "ForeName": "Dong-Young", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Young Noh", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Ryu", + "abbrevName": "Ryu HS", + "email": "karlnash@naver.com", + "isCollectiveName": false, + "name": "Han Suk Ryu", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Han", + "LastName": "Ryu", + "email": [ + "karlnash@naver.com" + ], + "name": "Han Suk Ryu" + } + ] + }, + "doi": "10.1007/s00428-016-1953-6", + "pmid": "27184798", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Virchows Arch 469 2016", + "title": "Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer." + } + }, + { + "pmid": "28423652", + "pubmed": { + "ISODate": "2017-04-25T00:00:00.000Z", + "abstract": "MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.", + "authors": { + "abbreviation": "Rosa Drago-Ferrante, Francesca Pentimalli, Daniela Carlisi, ..., Riccardo Di Fiore", + "authorList": [ + { + "ForeName": "Rosa", + "LastName": "Drago-Ferrante", + "abbrevName": "Drago-Ferrante R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Drago-Ferrante", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Pentimalli", + "abbrevName": "Pentimalli F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Pentimalli", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Carlisi", + "abbrevName": "Carlisi D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Carlisi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "De Blasio", + "abbrevName": "De Blasio A", + "email": null, + "isCollectiveName": false, + "name": "Anna De Blasio", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Saliba", + "abbrevName": "Saliba C", + "email": null, + "isCollectiveName": false, + "name": "Christian Saliba", + "orcid": null + }, + { + "ForeName": "Shawn", + "LastName": "Baldacchino", + "abbrevName": "Baldacchino S", + "email": null, + "isCollectiveName": false, + "name": "Shawn Baldacchino", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Degaetano", + "abbrevName": "Degaetano J", + "email": null, + "isCollectiveName": false, + "name": "James Degaetano", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Debono", + "abbrevName": "Debono J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Debono", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Caruana-Dingli", + "abbrevName": "Caruana-Dingli G", + "email": null, + "isCollectiveName": false, + "name": "Gordon Caruana-Dingli", + "orcid": null + }, + { + "ForeName": "Godfrey", + "LastName": "Grech", + "abbrevName": "Grech G", + "email": null, + "isCollectiveName": false, + "name": "Godfrey Grech", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Scerri", + "abbrevName": "Scerri C", + "email": null, + "isCollectiveName": false, + "name": "Christian Scerri", + "orcid": null + }, + { + "ForeName": "Giovanni", + "LastName": "Tesoriere", + "abbrevName": "Tesoriere G", + "email": null, + "isCollectiveName": false, + "name": "Giovanni Tesoriere", + "orcid": null + }, + { + "ForeName": "Antonio", + "LastName": "Giordano", + "abbrevName": "Giordano A", + "email": null, + "isCollectiveName": false, + "name": "Antonio Giordano", + "orcid": null + }, + { + "ForeName": "Renza", + "LastName": "Vento", + "abbrevName": "Vento R", + "email": null, + "isCollectiveName": false, + "name": "Renza Vento", + "orcid": null + }, + { + "ForeName": "Riccardo", + "LastName": "Di Fiore", + "abbrevName": "Di Fiore R", + "email": null, + "isCollectiveName": false, + "name": "Riccardo Di Fiore", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.15960", + "pmid": "28423652", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 8 2017", + "title": "Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation." + } + }, + { + "pmid": "27137755", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": "The aggressiveness of triple-negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self-renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia-inducible factor-1α (HIF-1α) expression is associated with aggressiveness of cancer. Nonetheless, how HIF-1α expression is regulated and how HIF-1α induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF-1α expression has not yet been studied. Here, we show that clinically relevant low-dose FTI, tipifarnib (300 nM), decreased HIF-1α expression, migration and tumorsphere formation in human MDA-MB-231 TNBC cells under a normoxic condition. In contrast, the low-dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA-MB 231 cells. Tipifarnib-induced decrease in HIF-1α expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E-cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF-1α-Snail pathway. J. Cell. Physiol. 232: 192-201, 2017. © 2016 Wiley Periodicals, Inc.", + "authors": { + "abbreviation": "Tomokazu Tanaka, Yuichi Ikegami, Harumasa Nakazawa, ..., Masao Kaneki", + "authorList": [ + { + "ForeName": "Tomokazu", + "LastName": "Tanaka", + "abbrevName": "Tanaka T", + "email": null, + "isCollectiveName": false, + "name": "Tomokazu Tanaka", + "orcid": null + }, + { + "ForeName": "Yuichi", + "LastName": "Ikegami", + "abbrevName": "Ikegami Y", + "email": null, + "isCollectiveName": false, + "name": "Yuichi Ikegami", + "orcid": null + }, + { + "ForeName": "Harumasa", + "LastName": "Nakazawa", + "abbrevName": "Nakazawa H", + "email": null, + "isCollectiveName": false, + "name": "Harumasa Nakazawa", + "orcid": null + }, + { + "ForeName": "Naohide", + "LastName": "Kuriyama", + "abbrevName": "Kuriyama N", + "email": null, + "isCollectiveName": false, + "name": "Naohide Kuriyama", + "orcid": null + }, + { + "ForeName": "Miwa", + "LastName": "Oki", + "abbrevName": "Oki M", + "email": null, + "isCollectiveName": false, + "name": "Miwa Oki", + "orcid": null + }, + { + "ForeName": "Jun-Ichi", + "LastName": "Hanai", + "abbrevName": "Hanai J", + "email": null, + "isCollectiveName": false, + "name": "Jun-Ichi Hanai", + "orcid": null + }, + { + "ForeName": "Vikas", + "LastName": "Sukhatme", + "abbrevName": "Sukhatme VP", + "email": null, + "isCollectiveName": false, + "name": "Vikas P Sukhatme", + "orcid": null + }, + { + "ForeName": "Masao", + "LastName": "Kaneki", + "abbrevName": "Kaneki M", + "email": "mkaneki@helix.mgh.harvard.edu", + "isCollectiveName": false, + "name": "Masao Kaneki", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masao", + "LastName": "Kaneki", + "email": [ + "mkaneki@helix.mgh.harvard.edu" + ], + "name": "Masao Kaneki" + } + ] + }, + "doi": "10.1002/jcp.25411", + "pmid": "27137755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Physiol 232 2017", + "title": "Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1α and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro." + } + }, + { + "pmid": "26751287", + "pubmed": { + "ISODate": "2016-02-01T00:00:00.000Z", + "abstract": "Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.", + "authors": { + "abbreviation": "Aifu Lin, Chunlai Li, Zhen Xing, ..., Liuqing Yang", + "authorList": [ + { + "ForeName": "Aifu", + "LastName": "Lin", + "abbrevName": "Lin A", + "email": null, + "isCollectiveName": false, + "name": "Aifu Lin", + "orcid": null + }, + { + "ForeName": "Chunlai", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunlai Li", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Xing", + "abbrevName": "Xing Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Xing", + "orcid": null + }, + { + "ForeName": "Qingsong", + "LastName": "Hu", + "abbrevName": "Hu Q", + "email": null, + "isCollectiveName": false, + "name": "Qingsong Hu", + "orcid": null + }, + { + "ForeName": "Ke", + "LastName": "Liang", + "abbrevName": "Liang K", + "email": null, + "isCollectiveName": false, + "name": "Ke Liang", + "orcid": null + }, + { + "ForeName": "Leng", + "LastName": "Han", + "abbrevName": "Han L", + "email": null, + "isCollectiveName": false, + "name": "Leng Han", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Wang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Hawke", + "abbrevName": "Hawke DH", + "email": null, + "isCollectiveName": false, + "name": "David H Hawke", + "orcid": "0000-0002-6102-7843" + }, + { + "ForeName": "Shouyu", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shouyu Wang", + "orcid": null + }, + { + "ForeName": "Yanyan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhang", + "orcid": null + }, + { + "ForeName": "Yongkun", + "LastName": "Wei", + "abbrevName": "Wei Y", + "email": null, + "isCollectiveName": false, + "name": "Yongkun Wei", + "orcid": null + }, + { + "ForeName": "Guolin", + "LastName": "Ma", + "abbrevName": "Ma G", + "email": null, + "isCollectiveName": false, + "name": "Guolin Ma", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Park", + "abbrevName": "Park PK", + "email": null, + "isCollectiveName": false, + "name": "Peter K Park", + "orcid": null + }, + { + "ForeName": "Jianwei", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jianwei Zhou", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Zhou", + "orcid": null + }, + { + "ForeName": "Zhibin", + "LastName": "Hu", + "abbrevName": "Hu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhibin Hu", + "orcid": null + }, + { + "ForeName": "Yubin", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yubin Zhou", + "orcid": null + }, + { + "ForeName": "Jeffery", + "LastName": "Marks", + "abbrevName": "Marks JR", + "email": null, + "isCollectiveName": false, + "name": "Jeffery R Marks", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Han Liang", + "orcid": "0000-0001-7633-286X" + }, + { + "ForeName": "Mien-Chie", + "LastName": "Hung", + "abbrevName": "Hung MC", + "email": null, + "isCollectiveName": false, + "name": "Mien-Chie Hung", + "orcid": null + }, + { + "ForeName": "Chunru", + "LastName": "Lin", + "abbrevName": "Lin C", + "email": null, + "isCollectiveName": false, + "name": "Chunru Lin", + "orcid": null + }, + { + "ForeName": "Liuqing", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Liuqing Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3295", + "pmid": "26751287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer." + } + }, + { + "pmid": "35188449", + "pubmed": { + "ISODate": "2022-05-01T00:00:00.000Z", + "abstract": "There is no clear treatment guideline or individualized treatment plan for triple-negative breast cancer (TNBC). The aim of this study was to investigate more effective targets for TNBC-targeted therapy. MDA-MB-231 and BT549 cell lines were used to explore the function of LINC00649 on the proliferation, invasion, and migration of TNBC cells. A mice subcutaneous tumor model and a pulmonary metastasis model was established to identify the role of LINC00649 on the growth and metastasis of TNBC in vivo. LINC00649 was found to be a key molecule involved in the occurrence and development of TNBC by screening of public databases and detection of TNBC clinical samples. LINC00649 increased hypoxia-inducible factor 1α (HIF-1α) mRNA stability and protein expression by interacting with the nuclear factor 90 (NF90)/NF45 complex. In vitro, interference with LINC00649 inhibits MDA-MB-231 and BT549 cell proliferation, migration, and invasion, and the addition of HIF-1α revised this effect. In vivo experiments showed that LINC00649 promoted the growth and metastasis of TNBC. We demonstrated that LINC00649 interacts with the NF90/NF45 complex to increase the mRNA stability of HIF-1α and up-regulate HIF-1α expression, thereby inducing the proliferation, invasion, and migration of TNBC cells as well as tumor growth and metastasis.", + "authors": { + "abbreviation": "Jianhua Zhang, Chuang Du, Linfeng Zhang, ..., Jingruo Li", + "authorList": [ + { + "ForeName": "Jianhua", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jianhua Zhang", + "orcid": null + }, + { + "ForeName": "Chuang", + "LastName": "Du", + "abbrevName": "Du C", + "email": null, + "isCollectiveName": false, + "name": "Chuang Du", + "orcid": null + }, + { + "ForeName": "Linfeng", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Linfeng Zhang", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Wang", + "orcid": null + }, + { + "ForeName": "Yingying", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingying Zhang", + "orcid": null + }, + { + "ForeName": "Jingruo", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jingruo Li", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2022.2040283", + "pmid": "35188449", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Cycle 21 2022", + "title": "LncRNA LINC00649 promotes the growth and metastasis of triple-negative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex." + } + }, + { + "pmid": "26918606", + "pubmed": { + "ISODate": "2016-03-29T00:00:00.000Z", + "abstract": "Eukaryotic elongation factor 2 kinase (eEF2K), an emerging molecular target for cancer therapy, contributes to cancer proliferation, cell survival, tumorigenesis, and invasion, disease progression and drug resistance. Although eEF2K is highly up-regulated in various cancers, the mechanism of gene regulation has not been elucidated. In this study, we examined the role of Forkhead Box M1 (FOXM1) proto-oncogenic transcription factor in triple negative breast cancer (TNBC) cells and the regulation of eEF2K. We found that FOXM1 is highly upregulated in TNBC and its knockdown by RNA interference (siRNA) significantly inhibited eEF2K expression and suppressed cell proliferation, colony formation, migration, invasion and induced apoptotic cell death, recapitulating the effects of eEF2K inhibition. Knockdown of FOXM1 inhibited regulators of cell cycle, migration/invasion and survival, including cyclin D1, Src and MAPK-ERK signaling pathways, respectively. We also demonstrated that FOXM1 (1B and 1C isoforms) directly binds to and transcriptionally regulates eEF2K gene expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. Furthermore, in vivo inhibition of FOXM1 by liposomal siRNA-nanoparticles suppressed growth of MDA-MB-231 TNBC tumor xenografts in orthotopic models. In conclusion, our study provides the first evidence about the transcriptional regulation of eEF2K in TNBC and the role of FOXM1 in mediating breast cancer cell proliferation, survival, migration/invasion, progression and tumorgenesis and highlighting the potential of FOXM1/eEF2K axis as a molecular target in breast and other cancers.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Ahmed Ashour, Nermin Kahraman, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": null, + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.7672", + "pmid": "26918606", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 7 2016", + "title": "FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells." + } + }, + { + "pmid": "31264274", + "pubmed": { + "ISODate": "2019-10-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.", + "authors": { + "abbreviation": "Chen Gong, Jin Zou, Mingsheng Zhang, ..., Yong Li", + "authorList": [ + { + "ForeName": "Chen", + "LastName": "Gong", + "abbrevName": "Gong C", + "email": null, + "isCollectiveName": false, + "name": "Chen Gong", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zou", + "abbrevName": "Zou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zou", + "orcid": null + }, + { + "ForeName": "Mingsheng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mingsheng Zhang", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Shanshan", + "LastName": "Xu", + "abbrevName": "Xu S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Xu", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Zhu", + "orcid": null + }, + { + "ForeName": "Mengqi", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mengqi Yang", + "orcid": null + }, + { + "ForeName": "Dongjia", + "LastName": "Li", + "abbrevName": "Li D", + "email": null, + "isCollectiveName": false, + "name": "Dongjia Li", + "orcid": null + }, + { + "ForeName": "Yun", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yun Wang", + "orcid": null + }, + { + "ForeName": "Jialu", + "LastName": "Shi", + "abbrevName": "Shi J", + "email": null, + "isCollectiveName": false, + "name": "Jialu Shi", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Li", + "orcid": "0000-0003-4681-263X" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23079", + "pmid": "31264274", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer." + } + }, + { + "pmid": "30964885", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "Triple-Negative Breast Cancers (TNBCs) are the most difficult to treat subtype of breast cancer and are often associated with high nuclear expression of Snail and Cathepsin L (Cat L) protease. We have previously shown that Snail can increase Cat L expression/activity in prostate and breast cancer cells. This study investigated the role of CUX1 (a downstream substrate of Cat L) in TNBC. We showed that Cat L and CUX1 were highly expressed in TNBC patient tissue/cell lines, as compared to ER-positive samples, using cBioportal data and western blot/zymography analyses. Additionally, luciferase reporter and chromatin immunoprecipitation assays showed that CUX1 directly bound to estrogen receptor-alpha (ER-α) promoter in MDA-MB-468, a representative TNBC cell line, and that CUX1 siRNA could restore ER-α transcription and protein expression. Furthermore, Snail and CUX1 expression in various TNBC cell lines was inhibited by muscadine grape skin extract (MSKE, a natural grape product rich in anthocyanins) or Cat L inhibitor (Z-FY-CHO) leading to decreased cell invasion and migration. MSKE decreased cell viability and increased expression of apoptotic markers in MDA-MB-468 cells, with no effect on non-tumorigenic MCF10A cells. MSKE also decreased CUX1 binding to ER-α promoter and restored ER-α expression in TNBC cells, while both MSKE and CUX1 siRNA restored sensitivity to estradiol and 4-hydoxytamoxifen as shown by increased cell viability. Therefore, CUX1 activated by Snail-Cat L signaling may contribute to TNBC via ER-α repression, and may be a viable target for TNBC using natural products such as MSKE that targets cancer and not normal cells.", + "authors": { + "abbreviation": "Liza J Burton, Ohuod Hawsawi, Janae Sweeney, ..., Valerie Odero-Marah", + "authorList": [ + { + "ForeName": "Liza", + "LastName": "Burton", + "abbrevName": "Burton LJ", + "email": null, + "isCollectiveName": false, + "name": "Liza J Burton", + "orcid": null + }, + { + "ForeName": "Ohuod", + "LastName": "Hawsawi", + "abbrevName": "Hawsawi O", + "email": null, + "isCollectiveName": false, + "name": "Ohuod Hawsawi", + "orcid": null + }, + { + "ForeName": "Janae", + "LastName": "Sweeney", + "abbrevName": "Sweeney J", + "email": null, + "isCollectiveName": false, + "name": "Janae Sweeney", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Bowen", + "abbrevName": "Bowen N", + "email": null, + "isCollectiveName": false, + "name": "Nathan Bowen", + "orcid": "0000-0002-1609-6698" + }, + { + "ForeName": "Tamaro", + "LastName": "Hudson", + "abbrevName": "Hudson T", + "email": null, + "isCollectiveName": false, + "name": "Tamaro Hudson", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Odero-Marah", + "abbrevName": "Odero-Marah V", + "email": null, + "isCollectiveName": false, + "name": "Valerie Odero-Marah", + "orcid": "0000-0002-5238-9914" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0214844", + "pmid": "30964885", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 14 2019", + "title": "CCAAT-displacement protein/cut homeobox transcription factor (CUX1) represses estrogen receptor-alpha (ER-α) in triple-negative breast cancer cells and can be antagonized by muscadine grape skin extract (MSKE)." + } + }, + { + "pmid": "28239645", + "pubmed": { + "ISODate": "2017-02-23T00:00:00.000Z", + "abstract": "Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.", + "authors": { + "abbreviation": "Manfredi Ponente, Letizia Campanini, Roberto Cuttano, ..., Rosa Bernardi", + "authorList": [ + { + "ForeName": "Manfredi", + "LastName": "Ponente", + "abbrevName": "Ponente M", + "email": null, + "isCollectiveName": false, + "name": "Manfredi Ponente", + "orcid": null + }, + { + "ForeName": "Letizia", + "LastName": "Campanini", + "abbrevName": "Campanini L", + "email": null, + "isCollectiveName": false, + "name": "Letizia Campanini", + "orcid": null + }, + { + "ForeName": "Roberto", + "LastName": "Cuttano", + "abbrevName": "Cuttano R", + "email": null, + "isCollectiveName": false, + "name": "Roberto Cuttano", + "orcid": null + }, + { + "ForeName": "Andrea", + "LastName": "Piunti", + "abbrevName": "Piunti A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Piunti", + "orcid": null + }, + { + "ForeName": "Giacomo", + "LastName": "Delledonne", + "abbrevName": "Delledonne GA", + "email": null, + "isCollectiveName": false, + "name": "Giacomo A Delledonne", + "orcid": null + }, + { + "ForeName": "Nadia", + "LastName": "Coltella", + "abbrevName": "Coltella N", + "email": null, + "isCollectiveName": false, + "name": "Nadia Coltella", + "orcid": null + }, + { + "ForeName": "Roberta", + "LastName": "Valsecchi", + "abbrevName": "Valsecchi R", + "email": null, + "isCollectiveName": false, + "name": "Roberta Valsecchi", + "orcid": null + }, + { + "ForeName": "Alessandra", + "LastName": "Villa", + "abbrevName": "Villa A", + "email": null, + "isCollectiveName": false, + "name": "Alessandra Villa", + "orcid": null + }, + { + "ForeName": "Ugo", + "LastName": "Cavallaro", + "abbrevName": "Cavallaro U", + "email": null, + "isCollectiveName": false, + "name": "Ugo Cavallaro", + "orcid": null + }, + { + "ForeName": "Linda", + "LastName": "Pattini", + "abbrevName": "Pattini L", + "email": null, + "isCollectiveName": false, + "name": "Linda Pattini", + "orcid": null + }, + { + "ForeName": "Claudio", + "LastName": "Doglioni", + "abbrevName": "Doglioni C", + "email": null, + "isCollectiveName": false, + "name": "Claudio Doglioni", + "orcid": null + }, + { + "ForeName": "Rosa", + "LastName": "Bernardi", + "abbrevName": "Bernardi R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Bernardi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/jci.insight.87380", + "pmid": "28239645", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "JCI Insight 2 2017", + "title": "PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes." + } + }, + { + "pmid": "29333926", + "pubmed": { + "ISODate": "2018-04-03T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by poor patient prognosis and for which no targeted therapies are currently available. TNBC can be further categorized as either basal-like (BLBC) or quintuple-negative breast cancer (QNBC). In the present study, we aimed to identify novel molecular therapeutic targets for TNBC by analyzing the mRNA expression of TNBC-related genes in publicly available microarray data sets. We found that Engrailed 1 (EN1) was significantly overexpressed in TNBC. Using breast cancer cell lines, we found that EN1 was more highly expressed in TNBC than in other breast cancer subtypes. EN1 expression was analyzed in 199 TNBC paraffin-embedded tissue samples by immunohistochemistry. EN1 protein expression was positively associated with reduced overall survival (OS) rate in patients with QNBC, but not those with BLBC. The importance of EN1 expression in QNBC cell viability and tumorigenicity was evaluated using the QNBC cell lines, HCC38 and HCC1395. Based on our data, EN1 may promote the proliferation, migration, and multinucleation of QNBC cells, likely via the transcriptional activation of HDAC8, UTP11L, and ZIC3. We also demonstrated that actinomycin D effectively inhibits EN1 activity in QNBC cells. The results of the present study suggest that EN1 activity is highly clinically relevant to the survival prognosis of patients with QNBC and EN1 is a promising potential therapeutic target for future QNBC treatment.", + "authors": { + "abbreviation": "Yu Jin Kim, Minjung Sung, Ensel Oh, ..., Yoon-La Choi", + "authorList": [ + { + "ForeName": "Yu", + "LastName": "Kim", + "abbrevName": "Kim YJ", + "email": null, + "isCollectiveName": false, + "name": "Yu Jin Kim", + "orcid": null + }, + { + "ForeName": "Minjung", + "LastName": "Sung", + "abbrevName": "Sung M", + "email": null, + "isCollectiveName": false, + "name": "Minjung Sung", + "orcid": null + }, + { + "ForeName": "Ensel", + "LastName": "Oh", + "abbrevName": "Oh E", + "email": null, + "isCollectiveName": false, + "name": "Ensel Oh", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Vrancken", + "abbrevName": "Vrancken MV", + "email": null, + "isCollectiveName": false, + "name": "Michael Van Vrancken", + "orcid": null + }, + { + "ForeName": "Ji-Young", + "LastName": "Song", + "abbrevName": "Song JY", + "email": null, + "isCollectiveName": false, + "name": "Ji-Young Song", + "orcid": null + }, + { + "ForeName": "Kyungsoo", + "LastName": "Jung", + "abbrevName": "Jung K", + "email": null, + "isCollectiveName": false, + "name": "Kyungsoo Jung", + "orcid": null + }, + { + "ForeName": "Yoon-La", + "LastName": "Choi", + "abbrevName": "Choi YL", + "email": null, + "isCollectiveName": false, + "name": "Yoon-La Choi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2018.1423913", + "pmid": "29333926", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 19 2018", + "title": "Engrailed 1 overexpression as a potential prognostic marker in quintuple-negative breast cancer." + } + }, + { + "pmid": "32114388", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Liver cancer stem cells (CSCs) are critical determinants of HCC relapse and therapeutic resistance, but the mechanisms underlying the maintenance of CSCs are poorly understood. We aimed to explore the role of tumor repressor Zinc-fingers and homeoboxes 2 (ZHX2) in liver CSCs. METHODS: CD133+ or EPCAM+ stem-like liver cancer cells were sorted from tumor tissues of HCC patients and HCC cell lines by flow cytometry. In addition, sorafenib-resistant cells, tumor-sphere forming cells and side population (SP) cells were respectively cultured and isolated as hepatic CSCs. The tumor-initiating and chemoresistance properties of ZHX2-overexpressing and ZHX2-knockdown cells were analyzed in vivo and in vitro. Microarray, luciferase reporter assay, chromatin immunoprecipitation (ChIP) and ChIP-on-chip analyses were performed to explore ZHX2 target genes. The expression of ZHX2 and its target gene were determined by quantitative RT-PCR, western blot, immunofluorescence and immunohistochemical staining in hepatoma cells and tumor and adjacent tissues from HCC patients. RESULTS: ZHX2 expression was significantly reduced in liver CSCs from different origins. ZHX2 deficiency led to enhanced liver tumor progression and expansion of CSC populations in vitro and in vivo. Re-expression of ZHX2 restricted capabilities of hepatic CSCs in supporting tumor initiation, self-renewal and sorafenib-resistance. Mechanically, ZHX2 suppressed liver CSCs via inhibiting KDM2A-mediated demethylation of histone H3 lysine 36 (H3K36) at the promoter regions of stemness-associated transcription factors, such as NANOG, SOX4 and OCT4. Moreover, patients with lower expression of ZHX2 and higher expression of KDM2A in tumor tissues showed significantly poorer survival. CONCLUSION: ZHX2 counteracts stem cell traits through transcriptionally repressing KDM2A in HCC. Our data will aid in a better understanding of molecular mechanisms underlying HCC relapse and drug resistance.", + "authors": { + "abbreviation": "Qinghai Lin, Zhuanchang Wu, Xuetian Yue, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Ying He", + "orcid": null + }, + { + "ForeName": "Yutong", + "LastName": "Ge", + "abbrevName": "Ge Y", + "email": null, + "isCollectiveName": false, + "name": "Yutong Ge", + "orcid": null + }, + { + "ForeName": "Siyu", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Siyu Tan", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Song", + "abbrevName": "Song H", + "email": null, + "isCollectiveName": false, + "name": "Hui Song", + "orcid": null + }, + { + "ForeName": "Detian", + "LastName": "Yuan", + "abbrevName": "Yuan D", + "email": null, + "isCollectiveName": false, + "name": "Detian Yuan", + "orcid": null + }, + { + "ForeName": "Yaoqin", + "LastName": "Gong", + "abbrevName": "Gong Y", + "email": null, + "isCollectiveName": false, + "name": "Yaoqin Gong", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.ebiom.2020.102676", + "pmid": "32114388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EBioMedicine 53 2020", + "title": "ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation." + } + }, + { + "pmid": "34408002", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.", + "authors": { + "abbreviation": "Tian-Jian Yu, Ying-Ying Liu, Xiao-Guang Li, ..., Yi-Zhou Jiang", + "authorList": [ + { + "ForeName": "Tian-Jian", + "LastName": "Yu", + "abbrevName": "Yu TJ", + "email": null, + "isCollectiveName": false, + "name": "Tian-Jian Yu", + "orcid": null + }, + { + "ForeName": "Ying-Ying", + "LastName": "Liu", + "abbrevName": "Liu YY", + "email": null, + "isCollectiveName": false, + "name": "Ying-Ying Liu", + "orcid": null + }, + { + "ForeName": "Xiao-Guang", + "LastName": "Li", + "abbrevName": "Li XG", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Guang Li", + "orcid": null + }, + { + "ForeName": "Bi", + "LastName": "Lian", + "abbrevName": "Lian B", + "email": null, + "isCollectiveName": false, + "name": "Bi Lian", + "orcid": null + }, + { + "ForeName": "Xun-Xi", + "LastName": "Lu", + "abbrevName": "Lu XX", + "email": null, + "isCollectiveName": false, + "name": "Xun-Xi Lu", + "orcid": "0000-0002-5118-0377" + }, + { + "ForeName": "Xi", + "LastName": "Jin", + "abbrevName": "Jin X", + "email": null, + "isCollectiveName": false, + "name": "Xi Jin", + "orcid": null + }, + { + "ForeName": "Zhi-Ming", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Ming Shao", + "orcid": "0000-0001-8781-2455" + }, + { + "ForeName": "Xin", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Xin Hu", + "orcid": null + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "abbrevName": "Di GH", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Gen-Hong Di", + "orcid": null + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "abbrevName": "Jiang YZ", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Yi-Zhou Jiang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Hu", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Xin Hu" + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Gen-Hong Di" + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Yi-Zhou Jiang" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-21-0747", + "pmid": "34408002", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 81 2021", + "title": "PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "33824311", + "pubmed": { + "ISODate": "2021-04-06T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15-20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.", + "authors": { + "abbreviation": "Fengxia Chen, Qingqing Wang, Xiaoyan Yu, ..., Yunfeng Zhou", + "authorList": [ + { + "ForeName": "Fengxia", + "LastName": "Chen", + "abbrevName": "Chen F", + "email": null, + "isCollectiveName": false, + "name": "Fengxia Chen", + "orcid": null + }, + { + "ForeName": "Qingqing", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqing Wang", + "orcid": "0000-0002-6440-582X" + }, + { + "ForeName": "Xiaoyan", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyan Yu", + "orcid": null + }, + { + "ForeName": "Ningning", + "LastName": "Yang", + "abbrevName": "Yang N", + "email": null, + "isCollectiveName": false, + "name": "Ningning Yang", + "orcid": null + }, + { + "ForeName": "Yuan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Wang", + "orcid": "0000-0003-1894-0853" + }, + { + "ForeName": "Yangyang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yangyang Zeng", + "orcid": null + }, + { + "ForeName": "Zhewen", + "LastName": "Zheng", + "abbrevName": "Zheng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhewen Zheng", + "orcid": null + }, + { + "ForeName": "Fuxiang", + "LastName": "Zhou", + "abbrevName": "Zhou F", + "email": null, + "isCollectiveName": false, + "name": "Fuxiang Zhou", + "orcid": null + }, + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": "yfzhouwhu@163.com", + "isCollectiveName": false, + "name": "Yunfeng Zhou", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "email": [ + "yfzhouwhu@163.com" + ], + "name": "Yunfeng Zhou" + } + ] + }, + "doi": "10.1038/s41419-021-03661-4", + "pmid": "33824311", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis." + } + }, + { + "pmid": "24248265", + "pubmed": { + "ISODate": "2014-02-01T00:00:00.000Z", + "abstract": "UNLABELLED: Targeted therapy against triple-negative breast cancers, which lack expression of the estrogen, progesterone, and HER2 receptors, is not available and the overall response to cytotoxic chemotherapy is poor. One of the molecular hallmarks of triple-negative breast cancers is increased expression of genes that are transcriptionally activated by hypoxia-inducible factors (HIFs), which are implicated in many critical aspects of cancer progression including metabolism, angiogenesis, invasion, metastasis, and stem cell maintenance. Ganetespib is a second-generation inhibitor of heat shock protein 90 (HSP90), a molecular chaperone that is essential for the stability and function of multiple client proteins in cancer cells including HIF-1α. In this study, human MDA-MB-231 and MDA-MB-435 triple-negative breast cancer cells were injected into the mammary fat pad of immunodeficient mice that received weekly intravenous injections of ganetespib or vehicle following the development of palpable tumors. Ganetespib treatment markedly impaired primary tumor growth and vascularization, and eliminated local tissue invasion and distant metastasis to regional lymph nodes and lungs. Ganetespib treatment also significantly reduced the number of Aldefluor-positive cancer stem cells in the primary tumor. Primary tumors of ganetespib-treated mice had significantly reduced levels of HIF-1α (but not HIF-2α) protein and of HIF-1 target gene mRNAs encoding proteins that play key roles in angiogenesis, metabolism, invasion, and metastasis, thereby providing a molecular basis for observed effects of the drug on the growth and metastasis of triple-negative breast cancer. KEY MESSAGES: Triple-negative breast cancers (TNBCs) respond poorly to available chemotherapy. TNBCs overexpress genes regulated by hypoxia-inducible factors (HIFs). Ganetespib induces degradation of HSP90 client proteins, including HIF-1α. Ganetespib inhibited TNBC orthotopic tumor growth, invasion, and metastasis. Ganetespib inhibited expression of HIF-1 target genes involved in TNBC progression.", + "authors": { + "abbreviation": "Lisha Xiang, Daniele M Gilkes, Pallavi Chaturvedi, ..., Gregg L Semenza", + "authorList": [ + { + "ForeName": "Lisha", + "LastName": "Xiang", + "abbrevName": "Xiang L", + "email": null, + "isCollectiveName": false, + "name": "Lisha Xiang", + "orcid": null + }, + { + "ForeName": "Daniele", + "LastName": "Gilkes", + "abbrevName": "Gilkes DM", + "email": null, + "isCollectiveName": false, + "name": "Daniele M Gilkes", + "orcid": null + }, + { + "ForeName": "Pallavi", + "LastName": "Chaturvedi", + "abbrevName": "Chaturvedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Chaturvedi", + "orcid": null + }, + { + "ForeName": "Weibo", + "LastName": "Luo", + "abbrevName": "Luo W", + "email": null, + "isCollectiveName": false, + "name": "Weibo Luo", + "orcid": null + }, + { + "ForeName": "Hongxia", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Hongxia Hu", + "orcid": null + }, + { + "ForeName": "Naoharu", + "LastName": "Takano", + "abbrevName": "Takano N", + "email": null, + "isCollectiveName": false, + "name": "Naoharu Takano", + "orcid": null + }, + { + "ForeName": "Houjie", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Houjie Liang", + "orcid": null + }, + { + "ForeName": "Gregg", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": null, + "isCollectiveName": false, + "name": "Gregg L Semenza", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s00109-013-1102-5", + "pmid": "24248265", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Med (Berl) 92 2014", + "title": "Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer." + } + }, + { + "pmid": "25920936", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.", + "authors": { + "abbreviation": "Shuang Li, Qingzhu Wei, Qin Li, ..., Qiang Xiao", + "authorList": [ + { + "ForeName": "Shuang", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuang Li", + "orcid": null + }, + { + "ForeName": "Qingzhu", + "LastName": "Wei", + "abbrevName": "Wei Q", + "email": null, + "isCollectiveName": false, + "name": "Qingzhu Wei", + "orcid": null + }, + { + "ForeName": "Qin", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qin Li", + "orcid": null + }, + { + "ForeName": "Bin", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bin Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Xiao", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2015.1040958", + "pmid": "25920936", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 16 2015", + "title": "Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer." + } + }, + { + "pmid": "31683461", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "OBJECTIVE: To investigate the effect of ZHX2 on lung cancer cells proliferation and apoptosis. MATERIALS AND METHODS: The mRNA and protein expression of ZHX2 were detected by qRT-PCR and western blot, respectively. The human lung cancer cells were divided into Control, NC, ZHX2, SB, and ZHX2 + Ani groups. The cell proliferation was detected by CCK-8 assay and the cell migration and invasion were detected by Transwell assay. Cell apoptosis was detected by flow cytometry. Apoptosis and p38MAPK signaling pathway related proteins were detected by western blot. The nude mice model of lung cancer xenograft was constructed. The tumor volume and tumor weight were measured. The expression of PCNA protein in tumor tissues was detected by immunohistochemistry. The apoptosis of tumor cells was detected by TUNEL staining. The ZHX2 and p38MAPK signaling pathway related proteins in tumor tissues were detected by western blot. RESULTS: The expression of ZHX2 gene and protein in the cancer cell lines were significantly decreased. Compared with control and NC groups, the cells proliferation, migration and invasion were inhibited in ZHX2 and SB groups, while the apoptosis and apoptosis related proteins were increased (p< 0.05). Meanwhile, compared with ZHX2 group, the tumor growth rate, volume, weight, the percentage of PCNA-positive cells, and p-P38 MAPK/P38 MAPK were increased significantly in ZHX2 + Ani group, while the apoptotic index and the expression of MMP-9 protein were significantly decreased (p< 0.05). CONCLUSION: ZHX2 could inhibit proliferation and promote apoptosis of lung cancer cells by inhibiting p38MAPK signaling pathway.", + "authors": { + "abbreviation": "Xudong Tian, Yadong Wang, Shuhai Li, ..., Hui Tian", + "authorList": [ + { + "ForeName": "Xudong", + "LastName": "Tian", + "abbrevName": "Tian X", + "email": null, + "isCollectiveName": false, + "name": "Xudong Tian", + "orcid": null + }, + { + "ForeName": "Yadong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yadong Wang", + "orcid": null + }, + { + "ForeName": "Shuhai", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuhai Li", + "orcid": null + }, + { + "ForeName": "Weiming", + "LastName": "Yue", + "abbrevName": "Yue W", + "email": null, + "isCollectiveName": false, + "name": "Weiming Yue", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Tian", + "abbrevName": "Tian H", + "email": null, + "isCollectiveName": false, + "name": "Hui Tian", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3233/CBM-190514", + "pmid": "31683461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Biomark 27 2020", + "title": "ZHX2 inhibits proliferation and promotes apoptosis of human lung cancer cells through targeting p38MAPK pathway." + } + }, + { + "pmid": "28361350", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin β1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin β1 (ITGB1) gene expression have not been well elucidated. METHODS: Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin β1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin β1 gene and drives its expression. RESULTS: We demonstrated that FOXM1 directly binds to the promoter of integrin β1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells. CONCLUSION: Our study suggests that FOXM1 transcription factor regulates Integrin β1 gene expression and that FOXM1/ Integrin-β1/FAK axis may play an important role in the progression of TNBC.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Nermin Kahraman, Ahmed Ashour, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": "bozpolat@mdanderson.org", + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "email": [ + "bozpolat@mdanderson.org" + ], + "name": "Bulent Ozpolat" + } + ] + }, + "doi": "10.1007/s10549-017-4207-7", + "pmid": "28361350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res Treat 163 2017", + "title": "FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer." + } + }, + { + "pmid": "30784286", + "pubmed": { + "ISODate": "2019-05-23T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The unclear molecular mechanisms underlying could provide important theoretical basis for the prevention and control of HCC. This study performed chromatin immunoprecipitation-sequencing (ChIP-seq) to analyze the binding sites between zinc fingers and homeoboxes 2 (ZHX2) and its genome-wide target genes, and bioinformatics was used to analyze their gene transcription regulation network. Immunohistochemistry was used to detect the ZHX2 expression in HCC, and its association with the clinicopathological characteristics of HCC. Results of RT-PCR and western blot showed the expression of ZHX2 in HepG2 cells was obviously lower compared with normal liver cells. ZHX2 could be amplified in ChIP products, then ChIP-seq reveals there were 232 genes binding in promoter regions. GO analysis of functions revealed these genes were mainly associated with biological processes (BP), cellular components (CC), and molecular functions (MF). In addition, PTEN was found enriched in certain biological functions in BP analysis. Then, four pathways of these genes based on Kyoto Encyclopedia of Genes and Genomes (KEGG) were found P<0.05. Last analysis of immunohistochemistry showed the rates of ZHX2 expression and PTEN expression in paracancerous tissues both were significantly higher than that in HCC tissues (P=0.042; P<0.001), with negative correlations with AFP values (r=-0.246, P=0.040; r=-0.263, P=0.028). Further, PTEN expression was positively correlated with the differentiation level in HCC tissues (r=0.267, P=0.025). Spearman correlation analysis revealed that the expression profiles of ZHX2 and PTEN were positively correlated in HCC tissues (r=0.258, P=0.031). This study is the first to use ChIP-seq technology to analyze the specific regulatory mechanisms of the transcription suppressor ZHX2 in the context of HCC at the genome level.", + "authors": { + "abbreviation": "Z Lv, R He, M Huang, ..., G Chen", + "authorList": [ + { + "ForeName": "Z", + "LastName": "Lv", + "abbrevName": "Lv Z", + "email": null, + "isCollectiveName": false, + "name": "Z Lv", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "He", + "abbrevName": "He R", + "email": null, + "isCollectiveName": false, + "name": "R He", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Huang", + "abbrevName": "Huang M", + "email": null, + "isCollectiveName": false, + "name": "M Huang", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Zhao", + "abbrevName": "Zhao G", + "email": null, + "isCollectiveName": false, + "name": "G Zhao", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Ma", + "abbrevName": "Ma J", + "email": null, + "isCollectiveName": false, + "name": "J Ma", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": null, + "isCollectiveName": false, + "name": "G Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.4149/neo_2018_180806N593", + "pmid": "30784286", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Neoplasma 66 2019", + "title": "Targeting genes and signaling pathways of transcriptional suppressor ZHX2 in hepatocellular carcinoma: a Chromatin Immunoprecipitation-sequencing (ChIP-seq) investigation." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2022-12-10T08:44:02.347Z", + "_newestOpId": "08cf2332-41f9-4119-91ec-0228d8f84f48", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "609185" + }, + { + "db": "HGNC", + "id": "HGNC:18513" + }, + { + "db": "Ensembl", + "id": "ENSG00000178764" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.855772, + "formulae": null, + "id": "22882", + "inchi": null, + "inchiKey": null, + "mass": null, + "monoisotopicMass": null, + "name": "ZHX2", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "AFR1", + "RAF", + "zinc fingers and homeoboxes protein 2", + "AFP regulator 1", + "alpha-fetoprotein regulator 1", + "regulator of AFP", + "transcription factor ZHX2", + "zinc finger and homeodomain protein 2", + "zinc fingers and homeoboxes 2" + ], + "summary": null, + "synonyms": [ + "AFR1", + "RAF", + "zinc fingers and homeoboxes protein 2", + "AFP regulator 1", + "alpha-fetoprotein regulator 1", + "regulator of AFP", + "transcription factor ZHX2", + "zinc finger and homeodomain protein 2", + "zinc fingers and homeoboxes 2" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "13f57ee3-df7d-4ec8-b8ca-0efdd62f99d5", + "liveId": "7615b7ab-4f47-467a-98ef-c49f1adb1fe1", + "lock": null, + "locked": false, + "name": "ZHX2", + "parentId": "3fd6a28f-483e-4eb4-ab6f-0a9025bd9cd1", + "position": { + "x": 316.0713463751438, + "y": 148.49271192942072 + }, + "relatedPapers": [ + { + "pmid": "25195714", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Glypican 3 (GPC3) has been paid particular attention owing to its potential as diagnosis marker for hepatocellular carcinoma (HCC). Identifying the mechanisms regulating the reactivation of GPC3 in HCC appears to be clinically meaningful. Previous study identified zinc-fingers and homeoboxes 2 (ZHX2) as transcriptional factor responsible for postnatal repression of GPC3 in mice. Here, in this study, we provided the first evidence that down regulated ZHX2 is responsible for GPC3 reactivation in HCC. First, inverse correlation of ZHX2 with GPC3 expression was shown in cultured liver cell lines. Second, ZHX2 overexpression significantly decreased GPC3 expression, while ZHX2 knockdown effectively increased GPC3 level in different HCC cell lines. Consistently, dual luciferase and ChIP assay showed that ZHX2 dose-dependently suppressed GPC3 promoter activity by binding with the core promoter. More importantly, immunohistochemical staining demonstrated the inverse correlation between nuclear ZHX2 with GPC3 expression in HCC tissues. Further in vitro analysis showed that nuclear translocation was crucial for ZHX2 mediated repression on GPC3 transcription. Taken together, our results prove that ZHX2 suppresses GPC3 transcription by binding with its core promoter and reduced nucleic ZHX2 expression may be involved in GPC3 reactivation in HCC.", + "authors": { + "abbreviation": "Fang Luan, Peng Liu, Hongxin Ma, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Fang", + "LastName": "Luan", + "abbrevName": "Luan F", + "email": null, + "isCollectiveName": false, + "name": "Fang Luan", + "orcid": null + }, + { + "ForeName": "Peng", + "LastName": "Liu", + "abbrevName": "Liu P", + "email": null, + "isCollectiveName": false, + "name": "Peng Liu", + "orcid": null + }, + { + "ForeName": "Hongxin", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Ma", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Liu", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.biocel.2014.08.021", + "pmid": "25195714", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Biochem Cell Biol 55 2014", + "title": "Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma." + } + }, + { + "pmid": "28239645", + "pubmed": { + "ISODate": "2017-02-23T00:00:00.000Z", + "abstract": "Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.", + "authors": { + "abbreviation": "Manfredi Ponente, Letizia Campanini, Roberto Cuttano, ..., Rosa Bernardi", + "authorList": [ + { + "ForeName": "Manfredi", + "LastName": "Ponente", + "abbrevName": "Ponente M", + "email": null, + "isCollectiveName": false, + "name": "Manfredi Ponente", + "orcid": null + }, + { + "ForeName": "Letizia", + "LastName": "Campanini", + "abbrevName": "Campanini L", + "email": null, + "isCollectiveName": false, + "name": "Letizia Campanini", + "orcid": null + }, + { + "ForeName": "Roberto", + "LastName": "Cuttano", + "abbrevName": "Cuttano R", + "email": null, + "isCollectiveName": false, + "name": "Roberto Cuttano", + "orcid": null + }, + { + "ForeName": "Andrea", + "LastName": "Piunti", + "abbrevName": "Piunti A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Piunti", + "orcid": null + }, + { + "ForeName": "Giacomo", + "LastName": "Delledonne", + "abbrevName": "Delledonne GA", + "email": null, + "isCollectiveName": false, + "name": "Giacomo A Delledonne", + "orcid": null + }, + { + "ForeName": "Nadia", + "LastName": "Coltella", + "abbrevName": "Coltella N", + "email": null, + "isCollectiveName": false, + "name": "Nadia Coltella", + "orcid": null + }, + { + "ForeName": "Roberta", + "LastName": "Valsecchi", + "abbrevName": "Valsecchi R", + "email": null, + "isCollectiveName": false, + "name": "Roberta Valsecchi", + "orcid": null + }, + { + "ForeName": "Alessandra", + "LastName": "Villa", + "abbrevName": "Villa A", + "email": null, + "isCollectiveName": false, + "name": "Alessandra Villa", + "orcid": null + }, + { + "ForeName": "Ugo", + "LastName": "Cavallaro", + "abbrevName": "Cavallaro U", + "email": null, + "isCollectiveName": false, + "name": "Ugo Cavallaro", + "orcid": null + }, + { + "ForeName": "Linda", + "LastName": "Pattini", + "abbrevName": "Pattini L", + "email": null, + "isCollectiveName": false, + "name": "Linda Pattini", + "orcid": null + }, + { + "ForeName": "Claudio", + "LastName": "Doglioni", + "abbrevName": "Doglioni C", + "email": null, + "isCollectiveName": false, + "name": "Claudio Doglioni", + "orcid": null + }, + { + "ForeName": "Rosa", + "LastName": "Bernardi", + "abbrevName": "Bernardi R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Bernardi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/jci.insight.87380", + "pmid": "28239645", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "JCI Insight 2 2017", + "title": "PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes." + } + }, + { + "pmid": "28054302", + "pubmed": { + "ISODate": "2017-04-01T00:00:00.000Z", + "abstract": "PURPOSE: Despite advances that have been made in systemic chemotherapy, the prognosis of advanced triple-negative breast cancer (TNBC) patients is still poor. The identification of key factors governing TNBC development is considered imperative for the development of novel effective therapeutic approaches. Previously, it has been reported that microRNA (miR)-761 may act as either a tumor suppressor or as an oncogene in different types of cancer. Here, we aimed at assessing the biological role of this miRNA in TNBC. METHODS: First, we measured the expression of miR-761 in primary breast cancer tissues and breast cancer-derived cell lines using qRT-PCR. Subsequently, over-expression and silencing experiments were performed to determine the role of miR-761 in TNBC cell proliferation, colony formation, migration and invasion in vitro. The in vivo role of miR-761 in TNBC growth and metastasis was determined in mouse models. Bioinformatics analyses, dual-luciferase reporter assays, Western blot analyses and rescue experiments were performed to identify miR-761 target gene(s). RESULTS: We found that miR-761 was up-regulated in primary breast cancer tissues and its derived cell lines and, particularly, in TNBC tissues and cell lines. We also found that exogenous miR-761 over-expression augmented in vitro TNBC cell proliferation, colony formation, migration and invasion, whereas miR-761 down-regulation impaired these features. In vivo, we found that miR-761 over-expression facilitated TNBC growth and lung metastasis. Mechanistically, miR-761 was found to negatively regulate the expression of tripartite motif-containing 29 (TRIM29) in TNBC cells by binding to the 3'-untranslated region of its mRNA. In conformity with these results, a significant negative correlation between miR-761 expression and TRIM29 protein expression was noted in primary TNBC tissues (r = -0.452, p = 0.0126). We also found that exogenous TRIM29 over-expression reversed the proliferative and invasive capacities of TNBC cells. CONCLUSIONS: Our data indicate that miR-761 acts as an oncogene in TNBC. This mode of action can, at least partially, be ascribed to the down-regulation of its target TRIM29. We suggest that miR-761 may serve as a promising therapeutic target for TNBC.", + "authors": { + "abbreviation": "Guang-Cheng Guo, Jia-Xiang Wang, Ming-Li Han, ..., Lin Li", + "authorList": [ + { + "ForeName": "Guang-Cheng", + "LastName": "Guo", + "abbrevName": "Guo GC", + "email": null, + "isCollectiveName": false, + "name": "Guang-Cheng Guo", + "orcid": null + }, + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "abbrevName": "Wang JX", + "email": "ggc503@126.com", + "isCollectiveName": false, + "name": "Jia-Xiang Wang", + "orcid": null + }, + { + "ForeName": "Ming-Li", + "LastName": "Han", + "abbrevName": "Han ML", + "email": null, + "isCollectiveName": false, + "name": "Ming-Li Han", + "orcid": null + }, + { + "ForeName": "Lian-Ping", + "LastName": "Zhang", + "abbrevName": "Zhang LP", + "email": null, + "isCollectiveName": false, + "name": "Lian-Ping Zhang", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Lin Li", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "email": [ + "ggc503@126.com" + ], + "name": "Jia-Xiang Wang" + } + ] + }, + "doi": "10.1007/s13402-016-0312-6", + "pmid": "28054302", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Oncol (Dordr) 40 2017", + "title": "microRNA-761 induces aggressive phenotypes in triple-negative breast cancer cells by repressing TRIM29 expression." + } + }, + { + "pmid": "30026228", + "pubmed": { + "ISODate": "2018-07-20T00:00:00.000Z", + "abstract": "Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.", + "authors": { + "abbreviation": "Jing Zhang, Tao Wu, Jeremy Simon, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": "0000-0001-6438-9113" + }, + { + "ForeName": "Tao", + "LastName": "Wu", + "abbrevName": "Wu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wu", + "orcid": "0000-0001-5380-3905" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon J", + "email": null, + "isCollectiveName": false, + "name": "Jeremy Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": "0000-0002-3961-9009" + }, + { + "ForeName": "Ryoichi", + "LastName": "Saito", + "abbrevName": "Saito R", + "email": null, + "isCollectiveName": false, + "name": "Ryoichi Saito", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Xian-De", + "LastName": "Liu", + "abbrevName": "Liu XD", + "email": null, + "isCollectiveName": false, + "name": "Xian-De Liu", + "orcid": "0000-0002-9639-0458" + }, + { + "ForeName": "Eric", + "LastName": "Jonasch", + "abbrevName": "Jonasch E", + "email": null, + "isCollectiveName": false, + "name": "Eric Jonasch", + "orcid": "0000-0003-0943-2806" + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Xiaosai", + "LastName": "Yao", + "abbrevName": "Yao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaosai Yao", + "orcid": "0000-0001-9729-0726" + }, + { + "ForeName": "Bin", + "LastName": "Teh", + "abbrevName": "Teh BT", + "email": null, + "isCollectiveName": false, + "name": "Bin Tean Teh", + "orcid": "0000-0003-1514-1124" + }, + { + "ForeName": "Patrick", + "LastName": "Tan", + "abbrevName": "Tan P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Tan", + "orcid": null + }, + { + "ForeName": "Xingnan", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xingnan Zheng", + "orcid": "0000-0003-3034-4421" + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": "0000-0001-5337-4901" + }, + { + "ForeName": "Cortney", + "LastName": "Lawrence", + "abbrevName": "Lawrence C", + "email": null, + "isCollectiveName": false, + "name": "Cortney Lawrence", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Fan", + "abbrevName": "Fan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Fan", + "orcid": "0000-0003-3842-2391" + }, + { + "ForeName": "Jiang", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiang Geng", + "orcid": "0000-0002-7202-2167" + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Kai", + "LastName": "Hong", + "abbrevName": "Hong K", + "email": null, + "isCollectiveName": false, + "name": "Kai Hong", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Joel", + "LastName": "Parker", + "abbrevName": "Parker JS", + "email": null, + "isCollectiveName": false, + "name": "Joel S Parker", + "orcid": "0000-0003-2080-6901" + }, + { + "ForeName": "J", + "LastName": "Auman", + "abbrevName": "Auman JT", + "email": null, + "isCollectiveName": false, + "name": "J Todd Auman", + "orcid": "0000-0002-9328-8829" + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "W", + "LastName": "Rathmell", + "abbrevName": "Rathmell WK", + "email": null, + "isCollectiveName": false, + "name": "W Kimryn Rathmell", + "orcid": "0000-0002-4984-0225" + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Kirschner", + "abbrevName": "Kirschner MW", + "email": null, + "isCollectiveName": false, + "name": "Marc W Kirschner", + "orcid": "0000-0001-6540-6130" + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": "0000-0002-0574-4856" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": "0000-0003-1246-1333" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "qing_zhang@med.unc.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "qing_zhang@med.unc.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1126/science.aap8411", + "pmid": "30026228", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 361 2018", + "title": "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma." + } + }, + { + "pmid": "26751287", + "pubmed": { + "ISODate": "2016-02-01T00:00:00.000Z", + "abstract": "Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.", + "authors": { + "abbreviation": "Aifu Lin, Chunlai Li, Zhen Xing, ..., Liuqing Yang", + "authorList": [ + { + "ForeName": "Aifu", + "LastName": "Lin", + "abbrevName": "Lin A", + "email": null, + "isCollectiveName": false, + "name": "Aifu Lin", + "orcid": null + }, + { + "ForeName": "Chunlai", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunlai Li", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Xing", + "abbrevName": "Xing Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Xing", + "orcid": null + }, + { + "ForeName": "Qingsong", + "LastName": "Hu", + "abbrevName": "Hu Q", + "email": null, + "isCollectiveName": false, + "name": "Qingsong Hu", + "orcid": null + }, + { + "ForeName": "Ke", + "LastName": "Liang", + "abbrevName": "Liang K", + "email": null, + "isCollectiveName": false, + "name": "Ke Liang", + "orcid": null + }, + { + "ForeName": "Leng", + "LastName": "Han", + "abbrevName": "Han L", + "email": null, + "isCollectiveName": false, + "name": "Leng Han", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Wang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Hawke", + "abbrevName": "Hawke DH", + "email": null, + "isCollectiveName": false, + "name": "David H Hawke", + "orcid": "0000-0002-6102-7843" + }, + { + "ForeName": "Shouyu", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shouyu Wang", + "orcid": null + }, + { + "ForeName": "Yanyan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhang", + "orcid": null + }, + { + "ForeName": "Yongkun", + "LastName": "Wei", + "abbrevName": "Wei Y", + "email": null, + "isCollectiveName": false, + "name": "Yongkun Wei", + "orcid": null + }, + { + "ForeName": "Guolin", + "LastName": "Ma", + "abbrevName": "Ma G", + "email": null, + "isCollectiveName": false, + "name": "Guolin Ma", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Park", + "abbrevName": "Park PK", + "email": null, + "isCollectiveName": false, + "name": "Peter K Park", + "orcid": null + }, + { + "ForeName": "Jianwei", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jianwei Zhou", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Zhou", + "orcid": null + }, + { + "ForeName": "Zhibin", + "LastName": "Hu", + "abbrevName": "Hu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhibin Hu", + "orcid": null + }, + { + "ForeName": "Yubin", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yubin Zhou", + "orcid": null + }, + { + "ForeName": "Jeffery", + "LastName": "Marks", + "abbrevName": "Marks JR", + "email": null, + "isCollectiveName": false, + "name": "Jeffery R Marks", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Han Liang", + "orcid": "0000-0001-7633-286X" + }, + { + "ForeName": "Mien-Chie", + "LastName": "Hung", + "abbrevName": "Hung MC", + "email": null, + "isCollectiveName": false, + "name": "Mien-Chie Hung", + "orcid": null + }, + { + "ForeName": "Chunru", + "LastName": "Lin", + "abbrevName": "Lin C", + "email": null, + "isCollectiveName": false, + "name": "Chunru Lin", + "orcid": null + }, + { + "ForeName": "Liuqing", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Liuqing Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3295", + "pmid": "26751287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer." + } + }, + { + "pmid": "27137755", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": "The aggressiveness of triple-negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self-renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia-inducible factor-1α (HIF-1α) expression is associated with aggressiveness of cancer. Nonetheless, how HIF-1α expression is regulated and how HIF-1α induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF-1α expression has not yet been studied. Here, we show that clinically relevant low-dose FTI, tipifarnib (300 nM), decreased HIF-1α expression, migration and tumorsphere formation in human MDA-MB-231 TNBC cells under a normoxic condition. In contrast, the low-dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA-MB 231 cells. Tipifarnib-induced decrease in HIF-1α expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E-cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF-1α-Snail pathway. J. Cell. Physiol. 232: 192-201, 2017. © 2016 Wiley Periodicals, Inc.", + "authors": { + "abbreviation": "Tomokazu Tanaka, Yuichi Ikegami, Harumasa Nakazawa, ..., Masao Kaneki", + "authorList": [ + { + "ForeName": "Tomokazu", + "LastName": "Tanaka", + "abbrevName": "Tanaka T", + "email": null, + "isCollectiveName": false, + "name": "Tomokazu Tanaka", + "orcid": null + }, + { + "ForeName": "Yuichi", + "LastName": "Ikegami", + "abbrevName": "Ikegami Y", + "email": null, + "isCollectiveName": false, + "name": "Yuichi Ikegami", + "orcid": null + }, + { + "ForeName": "Harumasa", + "LastName": "Nakazawa", + "abbrevName": "Nakazawa H", + "email": null, + "isCollectiveName": false, + "name": "Harumasa Nakazawa", + "orcid": null + }, + { + "ForeName": "Naohide", + "LastName": "Kuriyama", + "abbrevName": "Kuriyama N", + "email": null, + "isCollectiveName": false, + "name": "Naohide Kuriyama", + "orcid": null + }, + { + "ForeName": "Miwa", + "LastName": "Oki", + "abbrevName": "Oki M", + "email": null, + "isCollectiveName": false, + "name": "Miwa Oki", + "orcid": null + }, + { + "ForeName": "Jun-Ichi", + "LastName": "Hanai", + "abbrevName": "Hanai J", + "email": null, + "isCollectiveName": false, + "name": "Jun-Ichi Hanai", + "orcid": null + }, + { + "ForeName": "Vikas", + "LastName": "Sukhatme", + "abbrevName": "Sukhatme VP", + "email": null, + "isCollectiveName": false, + "name": "Vikas P Sukhatme", + "orcid": null + }, + { + "ForeName": "Masao", + "LastName": "Kaneki", + "abbrevName": "Kaneki M", + "email": "mkaneki@helix.mgh.harvard.edu", + "isCollectiveName": false, + "name": "Masao Kaneki", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masao", + "LastName": "Kaneki", + "email": [ + "mkaneki@helix.mgh.harvard.edu" + ], + "name": "Masao Kaneki" + } + ] + }, + "doi": "10.1002/jcp.25411", + "pmid": "27137755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Physiol 232 2017", + "title": "Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1α and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro." + } + }, + { + "pmid": "35188449", + "pubmed": { + "ISODate": "2022-05-01T00:00:00.000Z", + "abstract": "There is no clear treatment guideline or individualized treatment plan for triple-negative breast cancer (TNBC). The aim of this study was to investigate more effective targets for TNBC-targeted therapy. MDA-MB-231 and BT549 cell lines were used to explore the function of LINC00649 on the proliferation, invasion, and migration of TNBC cells. A mice subcutaneous tumor model and a pulmonary metastasis model was established to identify the role of LINC00649 on the growth and metastasis of TNBC in vivo. LINC00649 was found to be a key molecule involved in the occurrence and development of TNBC by screening of public databases and detection of TNBC clinical samples. LINC00649 increased hypoxia-inducible factor 1α (HIF-1α) mRNA stability and protein expression by interacting with the nuclear factor 90 (NF90)/NF45 complex. In vitro, interference with LINC00649 inhibits MDA-MB-231 and BT549 cell proliferation, migration, and invasion, and the addition of HIF-1α revised this effect. In vivo experiments showed that LINC00649 promoted the growth and metastasis of TNBC. We demonstrated that LINC00649 interacts with the NF90/NF45 complex to increase the mRNA stability of HIF-1α and up-regulate HIF-1α expression, thereby inducing the proliferation, invasion, and migration of TNBC cells as well as tumor growth and metastasis.", + "authors": { + "abbreviation": "Jianhua Zhang, Chuang Du, Linfeng Zhang, ..., Jingruo Li", + "authorList": [ + { + "ForeName": "Jianhua", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jianhua Zhang", + "orcid": null + }, + { + "ForeName": "Chuang", + "LastName": "Du", + "abbrevName": "Du C", + "email": null, + "isCollectiveName": false, + "name": "Chuang Du", + "orcid": null + }, + { + "ForeName": "Linfeng", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Linfeng Zhang", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Wang", + "orcid": null + }, + { + "ForeName": "Yingying", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingying Zhang", + "orcid": null + }, + { + "ForeName": "Jingruo", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jingruo Li", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2022.2040283", + "pmid": "35188449", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Cycle 21 2022", + "title": "LncRNA LINC00649 promotes the growth and metastasis of triple-negative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex." + } + }, + { + "pmid": "33824311", + "pubmed": { + "ISODate": "2021-04-06T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15-20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.", + "authors": { + "abbreviation": "Fengxia Chen, Qingqing Wang, Xiaoyan Yu, ..., Yunfeng Zhou", + "authorList": [ + { + "ForeName": "Fengxia", + "LastName": "Chen", + "abbrevName": "Chen F", + "email": null, + "isCollectiveName": false, + "name": "Fengxia Chen", + "orcid": null + }, + { + "ForeName": "Qingqing", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqing Wang", + "orcid": "0000-0002-6440-582X" + }, + { + "ForeName": "Xiaoyan", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyan Yu", + "orcid": null + }, + { + "ForeName": "Ningning", + "LastName": "Yang", + "abbrevName": "Yang N", + "email": null, + "isCollectiveName": false, + "name": "Ningning Yang", + "orcid": null + }, + { + "ForeName": "Yuan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Wang", + "orcid": "0000-0003-1894-0853" + }, + { + "ForeName": "Yangyang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yangyang Zeng", + "orcid": null + }, + { + "ForeName": "Zhewen", + "LastName": "Zheng", + "abbrevName": "Zheng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhewen Zheng", + "orcid": null + }, + { + "ForeName": "Fuxiang", + "LastName": "Zhou", + "abbrevName": "Zhou F", + "email": null, + "isCollectiveName": false, + "name": "Fuxiang Zhou", + "orcid": null + }, + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": "yfzhouwhu@163.com", + "isCollectiveName": false, + "name": "Yunfeng Zhou", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "email": [ + "yfzhouwhu@163.com" + ], + "name": "Yunfeng Zhou" + } + ] + }, + "doi": "10.1038/s41419-021-03661-4", + "pmid": "33824311", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis." + } + }, + { + "pmid": "25920936", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.", + "authors": { + "abbreviation": "Shuang Li, Qingzhu Wei, Qin Li, ..., Qiang Xiao", + "authorList": [ + { + "ForeName": "Shuang", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuang Li", + "orcid": null + }, + { + "ForeName": "Qingzhu", + "LastName": "Wei", + "abbrevName": "Wei Q", + "email": null, + "isCollectiveName": false, + "name": "Qingzhu Wei", + "orcid": null + }, + { + "ForeName": "Qin", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qin Li", + "orcid": null + }, + { + "ForeName": "Bin", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bin Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Xiao", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2015.1040958", + "pmid": "25920936", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 16 2015", + "title": "Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer." + } + }, + { + "pmid": "32114388", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Liver cancer stem cells (CSCs) are critical determinants of HCC relapse and therapeutic resistance, but the mechanisms underlying the maintenance of CSCs are poorly understood. We aimed to explore the role of tumor repressor Zinc-fingers and homeoboxes 2 (ZHX2) in liver CSCs. METHODS: CD133+ or EPCAM+ stem-like liver cancer cells were sorted from tumor tissues of HCC patients and HCC cell lines by flow cytometry. In addition, sorafenib-resistant cells, tumor-sphere forming cells and side population (SP) cells were respectively cultured and isolated as hepatic CSCs. The tumor-initiating and chemoresistance properties of ZHX2-overexpressing and ZHX2-knockdown cells were analyzed in vivo and in vitro. Microarray, luciferase reporter assay, chromatin immunoprecipitation (ChIP) and ChIP-on-chip analyses were performed to explore ZHX2 target genes. The expression of ZHX2 and its target gene were determined by quantitative RT-PCR, western blot, immunofluorescence and immunohistochemical staining in hepatoma cells and tumor and adjacent tissues from HCC patients. RESULTS: ZHX2 expression was significantly reduced in liver CSCs from different origins. ZHX2 deficiency led to enhanced liver tumor progression and expansion of CSC populations in vitro and in vivo. Re-expression of ZHX2 restricted capabilities of hepatic CSCs in supporting tumor initiation, self-renewal and sorafenib-resistance. Mechanically, ZHX2 suppressed liver CSCs via inhibiting KDM2A-mediated demethylation of histone H3 lysine 36 (H3K36) at the promoter regions of stemness-associated transcription factors, such as NANOG, SOX4 and OCT4. Moreover, patients with lower expression of ZHX2 and higher expression of KDM2A in tumor tissues showed significantly poorer survival. CONCLUSION: ZHX2 counteracts stem cell traits through transcriptionally repressing KDM2A in HCC. Our data will aid in a better understanding of molecular mechanisms underlying HCC relapse and drug resistance.", + "authors": { + "abbreviation": "Qinghai Lin, Zhuanchang Wu, Xuetian Yue, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Ying He", + "orcid": null + }, + { + "ForeName": "Yutong", + "LastName": "Ge", + "abbrevName": "Ge Y", + "email": null, + "isCollectiveName": false, + "name": "Yutong Ge", + "orcid": null + }, + { + "ForeName": "Siyu", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Siyu Tan", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Song", + "abbrevName": "Song H", + "email": null, + "isCollectiveName": false, + "name": "Hui Song", + "orcid": null + }, + { + "ForeName": "Detian", + "LastName": "Yuan", + "abbrevName": "Yuan D", + "email": null, + "isCollectiveName": false, + "name": "Detian Yuan", + "orcid": null + }, + { + "ForeName": "Yaoqin", + "LastName": "Gong", + "abbrevName": "Gong Y", + "email": null, + "isCollectiveName": false, + "name": "Yaoqin Gong", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.ebiom.2020.102676", + "pmid": "32114388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EBioMedicine 53 2020", + "title": "ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation." + } + }, + { + "pmid": "29333926", + "pubmed": { + "ISODate": "2018-04-03T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by poor patient prognosis and for which no targeted therapies are currently available. TNBC can be further categorized as either basal-like (BLBC) or quintuple-negative breast cancer (QNBC). In the present study, we aimed to identify novel molecular therapeutic targets for TNBC by analyzing the mRNA expression of TNBC-related genes in publicly available microarray data sets. We found that Engrailed 1 (EN1) was significantly overexpressed in TNBC. Using breast cancer cell lines, we found that EN1 was more highly expressed in TNBC than in other breast cancer subtypes. EN1 expression was analyzed in 199 TNBC paraffin-embedded tissue samples by immunohistochemistry. EN1 protein expression was positively associated with reduced overall survival (OS) rate in patients with QNBC, but not those with BLBC. The importance of EN1 expression in QNBC cell viability and tumorigenicity was evaluated using the QNBC cell lines, HCC38 and HCC1395. Based on our data, EN1 may promote the proliferation, migration, and multinucleation of QNBC cells, likely via the transcriptional activation of HDAC8, UTP11L, and ZIC3. We also demonstrated that actinomycin D effectively inhibits EN1 activity in QNBC cells. The results of the present study suggest that EN1 activity is highly clinically relevant to the survival prognosis of patients with QNBC and EN1 is a promising potential therapeutic target for future QNBC treatment.", + "authors": { + "abbreviation": "Yu Jin Kim, Minjung Sung, Ensel Oh, ..., Yoon-La Choi", + "authorList": [ + { + "ForeName": "Yu", + "LastName": "Kim", + "abbrevName": "Kim YJ", + "email": null, + "isCollectiveName": false, + "name": "Yu Jin Kim", + "orcid": null + }, + { + "ForeName": "Minjung", + "LastName": "Sung", + "abbrevName": "Sung M", + "email": null, + "isCollectiveName": false, + "name": "Minjung Sung", + "orcid": null + }, + { + "ForeName": "Ensel", + "LastName": "Oh", + "abbrevName": "Oh E", + "email": null, + "isCollectiveName": false, + "name": "Ensel Oh", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Vrancken", + "abbrevName": "Vrancken MV", + "email": null, + "isCollectiveName": false, + "name": "Michael Van Vrancken", + "orcid": null + }, + { + "ForeName": "Ji-Young", + "LastName": "Song", + "abbrevName": "Song JY", + "email": null, + "isCollectiveName": false, + "name": "Ji-Young Song", + "orcid": null + }, + { + "ForeName": "Kyungsoo", + "LastName": "Jung", + "abbrevName": "Jung K", + "email": null, + "isCollectiveName": false, + "name": "Kyungsoo Jung", + "orcid": null + }, + { + "ForeName": "Yoon-La", + "LastName": "Choi", + "abbrevName": "Choi YL", + "email": null, + "isCollectiveName": false, + "name": "Yoon-La Choi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2018.1423913", + "pmid": "29333926", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 19 2018", + "title": "Engrailed 1 overexpression as a potential prognostic marker in quintuple-negative breast cancer." + } + }, + { + "pmid": "31683461", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "OBJECTIVE: To investigate the effect of ZHX2 on lung cancer cells proliferation and apoptosis. MATERIALS AND METHODS: The mRNA and protein expression of ZHX2 were detected by qRT-PCR and western blot, respectively. The human lung cancer cells were divided into Control, NC, ZHX2, SB, and ZHX2 + Ani groups. The cell proliferation was detected by CCK-8 assay and the cell migration and invasion were detected by Transwell assay. Cell apoptosis was detected by flow cytometry. Apoptosis and p38MAPK signaling pathway related proteins were detected by western blot. The nude mice model of lung cancer xenograft was constructed. The tumor volume and tumor weight were measured. The expression of PCNA protein in tumor tissues was detected by immunohistochemistry. The apoptosis of tumor cells was detected by TUNEL staining. The ZHX2 and p38MAPK signaling pathway related proteins in tumor tissues were detected by western blot. RESULTS: The expression of ZHX2 gene and protein in the cancer cell lines were significantly decreased. Compared with control and NC groups, the cells proliferation, migration and invasion were inhibited in ZHX2 and SB groups, while the apoptosis and apoptosis related proteins were increased (p< 0.05). Meanwhile, compared with ZHX2 group, the tumor growth rate, volume, weight, the percentage of PCNA-positive cells, and p-P38 MAPK/P38 MAPK were increased significantly in ZHX2 + Ani group, while the apoptotic index and the expression of MMP-9 protein were significantly decreased (p< 0.05). CONCLUSION: ZHX2 could inhibit proliferation and promote apoptosis of lung cancer cells by inhibiting p38MAPK signaling pathway.", + "authors": { + "abbreviation": "Xudong Tian, Yadong Wang, Shuhai Li, ..., Hui Tian", + "authorList": [ + { + "ForeName": "Xudong", + "LastName": "Tian", + "abbrevName": "Tian X", + "email": null, + "isCollectiveName": false, + "name": "Xudong Tian", + "orcid": null + }, + { + "ForeName": "Yadong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yadong Wang", + "orcid": null + }, + { + "ForeName": "Shuhai", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuhai Li", + "orcid": null + }, + { + "ForeName": "Weiming", + "LastName": "Yue", + "abbrevName": "Yue W", + "email": null, + "isCollectiveName": false, + "name": "Weiming Yue", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Tian", + "abbrevName": "Tian H", + "email": null, + "isCollectiveName": false, + "name": "Hui Tian", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3233/CBM-190514", + "pmid": "31683461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Biomark 27 2020", + "title": "ZHX2 inhibits proliferation and promotes apoptosis of human lung cancer cells through targeting p38MAPK pathway." + } + }, + { + "pmid": "36228375", + "pubmed": { + "ISODate": "2022-12-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly aggressive and hypoxic compared with other subtypes. The role of hypoxia inducible factor 1α (HIF-1α) as a key hypoxic transcription factor in oncogenic processes has been extensively studied. Recently, it has been shown that HIF-1α regulates the complex biological processes of TNBC, such as glycolysis, angiogenesis, invasion and metastasis, breast cancer stem cells (BCSCs) enrichment, and immune escape, to promote TNBC survival and development through the activation of downstream target genes. In addition, inflammatory mediators, oxygen levels, noncoding RNAs, complex signaling regulatory networks, epigenetic regulators are involved in the upstream regulatory expression of HIF-1α. However, further studies are needed to determine the potential and future directions of targeting HIF-1α in TNBC. This article discusses the expression of the HIF-1α transcription factor in TNBC. We also explored the mechanism by which HIF-1α drives TNBC progression. The potential significance of targeting HIF-1α for immunotherapy, chemotherapy, anti-angiogenic therapy, and photodynamic therapy is discussed. The intrinsic mechanism, existing problems and future directions of targeting HIF-1α are also studied.", + "authors": { + "abbreviation": "Qi Liu, Chengcheng Guan, Cui Liu, ..., Changgang Sun", + "authorList": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": "2020110892@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Qi Liu", + "orcid": null + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "abbrevName": "Guan C", + "email": "2020110896@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Chengcheng Guan", + "orcid": null + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": "2019101062@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Cui Liu", + "orcid": null + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "abbrevName": "Li H", + "email": "2019101020@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Huayao Li", + "orcid": null + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "2020111256@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Jibiao Wu", + "orcid": null + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "abbrevName": "Sun C", + "email": "zyxyscg@wfmc.edu.cn", + "isCollectiveName": false, + "name": "Changgang Sun", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "email": [ + "2020110892@sdutcm.edu.cn" + ], + "name": "Qi Liu" + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "email": [ + "2020110896@sdutcm.edu.cn" + ], + "name": "Chengcheng Guan" + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "email": [ + "2019101062@sdutcm.edu.cn" + ], + "name": "Cui Liu" + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "email": [ + "2019101020@sdutcm.edu.cn" + ], + "name": "Huayao Li" + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "email": [ + "2020111256@sdutcm.edu.cn" + ], + "name": "Jibiao Wu" + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "email": [ + "zyxyscg@wfmc.edu.cn" + ], + "name": "Changgang Sun" + } + ] + }, + "doi": "10.1016/j.biopha.2022.113861", + "pmid": "36228375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biomed Pharmacother 156 2022", + "title": "Targeting hypoxia-inducible factor-1alpha: A new strategy for triple-negative breast cancer therapy." + } + }, + { + "pmid": "32778144", + "pubmed": { + "ISODate": "2020-08-10T00:00:00.000Z", + "abstract": "BACKGROUND: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. METHODS: In order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation. RESULTS: We first determined that IL-1β expression correlates with the levels of HIF-1α as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1α, GPER and the IL-1β/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1β that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1β released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs. CONCLUSIONS: Our data shed new light on the role of hypoxia in the activation of the IL-1β/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.", + "authors": { + "abbreviation": "Rosamaria Lappano, Marianna Talia, Francesca Cirillo, ..., Marcello Maggiolini", + "authorList": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "abbrevName": "Lappano R", + "email": "rosamaria.lappano@unical.it", + "isCollectiveName": false, + "name": "Rosamaria Lappano", + "orcid": null + }, + { + "ForeName": "Marianna", + "LastName": "Talia", + "abbrevName": "Talia M", + "email": null, + "isCollectiveName": false, + "name": "Marianna Talia", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Cirillo", + "abbrevName": "Cirillo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Cirillo", + "orcid": null + }, + { + "ForeName": "Damiano", + "LastName": "Rigiracciolo", + "abbrevName": "Rigiracciolo DC", + "email": null, + "isCollectiveName": false, + "name": "Damiano Cosimo Rigiracciolo", + "orcid": null + }, + { + "ForeName": "Domenica", + "LastName": "Scordamaglia", + "abbrevName": "Scordamaglia D", + "email": null, + "isCollectiveName": false, + "name": "Domenica Scordamaglia", + "orcid": null + }, + { + "ForeName": "Rita", + "LastName": "Guzzi", + "abbrevName": "Guzzi R", + "email": null, + "isCollectiveName": false, + "name": "Rita Guzzi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Miglietta", + "abbrevName": "Miglietta AM", + "email": null, + "isCollectiveName": false, + "name": "Anna Maria Miglietta", + "orcid": null + }, + { + "ForeName": "Ernestina", + "LastName": "De Francesco", + "abbrevName": "De Francesco EM", + "email": null, + "isCollectiveName": false, + "name": "Ernestina Marianna De Francesco", + "orcid": null + }, + { + "ForeName": "Antonino", + "LastName": "Belfiore", + "abbrevName": "Belfiore A", + "email": null, + "isCollectiveName": false, + "name": "Antonino Belfiore", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "abbrevName": "Maggiolini M", + "email": "marcello.maggiolini@unical.it", + "isCollectiveName": false, + "name": "Marcello Maggiolini", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "email": [ + "rosamaria.lappano@unical.it" + ], + "name": "Rosamaria Lappano" + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "email": [ + "marcello.maggiolini@unical.it" + ], + "name": "Marcello Maggiolini" + } + ] + }, + "doi": "10.1186/s13046-020-01667-y", + "pmid": "32778144", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Exp Clin Cancer Res 39 2020", + "title": "The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)." + } + }, + { + "pmid": "24670641", + "pubmed": { + "ISODate": "2014-04-03T00:00:00.000Z", + "abstract": "Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Xi Chen, Dimitrios Iliopoulos, Qing Zhang, ..., Laurie H Glimcher", + "authorList": [ + { + "ForeName": "Xi", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xi Chen", + "orcid": null + }, + { + "ForeName": "Dimitrios", + "LastName": "Iliopoulos", + "abbrevName": "Iliopoulos D", + "email": null, + "isCollectiveName": false, + "name": "Dimitrios Iliopoulos", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + }, + { + "ForeName": "Qianzi", + "LastName": "Tang", + "abbrevName": "Tang Q", + "email": null, + "isCollectiveName": false, + "name": "Qianzi Tang", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Greenblatt", + "abbrevName": "Greenblatt MB", + "email": null, + "isCollectiveName": false, + "name": "Matthew B Greenblatt", + "orcid": null + }, + { + "ForeName": "Maria", + "LastName": "Hatziapostolou", + "abbrevName": "Hatziapostolou M", + "email": null, + "isCollectiveName": false, + "name": "Maria Hatziapostolou", + "orcid": null + }, + { + "ForeName": "Elgene", + "LastName": "Lim", + "abbrevName": "Lim E", + "email": null, + "isCollectiveName": false, + "name": "Elgene Lim", + "orcid": null + }, + { + "ForeName": "Wai", + "LastName": "Tam", + "abbrevName": "Tam WL", + "email": null, + "isCollectiveName": false, + "name": "Wai Leong Tam", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ni", + "abbrevName": "Ni M", + "email": null, + "isCollectiveName": false, + "name": "Min Ni", + "orcid": null + }, + { + "ForeName": "Yiwen", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yiwen Chen", + "orcid": null + }, + { + "ForeName": "Junhua", + "LastName": "Mai", + "abbrevName": "Mai J", + "email": null, + "isCollectiveName": false, + "name": "Junhua Mai", + "orcid": null + }, + { + "ForeName": "Haifa", + "LastName": "Shen", + "abbrevName": "Shen H", + "email": null, + "isCollectiveName": false, + "name": "Haifa Shen", + "orcid": null + }, + { + "ForeName": "Dorothy", + "LastName": "Hu", + "abbrevName": "Hu DZ", + "email": null, + "isCollectiveName": false, + "name": "Dorothy Z Hu", + "orcid": null + }, + { + "ForeName": "Stanley", + "LastName": "Adoro", + "abbrevName": "Adoro S", + "email": null, + "isCollectiveName": false, + "name": "Stanley Adoro", + "orcid": null + }, + { + "ForeName": "Bella", + "LastName": "Hu", + "abbrevName": "Hu B", + "email": null, + "isCollectiveName": false, + "name": "Bella Hu", + "orcid": null + }, + { + "ForeName": "Minkyung", + "LastName": "Song", + "abbrevName": "Song M", + "email": null, + "isCollectiveName": false, + "name": "Minkyung Song", + "orcid": null + }, + { + "ForeName": "Chen", + "LastName": "Tan", + "abbrevName": "Tan C", + "email": null, + "isCollectiveName": false, + "name": "Chen Tan", + "orcid": null + }, + { + "ForeName": "Melissa", + "LastName": "Landis", + "abbrevName": "Landis MD", + "email": null, + "isCollectiveName": false, + "name": "Melissa D Landis", + "orcid": null + }, + { + "ForeName": "Mauro", + "LastName": "Ferrari", + "abbrevName": "Ferrari M", + "email": null, + "isCollectiveName": false, + "name": "Mauro Ferrari", + "orcid": null + }, + { + "ForeName": "Sandra", + "LastName": "Shin", + "abbrevName": "Shin SJ", + "email": null, + "isCollectiveName": false, + "name": "Sandra J Shin", + "orcid": null + }, + { + "ForeName": "Myles", + "LastName": "Brown", + "abbrevName": "Brown M", + "email": null, + "isCollectiveName": false, + "name": "Myles Brown", + "orcid": null + }, + { + "ForeName": "Jenny", + "LastName": "Chang", + "abbrevName": "Chang JC", + "email": null, + "isCollectiveName": false, + "name": "Jenny C Chang", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XS", + "email": null, + "isCollectiveName": false, + "name": "X Shirley Liu", + "orcid": null + }, + { + "ForeName": "Laurie", + "LastName": "Glimcher", + "abbrevName": "Glimcher LH", + "email": null, + "isCollectiveName": false, + "name": "Laurie H Glimcher", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13119", + "pmid": "24670641", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 508 2014", + "title": "XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway." + } + }, + { + "pmid": "32382017", + "pubmed": { + "ISODate": "2020-05-07T00:00:00.000Z", + "abstract": "Zinc fingers and homeoboxes 2 (ZHX2) was found as a novel VHL substrate target, and acted as an oncogenic driver in ccRCC. However, the detailed mechanism of ZHX2 in ccRCC development remains elusive, and no research has focused on studying ZHX2 in drug resistance yet. A tissue microarray with 358 ccRCC samples was used to determine the expression of ZHX2 in ccRCC patients. VHL-deficient cell line 786-O and VHL-normal cell line CAKI-1 was used for lineage reprogramming by transfecting with lentivirus. The in vitro and in vivo experiments were performed with these new cell lines to determine the mechanism of ZHX2 in ccRCC development and drug resistance. Immunohistochemistry analysis showed that ZHX2 was not highly expressed in ccRCC tumor tissues, only 33.2% (119/358) patients have high ZHX2 expression. However, high ZHX2 was significantly associated with advanced Fuhrman grade (p = 0.004), and proved to be an independent prognosis factor for progression-free survival (p = 0.0003), while there is no significant correlation with overall survival. We further discovered that ZHX2 overexpression could increase VEGF secretion and transcriptional activate the MEK/ERK1/2 and promote its downstream targets. We also found ZHX2 overexpression induce Sunitinib resistance though activating autophagy and the combination treatment of Sunitinib and Chloroquine could significantly rescue the phenomenon. In summary, these results indicate that ZHX2 drivers cell growth, migration though increase VEGF expression, and transcriptional activate MEK/ERK1/2 signaling pathway, and could induce Sunitinib resistance by regulating self-protective autophagy, these may provide new insight in advanced ccRCC treatment.", + "authors": { + "abbreviation": "Liangsong Zhu, Rong Ding, Hao Yan, ..., Zongming Lin", + "authorList": [ + { + "ForeName": "Liangsong", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liangsong Zhu", + "orcid": null + }, + { + "ForeName": "Rong", + "LastName": "Ding", + "abbrevName": "Ding R", + "email": null, + "isCollectiveName": false, + "name": "Rong Ding", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Yan", + "abbrevName": "Yan H", + "email": null, + "isCollectiveName": false, + "name": "Hao Yan", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "med-zhangjin@vip.sina.com", + "isCollectiveName": false, + "name": "Jin Zhang", + "orcid": null + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "abbrevName": "Lin Z", + "email": "lin.zongming@zs-hospital.sh.cn", + "isCollectiveName": false, + "name": "Zongming Lin", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jin", + "LastName": "Zhang", + "email": [ + "med-zhangjin@vip.sina.com" + ], + "name": "Jin Zhang" + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "email": [ + "lin.zongming@zs-hospital.sh.cn" + ], + "name": "Zongming Lin" + } + ] + }, + "doi": "10.1038/s41419-020-2541-x", + "pmid": "32382017", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 11 2020", + "title": "ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma." + } + }, + { + "pmid": "31529195", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype. Extended periods of lactation protect against breast cancer development, but the mechanisms underlying this protection are unknown. We examined the effects of the milk protein alpha-casein over expression in the triple negative MDA-MB-231 breast cancer cell line. The effects of recombinant alpha-casein added exogenously to MDA-MB-231 breast cancer cells, and immortalised human fibroblasts were also investigated. We used transcriptional reporters to understand the signalling pathways downstream of alpha-casein in breast cancer cells and these fibroblasts that were activated by breast cancer cells. To extend our findings to the clinical setting, we analysed public gene expression datasets to further understand the relevance of these signalling pathways in triple negative breast cancer cells and patient samples. Finally, we used small molecular inhibitors to target relevant pathways and highlight these as potential candidates for the treatment of TN breast cancer. High levels of alpha-casein gene expression were predictive of good prognosis across 263 TNBC patient tumour samples. Alpha-casein over expression or exogenous addition reduces cancer stem cell (CSC) activity. HIF-1alpha was identified to be a key downstream target of alpha-casein, in both breast cancer cells and activated fibroblasts, and STAT transcription factors to be upstream of HIF-1alpha. Interestingly, HIF-1alpha is regulated by STAT3 in breast cancer cells, but STAT1 is the regulator of HIF-1alpha in activated fibroblasts. In analysis of 573 TNBC patient samples, alpha-casein expression, inversely correlated to HIF-1alpha, STAT3 and STAT1. STAT1 and STAT3 inhibitors target HIF-1alpha signalling in activated fibroblasts and MDA-MB-231 breast cancer cells respectively, and also abrogate CSC activities. Our findings provide an explanation for the protective effects of lactation in TNBC. Clinical data correlates high alpha-casein expression with increased recurrence-free survival in TNBC patients. Mechanistically, alpha-casein reduces breast cancer stem cell activity in vitro, and STAT3 and STAT1 were identified as regulators of pro-tumorigenic HIF-1alpha signalling in breast cancer cells and fibroblasts respectively.", + "authors": { + "abbreviation": "Kirsten E L Garner, Nathan J Hull, Andrew H Sims, ..., Robert B Clarke", + "authorList": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "abbrevName": "Garner KEL", + "email": "Kirsten.garner@manchester.ac.uk", + "isCollectiveName": false, + "name": "Kirsten E L Garner", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Hull", + "abbrevName": "Hull NJ", + "email": null, + "isCollectiveName": false, + "name": "Nathan J Hull", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Lamb", + "abbrevName": "Lamb R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lamb", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Clarke", + "abbrevName": "Clarke RB", + "email": null, + "isCollectiveName": false, + "name": "Robert B Clarke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "email": [ + "Kirsten.garner@manchester.ac.uk" + ], + "name": "Kirsten E L Garner" + } + ] + }, + "doi": "10.1007/s10911-019-09435-1", + "pmid": "31529195", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mammary Gland Biol Neoplasia 24 2019", + "title": "The Milk Protein Alpha-Casein Suppresses Triple Negative Breast Cancer Stem Cell Activity Via STAT and HIF-1alpha Signalling Pathways in Breast Cancer Cells and Fibroblasts." + } + }, + { + "pmid": "32770671", + "pubmed": { + "ISODate": "2020-12-01T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.", + "authors": { + "abbreviation": "Xiangguo Yu, Qinghai Lin, Zhuanchang Wu, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Yankun", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yankun Zhang", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Songbai", + "LastName": "Zhao", + "abbrevName": "Zhao S", + "email": null, + "isCollectiveName": false, + "name": "Songbai Zhao", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Chaojia", + "LastName": "Chen", + "abbrevName": "Chen C", + "email": null, + "isCollectiveName": false, + "name": "Chaojia Chen", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Chunyang", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunyang Li", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": "0000-0002-8121-4718" + } + ], + "contacts": [] + }, + "doi": "10.1002/path.5530", + "pmid": "32770671", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Pathol 252 2020", + "title": "ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p." + } + }, + { + "pmid": "31264274", + "pubmed": { + "ISODate": "2019-10-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.", + "authors": { + "abbreviation": "Chen Gong, Jin Zou, Mingsheng Zhang, ..., Yong Li", + "authorList": [ + { + "ForeName": "Chen", + "LastName": "Gong", + "abbrevName": "Gong C", + "email": null, + "isCollectiveName": false, + "name": "Chen Gong", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zou", + "abbrevName": "Zou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zou", + "orcid": null + }, + { + "ForeName": "Mingsheng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mingsheng Zhang", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Shanshan", + "LastName": "Xu", + "abbrevName": "Xu S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Xu", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Zhu", + "orcid": null + }, + { + "ForeName": "Mengqi", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mengqi Yang", + "orcid": null + }, + { + "ForeName": "Dongjia", + "LastName": "Li", + "abbrevName": "Li D", + "email": null, + "isCollectiveName": false, + "name": "Dongjia Li", + "orcid": null + }, + { + "ForeName": "Yun", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yun Wang", + "orcid": null + }, + { + "ForeName": "Jialu", + "LastName": "Shi", + "abbrevName": "Shi J", + "email": null, + "isCollectiveName": false, + "name": "Jialu Shi", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Li", + "orcid": "0000-0003-4681-263X" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23079", + "pmid": "31264274", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer." + } + }, + { + "pmid": "35867755", + "pubmed": { + "ISODate": "2022-07-12T00:00:00.000Z", + "abstract": "Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Zhaoping Qiu, Weijie Guo, Bo Dong, ..., Yadi Wu", + "authorList": [ + { + "ForeName": "Zhaoping", + "LastName": "Qiu", + "abbrevName": "Qiu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaoping Qiu", + "orcid": null + }, + { + "ForeName": "Weijie", + "LastName": "Guo", + "abbrevName": "Guo W", + "email": null, + "isCollectiveName": false, + "name": "Weijie Guo", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bo Dong", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Wang", + "orcid": null + }, + { + "ForeName": "Pan", + "LastName": "Deng", + "abbrevName": "Deng P", + "email": null, + "isCollectiveName": false, + "name": "Pan Deng", + "orcid": "0000-0003-2974-7389" + }, + { + "ForeName": "Chi", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Chi Wang", + "orcid": null + }, + { + "ForeName": "Jinpeng", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jinpeng Liu", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + }, + { + "ForeName": "Rudolf", + "LastName": "Grosschedl", + "abbrevName": "Grosschedl R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Grosschedl", + "orcid": null + }, + { + "ForeName": "Zhiyong", + "LastName": "Yu", + "abbrevName": "Yu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyong Yu", + "orcid": null + }, + { + "ForeName": "Jiong", + "LastName": "Deng", + "abbrevName": "Deng J", + "email": null, + "isCollectiveName": false, + "name": "Jiong Deng", + "orcid": null + }, + { + "ForeName": "Yadi", + "LastName": "Wu", + "abbrevName": "Wu Y", + "email": null, + "isCollectiveName": false, + "name": "Yadi Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119518119", + "pmid": "35867755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "EBF1 promotes triple-negative breast cancer progression by surveillance of the HIF1α pathway." + } + }, + { + "pmid": "36037364", + "pubmed": { + "ISODate": "2022-09-06T00:00:00.000Z", + "abstract": "Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.", + "authors": { + "abbreviation": "Haibiao Xie, Jin Zhou, Xijuan Liu, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Haibiao", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haibiao Xie", + "orcid": "0000-0001-6729-8479" + }, + { + "ForeName": "Jin", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zhou", + "orcid": null + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Yawei", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yawei Xu", + "orcid": null + }, + { + "ForeName": "Austin", + "LastName": "Hepperla", + "abbrevName": "Hepperla AJ", + "email": null, + "isCollectiveName": false, + "name": "Austin J Hepperla", + "orcid": "0000-0002-0107-2001" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Tao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Yao", + "abbrevName": "Yao H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Yao", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": "0000-0002-9073-3835" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Gong", + "abbrevName": "Gong K", + "email": null, + "isCollectiveName": false, + "name": "Kan Gong", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119854119", + "pmid": "36037364", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer." + } + }, + { + "pmid": "24248265", + "pubmed": { + "ISODate": "2014-02-01T00:00:00.000Z", + "abstract": "UNLABELLED: Targeted therapy against triple-negative breast cancers, which lack expression of the estrogen, progesterone, and HER2 receptors, is not available and the overall response to cytotoxic chemotherapy is poor. One of the molecular hallmarks of triple-negative breast cancers is increased expression of genes that are transcriptionally activated by hypoxia-inducible factors (HIFs), which are implicated in many critical aspects of cancer progression including metabolism, angiogenesis, invasion, metastasis, and stem cell maintenance. Ganetespib is a second-generation inhibitor of heat shock protein 90 (HSP90), a molecular chaperone that is essential for the stability and function of multiple client proteins in cancer cells including HIF-1α. In this study, human MDA-MB-231 and MDA-MB-435 triple-negative breast cancer cells were injected into the mammary fat pad of immunodeficient mice that received weekly intravenous injections of ganetespib or vehicle following the development of palpable tumors. Ganetespib treatment markedly impaired primary tumor growth and vascularization, and eliminated local tissue invasion and distant metastasis to regional lymph nodes and lungs. Ganetespib treatment also significantly reduced the number of Aldefluor-positive cancer stem cells in the primary tumor. Primary tumors of ganetespib-treated mice had significantly reduced levels of HIF-1α (but not HIF-2α) protein and of HIF-1 target gene mRNAs encoding proteins that play key roles in angiogenesis, metabolism, invasion, and metastasis, thereby providing a molecular basis for observed effects of the drug on the growth and metastasis of triple-negative breast cancer. KEY MESSAGES: Triple-negative breast cancers (TNBCs) respond poorly to available chemotherapy. TNBCs overexpress genes regulated by hypoxia-inducible factors (HIFs). Ganetespib induces degradation of HSP90 client proteins, including HIF-1α. Ganetespib inhibited TNBC orthotopic tumor growth, invasion, and metastasis. Ganetespib inhibited expression of HIF-1 target genes involved in TNBC progression.", + "authors": { + "abbreviation": "Lisha Xiang, Daniele M Gilkes, Pallavi Chaturvedi, ..., Gregg L Semenza", + "authorList": [ + { + "ForeName": "Lisha", + "LastName": "Xiang", + "abbrevName": "Xiang L", + "email": null, + "isCollectiveName": false, + "name": "Lisha Xiang", + "orcid": null + }, + { + "ForeName": "Daniele", + "LastName": "Gilkes", + "abbrevName": "Gilkes DM", + "email": null, + "isCollectiveName": false, + "name": "Daniele M Gilkes", + "orcid": null + }, + { + "ForeName": "Pallavi", + "LastName": "Chaturvedi", + "abbrevName": "Chaturvedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Chaturvedi", + "orcid": null + }, + { + "ForeName": "Weibo", + "LastName": "Luo", + "abbrevName": "Luo W", + "email": null, + "isCollectiveName": false, + "name": "Weibo Luo", + "orcid": null + }, + { + "ForeName": "Hongxia", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Hongxia Hu", + "orcid": null + }, + { + "ForeName": "Naoharu", + "LastName": "Takano", + "abbrevName": "Takano N", + "email": null, + "isCollectiveName": false, + "name": "Naoharu Takano", + "orcid": null + }, + { + "ForeName": "Houjie", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Houjie Liang", + "orcid": null + }, + { + "ForeName": "Gregg", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": null, + "isCollectiveName": false, + "name": "Gregg L Semenza", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s00109-013-1102-5", + "pmid": "24248265", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Med (Berl) 92 2014", + "title": "Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer." + } + }, + { + "pmid": "26825173", + "pubmed": { + "ISODate": "2016-03-15T00:00:00.000Z", + "abstract": "Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.", + "authors": { + "abbreviation": "Tarah M Regan Anderson, Shi Hong Ma, Ganesh V Raj, ..., Carol A Lange", + "authorList": [ + { + "ForeName": "Tarah", + "LastName": "Regan Anderson", + "abbrevName": "Regan Anderson TM", + "email": null, + "isCollectiveName": false, + "name": "Tarah M Regan Anderson", + "orcid": null + }, + { + "ForeName": "Shi", + "LastName": "Ma", + "abbrevName": "Ma SH", + "email": null, + "isCollectiveName": false, + "name": "Shi Hong Ma", + "orcid": null + }, + { + "ForeName": "Ganesh", + "LastName": "Raj", + "abbrevName": "Raj GV", + "email": null, + "isCollectiveName": false, + "name": "Ganesh V Raj", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Cidlowski", + "abbrevName": "Cidlowski JA", + "email": null, + "isCollectiveName": false, + "name": "John A Cidlowski", + "orcid": null + }, + { + "ForeName": "Taylor", + "LastName": "Helle", + "abbrevName": "Helle TM", + "email": null, + "isCollectiveName": false, + "name": "Taylor M Helle", + "orcid": null + }, + { + "ForeName": "Todd", + "LastName": "Knutson", + "abbrevName": "Knutson TP", + "email": null, + "isCollectiveName": false, + "name": "Todd P Knutson", + "orcid": null + }, + { + "ForeName": "Raisa", + "LastName": "Krutilina", + "abbrevName": "Krutilina RI", + "email": null, + "isCollectiveName": false, + "name": "Raisa I Krutilina", + "orcid": null + }, + { + "ForeName": "Tiffany", + "LastName": "Seagroves", + "abbrevName": "Seagroves TN", + "email": null, + "isCollectiveName": false, + "name": "Tiffany N Seagroves", + "orcid": null + }, + { + "ForeName": "Carol", + "LastName": "Lange", + "abbrevName": "Lange CA", + "email": "lange047@umn.edu", + "isCollectiveName": false, + "name": "Carol A Lange", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Carol", + "LastName": "Lange", + "email": [ + "lange047@umn.edu" + ], + "name": "Carol A Lange" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-2510", + "pmid": "26825173", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "30964885", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "Triple-Negative Breast Cancers (TNBCs) are the most difficult to treat subtype of breast cancer and are often associated with high nuclear expression of Snail and Cathepsin L (Cat L) protease. We have previously shown that Snail can increase Cat L expression/activity in prostate and breast cancer cells. This study investigated the role of CUX1 (a downstream substrate of Cat L) in TNBC. We showed that Cat L and CUX1 were highly expressed in TNBC patient tissue/cell lines, as compared to ER-positive samples, using cBioportal data and western blot/zymography analyses. Additionally, luciferase reporter and chromatin immunoprecipitation assays showed that CUX1 directly bound to estrogen receptor-alpha (ER-α) promoter in MDA-MB-468, a representative TNBC cell line, and that CUX1 siRNA could restore ER-α transcription and protein expression. Furthermore, Snail and CUX1 expression in various TNBC cell lines was inhibited by muscadine grape skin extract (MSKE, a natural grape product rich in anthocyanins) or Cat L inhibitor (Z-FY-CHO) leading to decreased cell invasion and migration. MSKE decreased cell viability and increased expression of apoptotic markers in MDA-MB-468 cells, with no effect on non-tumorigenic MCF10A cells. MSKE also decreased CUX1 binding to ER-α promoter and restored ER-α expression in TNBC cells, while both MSKE and CUX1 siRNA restored sensitivity to estradiol and 4-hydoxytamoxifen as shown by increased cell viability. Therefore, CUX1 activated by Snail-Cat L signaling may contribute to TNBC via ER-α repression, and may be a viable target for TNBC using natural products such as MSKE that targets cancer and not normal cells.", + "authors": { + "abbreviation": "Liza J Burton, Ohuod Hawsawi, Janae Sweeney, ..., Valerie Odero-Marah", + "authorList": [ + { + "ForeName": "Liza", + "LastName": "Burton", + "abbrevName": "Burton LJ", + "email": null, + "isCollectiveName": false, + "name": "Liza J Burton", + "orcid": null + }, + { + "ForeName": "Ohuod", + "LastName": "Hawsawi", + "abbrevName": "Hawsawi O", + "email": null, + "isCollectiveName": false, + "name": "Ohuod Hawsawi", + "orcid": null + }, + { + "ForeName": "Janae", + "LastName": "Sweeney", + "abbrevName": "Sweeney J", + "email": null, + "isCollectiveName": false, + "name": "Janae Sweeney", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Bowen", + "abbrevName": "Bowen N", + "email": null, + "isCollectiveName": false, + "name": "Nathan Bowen", + "orcid": "0000-0002-1609-6698" + }, + { + "ForeName": "Tamaro", + "LastName": "Hudson", + "abbrevName": "Hudson T", + "email": null, + "isCollectiveName": false, + "name": "Tamaro Hudson", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Odero-Marah", + "abbrevName": "Odero-Marah V", + "email": null, + "isCollectiveName": false, + "name": "Valerie Odero-Marah", + "orcid": "0000-0002-5238-9914" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0214844", + "pmid": "30964885", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 14 2019", + "title": "CCAAT-displacement protein/cut homeobox transcription factor (CUX1) represses estrogen receptor-alpha (ER-α) in triple-negative breast cancer cells and can be antagonized by muscadine grape skin extract (MSKE)." + } + }, + { + "pmid": "28361350", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin β1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin β1 (ITGB1) gene expression have not been well elucidated. METHODS: Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin β1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin β1 gene and drives its expression. RESULTS: We demonstrated that FOXM1 directly binds to the promoter of integrin β1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells. CONCLUSION: Our study suggests that FOXM1 transcription factor regulates Integrin β1 gene expression and that FOXM1/ Integrin-β1/FAK axis may play an important role in the progression of TNBC.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Nermin Kahraman, Ahmed Ashour, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": "bozpolat@mdanderson.org", + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "email": [ + "bozpolat@mdanderson.org" + ], + "name": "Bulent Ozpolat" + } + ] + }, + "doi": "10.1007/s10549-017-4207-7", + "pmid": "28361350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res Treat 163 2017", + "title": "FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer." + } + }, + { + "pmid": "26918606", + "pubmed": { + "ISODate": "2016-03-29T00:00:00.000Z", + "abstract": "Eukaryotic elongation factor 2 kinase (eEF2K), an emerging molecular target for cancer therapy, contributes to cancer proliferation, cell survival, tumorigenesis, and invasion, disease progression and drug resistance. Although eEF2K is highly up-regulated in various cancers, the mechanism of gene regulation has not been elucidated. In this study, we examined the role of Forkhead Box M1 (FOXM1) proto-oncogenic transcription factor in triple negative breast cancer (TNBC) cells and the regulation of eEF2K. We found that FOXM1 is highly upregulated in TNBC and its knockdown by RNA interference (siRNA) significantly inhibited eEF2K expression and suppressed cell proliferation, colony formation, migration, invasion and induced apoptotic cell death, recapitulating the effects of eEF2K inhibition. Knockdown of FOXM1 inhibited regulators of cell cycle, migration/invasion and survival, including cyclin D1, Src and MAPK-ERK signaling pathways, respectively. We also demonstrated that FOXM1 (1B and 1C isoforms) directly binds to and transcriptionally regulates eEF2K gene expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. Furthermore, in vivo inhibition of FOXM1 by liposomal siRNA-nanoparticles suppressed growth of MDA-MB-231 TNBC tumor xenografts in orthotopic models. In conclusion, our study provides the first evidence about the transcriptional regulation of eEF2K in TNBC and the role of FOXM1 in mediating breast cancer cell proliferation, survival, migration/invasion, progression and tumorgenesis and highlighting the potential of FOXM1/eEF2K axis as a molecular target in breast and other cancers.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Ahmed Ashour, Nermin Kahraman, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": null, + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.7672", + "pmid": "26918606", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 7 2016", + "title": "FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells." + } + }, + { + "pmid": "27184798", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer.", + "authors": { + "abbreviation": "Min-Sun Jin, Hyebin Lee, In Ae Park, ..., Han Suk Ryu", + "authorList": [ + { + "ForeName": "Min-Sun", + "LastName": "Jin", + "abbrevName": "Jin MS", + "email": null, + "isCollectiveName": false, + "name": "Min-Sun Jin", + "orcid": null + }, + { + "ForeName": "Hyebin", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "Hyebin Lee", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Park", + "abbrevName": "Park IA", + "email": null, + "isCollectiveName": false, + "name": "In Ae Park", + "orcid": null + }, + { + "ForeName": "Yul", + "LastName": "Chung", + "abbrevName": "Chung YR", + "email": null, + "isCollectiveName": false, + "name": "Yul Ri Chung", + "orcid": null + }, + { + "ForeName": "Seock-Ah", + "LastName": "Im", + "abbrevName": "Im SA", + "email": null, + "isCollectiveName": false, + "name": "Seock-Ah Im", + "orcid": null + }, + { + "ForeName": "Kyung-Hun", + "LastName": "Lee", + "abbrevName": "Lee KH", + "email": null, + "isCollectiveName": false, + "name": "Kyung-Hun Lee", + "orcid": null + }, + { + "ForeName": "Hyeong-Gon", + "LastName": "Moon", + "abbrevName": "Moon HG", + "email": null, + "isCollectiveName": false, + "name": "Hyeong-Gon Moon", + "orcid": null + }, + { + "ForeName": "Wonshik", + "LastName": "Han", + "abbrevName": "Han W", + "email": null, + "isCollectiveName": false, + "name": "Wonshik Han", + "orcid": null + }, + { + "ForeName": "Kyubo", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyubo Kim", + "orcid": null + }, + { + "ForeName": "Tae-Yong", + "LastName": "Kim", + "abbrevName": "Kim TY", + "email": null, + "isCollectiveName": false, + "name": "Tae-Yong Kim", + "orcid": null + }, + { + "ForeName": "Dong-Young", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Young Noh", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Ryu", + "abbrevName": "Ryu HS", + "email": "karlnash@naver.com", + "isCollectiveName": false, + "name": "Han Suk Ryu", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Han", + "LastName": "Ryu", + "email": [ + "karlnash@naver.com" + ], + "name": "Han Suk Ryu" + } + ] + }, + "doi": "10.1007/s00428-016-1953-6", + "pmid": "27184798", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Virchows Arch 469 2016", + "title": "Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer." + } + }, + { + "pmid": "34408002", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.", + "authors": { + "abbreviation": "Tian-Jian Yu, Ying-Ying Liu, Xiao-Guang Li, ..., Yi-Zhou Jiang", + "authorList": [ + { + "ForeName": "Tian-Jian", + "LastName": "Yu", + "abbrevName": "Yu TJ", + "email": null, + "isCollectiveName": false, + "name": "Tian-Jian Yu", + "orcid": null + }, + { + "ForeName": "Ying-Ying", + "LastName": "Liu", + "abbrevName": "Liu YY", + "email": null, + "isCollectiveName": false, + "name": "Ying-Ying Liu", + "orcid": null + }, + { + "ForeName": "Xiao-Guang", + "LastName": "Li", + "abbrevName": "Li XG", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Guang Li", + "orcid": null + }, + { + "ForeName": "Bi", + "LastName": "Lian", + "abbrevName": "Lian B", + "email": null, + "isCollectiveName": false, + "name": "Bi Lian", + "orcid": null + }, + { + "ForeName": "Xun-Xi", + "LastName": "Lu", + "abbrevName": "Lu XX", + "email": null, + "isCollectiveName": false, + "name": "Xun-Xi Lu", + "orcid": "0000-0002-5118-0377" + }, + { + "ForeName": "Xi", + "LastName": "Jin", + "abbrevName": "Jin X", + "email": null, + "isCollectiveName": false, + "name": "Xi Jin", + "orcid": null + }, + { + "ForeName": "Zhi-Ming", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Ming Shao", + "orcid": "0000-0001-8781-2455" + }, + { + "ForeName": "Xin", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Xin Hu", + "orcid": null + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "abbrevName": "Di GH", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Gen-Hong Di", + "orcid": null + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "abbrevName": "Jiang YZ", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Yi-Zhou Jiang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Hu", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Xin Hu" + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Gen-Hong Di" + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Yi-Zhou Jiang" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-21-0747", + "pmid": "34408002", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 81 2021", + "title": "PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "28423652", + "pubmed": { + "ISODate": "2017-04-25T00:00:00.000Z", + "abstract": "MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.", + "authors": { + "abbreviation": "Rosa Drago-Ferrante, Francesca Pentimalli, Daniela Carlisi, ..., Riccardo Di Fiore", + "authorList": [ + { + "ForeName": "Rosa", + "LastName": "Drago-Ferrante", + "abbrevName": "Drago-Ferrante R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Drago-Ferrante", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Pentimalli", + "abbrevName": "Pentimalli F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Pentimalli", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Carlisi", + "abbrevName": "Carlisi D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Carlisi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "De Blasio", + "abbrevName": "De Blasio A", + "email": null, + "isCollectiveName": false, + "name": "Anna De Blasio", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Saliba", + "abbrevName": "Saliba C", + "email": null, + "isCollectiveName": false, + "name": "Christian Saliba", + "orcid": null + }, + { + "ForeName": "Shawn", + "LastName": "Baldacchino", + "abbrevName": "Baldacchino S", + "email": null, + "isCollectiveName": false, + "name": "Shawn Baldacchino", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Degaetano", + "abbrevName": "Degaetano J", + "email": null, + "isCollectiveName": false, + "name": "James Degaetano", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Debono", + "abbrevName": "Debono J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Debono", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Caruana-Dingli", + "abbrevName": "Caruana-Dingli G", + "email": null, + "isCollectiveName": false, + "name": "Gordon Caruana-Dingli", + "orcid": null + }, + { + "ForeName": "Godfrey", + "LastName": "Grech", + "abbrevName": "Grech G", + "email": null, + "isCollectiveName": false, + "name": "Godfrey Grech", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Scerri", + "abbrevName": "Scerri C", + "email": null, + "isCollectiveName": false, + "name": "Christian Scerri", + "orcid": null + }, + { + "ForeName": "Giovanni", + "LastName": "Tesoriere", + "abbrevName": "Tesoriere G", + "email": null, + "isCollectiveName": false, + "name": "Giovanni Tesoriere", + "orcid": null + }, + { + "ForeName": "Antonio", + "LastName": "Giordano", + "abbrevName": "Giordano A", + "email": null, + "isCollectiveName": false, + "name": "Antonio Giordano", + "orcid": null + }, + { + "ForeName": "Renza", + "LastName": "Vento", + "abbrevName": "Vento R", + "email": null, + "isCollectiveName": false, + "name": "Renza Vento", + "orcid": null + }, + { + "ForeName": "Riccardo", + "LastName": "Di Fiore", + "abbrevName": "Di Fiore R", + "email": null, + "isCollectiveName": false, + "name": "Riccardo Di Fiore", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.15960", + "pmid": "28423652", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 8 2017", + "title": "Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation." + } + }, + { + "pmid": "30784286", + "pubmed": { + "ISODate": "2019-05-23T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The unclear molecular mechanisms underlying could provide important theoretical basis for the prevention and control of HCC. This study performed chromatin immunoprecipitation-sequencing (ChIP-seq) to analyze the binding sites between zinc fingers and homeoboxes 2 (ZHX2) and its genome-wide target genes, and bioinformatics was used to analyze their gene transcription regulation network. Immunohistochemistry was used to detect the ZHX2 expression in HCC, and its association with the clinicopathological characteristics of HCC. Results of RT-PCR and western blot showed the expression of ZHX2 in HepG2 cells was obviously lower compared with normal liver cells. ZHX2 could be amplified in ChIP products, then ChIP-seq reveals there were 232 genes binding in promoter regions. GO analysis of functions revealed these genes were mainly associated with biological processes (BP), cellular components (CC), and molecular functions (MF). In addition, PTEN was found enriched in certain biological functions in BP analysis. Then, four pathways of these genes based on Kyoto Encyclopedia of Genes and Genomes (KEGG) were found P<0.05. Last analysis of immunohistochemistry showed the rates of ZHX2 expression and PTEN expression in paracancerous tissues both were significantly higher than that in HCC tissues (P=0.042; P<0.001), with negative correlations with AFP values (r=-0.246, P=0.040; r=-0.263, P=0.028). Further, PTEN expression was positively correlated with the differentiation level in HCC tissues (r=0.267, P=0.025). Spearman correlation analysis revealed that the expression profiles of ZHX2 and PTEN were positively correlated in HCC tissues (r=0.258, P=0.031). This study is the first to use ChIP-seq technology to analyze the specific regulatory mechanisms of the transcription suppressor ZHX2 in the context of HCC at the genome level.", + "authors": { + "abbreviation": "Z Lv, R He, M Huang, ..., G Chen", + "authorList": [ + { + "ForeName": "Z", + "LastName": "Lv", + "abbrevName": "Lv Z", + "email": null, + "isCollectiveName": false, + "name": "Z Lv", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "He", + "abbrevName": "He R", + "email": null, + "isCollectiveName": false, + "name": "R He", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Huang", + "abbrevName": "Huang M", + "email": null, + "isCollectiveName": false, + "name": "M Huang", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Zhao", + "abbrevName": "Zhao G", + "email": null, + "isCollectiveName": false, + "name": "G Zhao", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Ma", + "abbrevName": "Ma J", + "email": null, + "isCollectiveName": false, + "name": "J Ma", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": null, + "isCollectiveName": false, + "name": "G Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.4149/neo_2018_180806N593", + "pmid": "30784286", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Neoplasma 66 2019", + "title": "Targeting genes and signaling pathways of transcriptional suppressor ZHX2 in hepatocellular carcinoma: a Chromatin Immunoprecipitation-sequencing (ChIP-seq) investigation." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-12-10T08:45:48.864Z", + "_newestOpId": "f19c1925-2d93-406c-9abe-60c1b4db5686", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "603348" + }, + { + "db": "HGNC", + "id": "HGNC:4910" + }, + { + "db": "Ensembl", + "id": "ENSG00000100644" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.863279, + "id": "3091", + "name": "HIF1A", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "HIF-1-alpha", + "HIF-1A", + "HIF-1alpha", + "HIF1", + "HIF1-ALPHA", + "hypoxia-inducible factor1alpha", + "hypoxia inducible factor 1 subunit alpha", + "PAS domain-containing protein 8\", \"Class E basic helix-loop-helix protein 78\", \"Member of PAS protein 1", + "member of PAS superfamily 1", + "MOP1" + ], + "synonyms": [ + "HIF-1-alpha", + "HIF-1A", + "HIF-1alpha", + "HIF1", + "HIF1-ALPHA", + "MOP1", + "PASD8", + "bHLHe78", + "hypoxia-inducible factor 1-alpha", + "ARNT interacting protein", + "PAS domain-containing protein 8", + "PAS domain-containing protein 8\", \"Class E basic helix-loop-helix protein 78\", \"Member of PAS protein 1", + "basic-helix-loop-helix-PAS protein MOP1", + "class E basic helix-loop-helix protein 78", + "hypoxia inducible factor 1 alpha subunit", + "hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)", + "hypoxia-inducible factor1alpha", + "member of PAS protein 1", + "member of PAS superfamily 1", + "hypoxia inducible factor 1 subunit alpha" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "3295573e-31b2-40c4-99f1-4dbf6a34990a", + "liveId": "85109400-9680-4b2c-a8c7-6fe0fbc2b96a", + "lock": null, + "locked": false, + "name": "HIF1a", + "parentId": "3fd6a28f-483e-4eb4-ab6f-0a9025bd9cd1", + "position": { + "x": 342.41983122362853, + "y": 147.3563482930571 + }, + "relatedPapers": [ + { + "pmid": "30026228", + "pubmed": { + "ISODate": "2018-07-20T00:00:00.000Z", + "abstract": "Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.", + "authors": { + "abbreviation": "Jing Zhang, Tao Wu, Jeremy Simon, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": "0000-0001-6438-9113" + }, + { + "ForeName": "Tao", + "LastName": "Wu", + "abbrevName": "Wu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wu", + "orcid": "0000-0001-5380-3905" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon J", + "email": null, + "isCollectiveName": false, + "name": "Jeremy Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": "0000-0002-3961-9009" + }, + { + "ForeName": "Ryoichi", + "LastName": "Saito", + "abbrevName": "Saito R", + "email": null, + "isCollectiveName": false, + "name": "Ryoichi Saito", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Xian-De", + "LastName": "Liu", + "abbrevName": "Liu XD", + "email": null, + "isCollectiveName": false, + "name": "Xian-De Liu", + "orcid": "0000-0002-9639-0458" + }, + { + "ForeName": "Eric", + "LastName": "Jonasch", + "abbrevName": "Jonasch E", + "email": null, + "isCollectiveName": false, + "name": "Eric Jonasch", + "orcid": "0000-0003-0943-2806" + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Xiaosai", + "LastName": "Yao", + "abbrevName": "Yao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaosai Yao", + "orcid": "0000-0001-9729-0726" + }, + { + "ForeName": "Bin", + "LastName": "Teh", + "abbrevName": "Teh BT", + "email": null, + "isCollectiveName": false, + "name": "Bin Tean Teh", + "orcid": "0000-0003-1514-1124" + }, + { + "ForeName": "Patrick", + "LastName": "Tan", + "abbrevName": "Tan P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Tan", + "orcid": null + }, + { + "ForeName": "Xingnan", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xingnan Zheng", + "orcid": "0000-0003-3034-4421" + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": "0000-0001-5337-4901" + }, + { + "ForeName": "Cortney", + "LastName": "Lawrence", + "abbrevName": "Lawrence C", + "email": null, + "isCollectiveName": false, + "name": "Cortney Lawrence", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Fan", + "abbrevName": "Fan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Fan", + "orcid": "0000-0003-3842-2391" + }, + { + "ForeName": "Jiang", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiang Geng", + "orcid": "0000-0002-7202-2167" + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Kai", + "LastName": "Hong", + "abbrevName": "Hong K", + "email": null, + "isCollectiveName": false, + "name": "Kai Hong", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Joel", + "LastName": "Parker", + "abbrevName": "Parker JS", + "email": null, + "isCollectiveName": false, + "name": "Joel S Parker", + "orcid": "0000-0003-2080-6901" + }, + { + "ForeName": "J", + "LastName": "Auman", + "abbrevName": "Auman JT", + "email": null, + "isCollectiveName": false, + "name": "J Todd Auman", + "orcid": "0000-0002-9328-8829" + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "W", + "LastName": "Rathmell", + "abbrevName": "Rathmell WK", + "email": null, + "isCollectiveName": false, + "name": "W Kimryn Rathmell", + "orcid": "0000-0002-4984-0225" + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Kirschner", + "abbrevName": "Kirschner MW", + "email": null, + "isCollectiveName": false, + "name": "Marc W Kirschner", + "orcid": "0000-0001-6540-6130" + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": "0000-0002-0574-4856" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": "0000-0003-1246-1333" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "qing_zhang@med.unc.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "qing_zhang@med.unc.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1126/science.aap8411", + "pmid": "30026228", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 361 2018", + "title": "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma." + } + }, + { + "pmid": "27137755", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": "The aggressiveness of triple-negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self-renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia-inducible factor-1α (HIF-1α) expression is associated with aggressiveness of cancer. Nonetheless, how HIF-1α expression is regulated and how HIF-1α induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF-1α expression has not yet been studied. Here, we show that clinically relevant low-dose FTI, tipifarnib (300 nM), decreased HIF-1α expression, migration and tumorsphere formation in human MDA-MB-231 TNBC cells under a normoxic condition. In contrast, the low-dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA-MB 231 cells. Tipifarnib-induced decrease in HIF-1α expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E-cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF-1α-Snail pathway. J. Cell. Physiol. 232: 192-201, 2017. © 2016 Wiley Periodicals, Inc.", + "authors": { + "abbreviation": "Tomokazu Tanaka, Yuichi Ikegami, Harumasa Nakazawa, ..., Masao Kaneki", + "authorList": [ + { + "ForeName": "Tomokazu", + "LastName": "Tanaka", + "abbrevName": "Tanaka T", + "email": null, + "isCollectiveName": false, + "name": "Tomokazu Tanaka", + "orcid": null + }, + { + "ForeName": "Yuichi", + "LastName": "Ikegami", + "abbrevName": "Ikegami Y", + "email": null, + "isCollectiveName": false, + "name": "Yuichi Ikegami", + "orcid": null + }, + { + "ForeName": "Harumasa", + "LastName": "Nakazawa", + "abbrevName": "Nakazawa H", + "email": null, + "isCollectiveName": false, + "name": "Harumasa Nakazawa", + "orcid": null + }, + { + "ForeName": "Naohide", + "LastName": "Kuriyama", + "abbrevName": "Kuriyama N", + "email": null, + "isCollectiveName": false, + "name": "Naohide Kuriyama", + "orcid": null + }, + { + "ForeName": "Miwa", + "LastName": "Oki", + "abbrevName": "Oki M", + "email": null, + "isCollectiveName": false, + "name": "Miwa Oki", + "orcid": null + }, + { + "ForeName": "Jun-Ichi", + "LastName": "Hanai", + "abbrevName": "Hanai J", + "email": null, + "isCollectiveName": false, + "name": "Jun-Ichi Hanai", + "orcid": null + }, + { + "ForeName": "Vikas", + "LastName": "Sukhatme", + "abbrevName": "Sukhatme VP", + "email": null, + "isCollectiveName": false, + "name": "Vikas P Sukhatme", + "orcid": null + }, + { + "ForeName": "Masao", + "LastName": "Kaneki", + "abbrevName": "Kaneki M", + "email": "mkaneki@helix.mgh.harvard.edu", + "isCollectiveName": false, + "name": "Masao Kaneki", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masao", + "LastName": "Kaneki", + "email": [ + "mkaneki@helix.mgh.harvard.edu" + ], + "name": "Masao Kaneki" + } + ] + }, + "doi": "10.1002/jcp.25411", + "pmid": "27137755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Physiol 232 2017", + "title": "Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1α and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro." + } + }, + { + "pmid": "32382017", + "pubmed": { + "ISODate": "2020-05-07T00:00:00.000Z", + "abstract": "Zinc fingers and homeoboxes 2 (ZHX2) was found as a novel VHL substrate target, and acted as an oncogenic driver in ccRCC. However, the detailed mechanism of ZHX2 in ccRCC development remains elusive, and no research has focused on studying ZHX2 in drug resistance yet. A tissue microarray with 358 ccRCC samples was used to determine the expression of ZHX2 in ccRCC patients. VHL-deficient cell line 786-O and VHL-normal cell line CAKI-1 was used for lineage reprogramming by transfecting with lentivirus. The in vitro and in vivo experiments were performed with these new cell lines to determine the mechanism of ZHX2 in ccRCC development and drug resistance. Immunohistochemistry analysis showed that ZHX2 was not highly expressed in ccRCC tumor tissues, only 33.2% (119/358) patients have high ZHX2 expression. However, high ZHX2 was significantly associated with advanced Fuhrman grade (p = 0.004), and proved to be an independent prognosis factor for progression-free survival (p = 0.0003), while there is no significant correlation with overall survival. We further discovered that ZHX2 overexpression could increase VEGF secretion and transcriptional activate the MEK/ERK1/2 and promote its downstream targets. We also found ZHX2 overexpression induce Sunitinib resistance though activating autophagy and the combination treatment of Sunitinib and Chloroquine could significantly rescue the phenomenon. In summary, these results indicate that ZHX2 drivers cell growth, migration though increase VEGF expression, and transcriptional activate MEK/ERK1/2 signaling pathway, and could induce Sunitinib resistance by regulating self-protective autophagy, these may provide new insight in advanced ccRCC treatment.", + "authors": { + "abbreviation": "Liangsong Zhu, Rong Ding, Hao Yan, ..., Zongming Lin", + "authorList": [ + { + "ForeName": "Liangsong", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liangsong Zhu", + "orcid": null + }, + { + "ForeName": "Rong", + "LastName": "Ding", + "abbrevName": "Ding R", + "email": null, + "isCollectiveName": false, + "name": "Rong Ding", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Yan", + "abbrevName": "Yan H", + "email": null, + "isCollectiveName": false, + "name": "Hao Yan", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "med-zhangjin@vip.sina.com", + "isCollectiveName": false, + "name": "Jin Zhang", + "orcid": null + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "abbrevName": "Lin Z", + "email": "lin.zongming@zs-hospital.sh.cn", + "isCollectiveName": false, + "name": "Zongming Lin", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jin", + "LastName": "Zhang", + "email": [ + "med-zhangjin@vip.sina.com" + ], + "name": "Jin Zhang" + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "email": [ + "lin.zongming@zs-hospital.sh.cn" + ], + "name": "Zongming Lin" + } + ] + }, + "doi": "10.1038/s41419-020-2541-x", + "pmid": "32382017", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 11 2020", + "title": "ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma." + } + }, + { + "pmid": "29333926", + "pubmed": { + "ISODate": "2018-04-03T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by poor patient prognosis and for which no targeted therapies are currently available. TNBC can be further categorized as either basal-like (BLBC) or quintuple-negative breast cancer (QNBC). In the present study, we aimed to identify novel molecular therapeutic targets for TNBC by analyzing the mRNA expression of TNBC-related genes in publicly available microarray data sets. We found that Engrailed 1 (EN1) was significantly overexpressed in TNBC. Using breast cancer cell lines, we found that EN1 was more highly expressed in TNBC than in other breast cancer subtypes. EN1 expression was analyzed in 199 TNBC paraffin-embedded tissue samples by immunohistochemistry. EN1 protein expression was positively associated with reduced overall survival (OS) rate in patients with QNBC, but not those with BLBC. The importance of EN1 expression in QNBC cell viability and tumorigenicity was evaluated using the QNBC cell lines, HCC38 and HCC1395. Based on our data, EN1 may promote the proliferation, migration, and multinucleation of QNBC cells, likely via the transcriptional activation of HDAC8, UTP11L, and ZIC3. We also demonstrated that actinomycin D effectively inhibits EN1 activity in QNBC cells. The results of the present study suggest that EN1 activity is highly clinically relevant to the survival prognosis of patients with QNBC and EN1 is a promising potential therapeutic target for future QNBC treatment.", + "authors": { + "abbreviation": "Yu Jin Kim, Minjung Sung, Ensel Oh, ..., Yoon-La Choi", + "authorList": [ + { + "ForeName": "Yu", + "LastName": "Kim", + "abbrevName": "Kim YJ", + "email": null, + "isCollectiveName": false, + "name": "Yu Jin Kim", + "orcid": null + }, + { + "ForeName": "Minjung", + "LastName": "Sung", + "abbrevName": "Sung M", + "email": null, + "isCollectiveName": false, + "name": "Minjung Sung", + "orcid": null + }, + { + "ForeName": "Ensel", + "LastName": "Oh", + "abbrevName": "Oh E", + "email": null, + "isCollectiveName": false, + "name": "Ensel Oh", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Vrancken", + "abbrevName": "Vrancken MV", + "email": null, + "isCollectiveName": false, + "name": "Michael Van Vrancken", + "orcid": null + }, + { + "ForeName": "Ji-Young", + "LastName": "Song", + "abbrevName": "Song JY", + "email": null, + "isCollectiveName": false, + "name": "Ji-Young Song", + "orcid": null + }, + { + "ForeName": "Kyungsoo", + "LastName": "Jung", + "abbrevName": "Jung K", + "email": null, + "isCollectiveName": false, + "name": "Kyungsoo Jung", + "orcid": null + }, + { + "ForeName": "Yoon-La", + "LastName": "Choi", + "abbrevName": "Choi YL", + "email": null, + "isCollectiveName": false, + "name": "Yoon-La Choi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2018.1423913", + "pmid": "29333926", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 19 2018", + "title": "Engrailed 1 overexpression as a potential prognostic marker in quintuple-negative breast cancer." + } + }, + { + "pmid": "35867755", + "pubmed": { + "ISODate": "2022-07-12T00:00:00.000Z", + "abstract": "Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Zhaoping Qiu, Weijie Guo, Bo Dong, ..., Yadi Wu", + "authorList": [ + { + "ForeName": "Zhaoping", + "LastName": "Qiu", + "abbrevName": "Qiu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaoping Qiu", + "orcid": null + }, + { + "ForeName": "Weijie", + "LastName": "Guo", + "abbrevName": "Guo W", + "email": null, + "isCollectiveName": false, + "name": "Weijie Guo", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bo Dong", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Wang", + "orcid": null + }, + { + "ForeName": "Pan", + "LastName": "Deng", + "abbrevName": "Deng P", + "email": null, + "isCollectiveName": false, + "name": "Pan Deng", + "orcid": "0000-0003-2974-7389" + }, + { + "ForeName": "Chi", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Chi Wang", + "orcid": null + }, + { + "ForeName": "Jinpeng", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jinpeng Liu", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + }, + { + "ForeName": "Rudolf", + "LastName": "Grosschedl", + "abbrevName": "Grosschedl R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Grosschedl", + "orcid": null + }, + { + "ForeName": "Zhiyong", + "LastName": "Yu", + "abbrevName": "Yu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyong Yu", + "orcid": null + }, + { + "ForeName": "Jiong", + "LastName": "Deng", + "abbrevName": "Deng J", + "email": null, + "isCollectiveName": false, + "name": "Jiong Deng", + "orcid": null + }, + { + "ForeName": "Yadi", + "LastName": "Wu", + "abbrevName": "Wu Y", + "email": null, + "isCollectiveName": false, + "name": "Yadi Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119518119", + "pmid": "35867755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "EBF1 promotes triple-negative breast cancer progression by surveillance of the HIF1α pathway." + } + }, + { + "pmid": "26751287", + "pubmed": { + "ISODate": "2016-02-01T00:00:00.000Z", + "abstract": "Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.", + "authors": { + "abbreviation": "Aifu Lin, Chunlai Li, Zhen Xing, ..., Liuqing Yang", + "authorList": [ + { + "ForeName": "Aifu", + "LastName": "Lin", + "abbrevName": "Lin A", + "email": null, + "isCollectiveName": false, + "name": "Aifu Lin", + "orcid": null + }, + { + "ForeName": "Chunlai", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunlai Li", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Xing", + "abbrevName": "Xing Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Xing", + "orcid": null + }, + { + "ForeName": "Qingsong", + "LastName": "Hu", + "abbrevName": "Hu Q", + "email": null, + "isCollectiveName": false, + "name": "Qingsong Hu", + "orcid": null + }, + { + "ForeName": "Ke", + "LastName": "Liang", + "abbrevName": "Liang K", + "email": null, + "isCollectiveName": false, + "name": "Ke Liang", + "orcid": null + }, + { + "ForeName": "Leng", + "LastName": "Han", + "abbrevName": "Han L", + "email": null, + "isCollectiveName": false, + "name": "Leng Han", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Wang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Hawke", + "abbrevName": "Hawke DH", + "email": null, + "isCollectiveName": false, + "name": "David H Hawke", + "orcid": "0000-0002-6102-7843" + }, + { + "ForeName": "Shouyu", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shouyu Wang", + "orcid": null + }, + { + "ForeName": "Yanyan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhang", + "orcid": null + }, + { + "ForeName": "Yongkun", + "LastName": "Wei", + "abbrevName": "Wei Y", + "email": null, + "isCollectiveName": false, + "name": "Yongkun Wei", + "orcid": null + }, + { + "ForeName": "Guolin", + "LastName": "Ma", + "abbrevName": "Ma G", + "email": null, + "isCollectiveName": false, + "name": "Guolin Ma", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Park", + "abbrevName": "Park PK", + "email": null, + "isCollectiveName": false, + "name": "Peter K Park", + "orcid": null + }, + { + "ForeName": "Jianwei", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jianwei Zhou", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Zhou", + "orcid": null + }, + { + "ForeName": "Zhibin", + "LastName": "Hu", + "abbrevName": "Hu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhibin Hu", + "orcid": null + }, + { + "ForeName": "Yubin", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yubin Zhou", + "orcid": null + }, + { + "ForeName": "Jeffery", + "LastName": "Marks", + "abbrevName": "Marks JR", + "email": null, + "isCollectiveName": false, + "name": "Jeffery R Marks", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Han Liang", + "orcid": "0000-0001-7633-286X" + }, + { + "ForeName": "Mien-Chie", + "LastName": "Hung", + "abbrevName": "Hung MC", + "email": null, + "isCollectiveName": false, + "name": "Mien-Chie Hung", + "orcid": null + }, + { + "ForeName": "Chunru", + "LastName": "Lin", + "abbrevName": "Lin C", + "email": null, + "isCollectiveName": false, + "name": "Chunru Lin", + "orcid": null + }, + { + "ForeName": "Liuqing", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Liuqing Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3295", + "pmid": "26751287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer." + } + }, + { + "pmid": "26918606", + "pubmed": { + "ISODate": "2016-03-29T00:00:00.000Z", + "abstract": "Eukaryotic elongation factor 2 kinase (eEF2K), an emerging molecular target for cancer therapy, contributes to cancer proliferation, cell survival, tumorigenesis, and invasion, disease progression and drug resistance. Although eEF2K is highly up-regulated in various cancers, the mechanism of gene regulation has not been elucidated. In this study, we examined the role of Forkhead Box M1 (FOXM1) proto-oncogenic transcription factor in triple negative breast cancer (TNBC) cells and the regulation of eEF2K. We found that FOXM1 is highly upregulated in TNBC and its knockdown by RNA interference (siRNA) significantly inhibited eEF2K expression and suppressed cell proliferation, colony formation, migration, invasion and induced apoptotic cell death, recapitulating the effects of eEF2K inhibition. Knockdown of FOXM1 inhibited regulators of cell cycle, migration/invasion and survival, including cyclin D1, Src and MAPK-ERK signaling pathways, respectively. We also demonstrated that FOXM1 (1B and 1C isoforms) directly binds to and transcriptionally regulates eEF2K gene expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. Furthermore, in vivo inhibition of FOXM1 by liposomal siRNA-nanoparticles suppressed growth of MDA-MB-231 TNBC tumor xenografts in orthotopic models. In conclusion, our study provides the first evidence about the transcriptional regulation of eEF2K in TNBC and the role of FOXM1 in mediating breast cancer cell proliferation, survival, migration/invasion, progression and tumorgenesis and highlighting the potential of FOXM1/eEF2K axis as a molecular target in breast and other cancers.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Ahmed Ashour, Nermin Kahraman, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": null, + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.7672", + "pmid": "26918606", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 7 2016", + "title": "FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells." + } + }, + { + "pmid": "24670641", + "pubmed": { + "ISODate": "2014-04-03T00:00:00.000Z", + "abstract": "Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Xi Chen, Dimitrios Iliopoulos, Qing Zhang, ..., Laurie H Glimcher", + "authorList": [ + { + "ForeName": "Xi", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xi Chen", + "orcid": null + }, + { + "ForeName": "Dimitrios", + "LastName": "Iliopoulos", + "abbrevName": "Iliopoulos D", + "email": null, + "isCollectiveName": false, + "name": "Dimitrios Iliopoulos", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + }, + { + "ForeName": "Qianzi", + "LastName": "Tang", + "abbrevName": "Tang Q", + "email": null, + "isCollectiveName": false, + "name": "Qianzi Tang", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Greenblatt", + "abbrevName": "Greenblatt MB", + "email": null, + "isCollectiveName": false, + "name": "Matthew B Greenblatt", + "orcid": null + }, + { + "ForeName": "Maria", + "LastName": "Hatziapostolou", + "abbrevName": "Hatziapostolou M", + "email": null, + "isCollectiveName": false, + "name": "Maria Hatziapostolou", + "orcid": null + }, + { + "ForeName": "Elgene", + "LastName": "Lim", + "abbrevName": "Lim E", + "email": null, + "isCollectiveName": false, + "name": "Elgene Lim", + "orcid": null + }, + { + "ForeName": "Wai", + "LastName": "Tam", + "abbrevName": "Tam WL", + "email": null, + "isCollectiveName": false, + "name": "Wai Leong Tam", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ni", + "abbrevName": "Ni M", + "email": null, + "isCollectiveName": false, + "name": "Min Ni", + "orcid": null + }, + { + "ForeName": "Yiwen", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yiwen Chen", + "orcid": null + }, + { + "ForeName": "Junhua", + "LastName": "Mai", + "abbrevName": "Mai J", + "email": null, + "isCollectiveName": false, + "name": "Junhua Mai", + "orcid": null + }, + { + "ForeName": "Haifa", + "LastName": "Shen", + "abbrevName": "Shen H", + "email": null, + "isCollectiveName": false, + "name": "Haifa Shen", + "orcid": null + }, + { + "ForeName": "Dorothy", + "LastName": "Hu", + "abbrevName": "Hu DZ", + "email": null, + "isCollectiveName": false, + "name": "Dorothy Z Hu", + "orcid": null + }, + { + "ForeName": "Stanley", + "LastName": "Adoro", + "abbrevName": "Adoro S", + "email": null, + "isCollectiveName": false, + "name": "Stanley Adoro", + "orcid": null + }, + { + "ForeName": "Bella", + "LastName": "Hu", + "abbrevName": "Hu B", + "email": null, + "isCollectiveName": false, + "name": "Bella Hu", + "orcid": null + }, + { + "ForeName": "Minkyung", + "LastName": "Song", + "abbrevName": "Song M", + "email": null, + "isCollectiveName": false, + "name": "Minkyung Song", + "orcid": null + }, + { + "ForeName": "Chen", + "LastName": "Tan", + "abbrevName": "Tan C", + "email": null, + "isCollectiveName": false, + "name": "Chen Tan", + "orcid": null + }, + { + "ForeName": "Melissa", + "LastName": "Landis", + "abbrevName": "Landis MD", + "email": null, + "isCollectiveName": false, + "name": "Melissa D Landis", + "orcid": null + }, + { + "ForeName": "Mauro", + "LastName": "Ferrari", + "abbrevName": "Ferrari M", + "email": null, + "isCollectiveName": false, + "name": "Mauro Ferrari", + "orcid": null + }, + { + "ForeName": "Sandra", + "LastName": "Shin", + "abbrevName": "Shin SJ", + "email": null, + "isCollectiveName": false, + "name": "Sandra J Shin", + "orcid": null + }, + { + "ForeName": "Myles", + "LastName": "Brown", + "abbrevName": "Brown M", + "email": null, + "isCollectiveName": false, + "name": "Myles Brown", + "orcid": null + }, + { + "ForeName": "Jenny", + "LastName": "Chang", + "abbrevName": "Chang JC", + "email": null, + "isCollectiveName": false, + "name": "Jenny C Chang", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XS", + "email": null, + "isCollectiveName": false, + "name": "X Shirley Liu", + "orcid": null + }, + { + "ForeName": "Laurie", + "LastName": "Glimcher", + "abbrevName": "Glimcher LH", + "email": null, + "isCollectiveName": false, + "name": "Laurie H Glimcher", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13119", + "pmid": "24670641", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 508 2014", + "title": "XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway." + } + }, + { + "pmid": "32770671", + "pubmed": { + "ISODate": "2020-12-01T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.", + "authors": { + "abbreviation": "Xiangguo Yu, Qinghai Lin, Zhuanchang Wu, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Yankun", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yankun Zhang", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Songbai", + "LastName": "Zhao", + "abbrevName": "Zhao S", + "email": null, + "isCollectiveName": false, + "name": "Songbai Zhao", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Chaojia", + "LastName": "Chen", + "abbrevName": "Chen C", + "email": null, + "isCollectiveName": false, + "name": "Chaojia Chen", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Chunyang", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunyang Li", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": "0000-0002-8121-4718" + } + ], + "contacts": [] + }, + "doi": "10.1002/path.5530", + "pmid": "32770671", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Pathol 252 2020", + "title": "ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p." + } + }, + { + "pmid": "32114388", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Liver cancer stem cells (CSCs) are critical determinants of HCC relapse and therapeutic resistance, but the mechanisms underlying the maintenance of CSCs are poorly understood. We aimed to explore the role of tumor repressor Zinc-fingers and homeoboxes 2 (ZHX2) in liver CSCs. METHODS: CD133+ or EPCAM+ stem-like liver cancer cells were sorted from tumor tissues of HCC patients and HCC cell lines by flow cytometry. In addition, sorafenib-resistant cells, tumor-sphere forming cells and side population (SP) cells were respectively cultured and isolated as hepatic CSCs. The tumor-initiating and chemoresistance properties of ZHX2-overexpressing and ZHX2-knockdown cells were analyzed in vivo and in vitro. Microarray, luciferase reporter assay, chromatin immunoprecipitation (ChIP) and ChIP-on-chip analyses were performed to explore ZHX2 target genes. The expression of ZHX2 and its target gene were determined by quantitative RT-PCR, western blot, immunofluorescence and immunohistochemical staining in hepatoma cells and tumor and adjacent tissues from HCC patients. RESULTS: ZHX2 expression was significantly reduced in liver CSCs from different origins. ZHX2 deficiency led to enhanced liver tumor progression and expansion of CSC populations in vitro and in vivo. Re-expression of ZHX2 restricted capabilities of hepatic CSCs in supporting tumor initiation, self-renewal and sorafenib-resistance. Mechanically, ZHX2 suppressed liver CSCs via inhibiting KDM2A-mediated demethylation of histone H3 lysine 36 (H3K36) at the promoter regions of stemness-associated transcription factors, such as NANOG, SOX4 and OCT4. Moreover, patients with lower expression of ZHX2 and higher expression of KDM2A in tumor tissues showed significantly poorer survival. CONCLUSION: ZHX2 counteracts stem cell traits through transcriptionally repressing KDM2A in HCC. Our data will aid in a better understanding of molecular mechanisms underlying HCC relapse and drug resistance.", + "authors": { + "abbreviation": "Qinghai Lin, Zhuanchang Wu, Xuetian Yue, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Ying He", + "orcid": null + }, + { + "ForeName": "Yutong", + "LastName": "Ge", + "abbrevName": "Ge Y", + "email": null, + "isCollectiveName": false, + "name": "Yutong Ge", + "orcid": null + }, + { + "ForeName": "Siyu", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Siyu Tan", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Song", + "abbrevName": "Song H", + "email": null, + "isCollectiveName": false, + "name": "Hui Song", + "orcid": null + }, + { + "ForeName": "Detian", + "LastName": "Yuan", + "abbrevName": "Yuan D", + "email": null, + "isCollectiveName": false, + "name": "Detian Yuan", + "orcid": null + }, + { + "ForeName": "Yaoqin", + "LastName": "Gong", + "abbrevName": "Gong Y", + "email": null, + "isCollectiveName": false, + "name": "Yaoqin Gong", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.ebiom.2020.102676", + "pmid": "32114388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EBioMedicine 53 2020", + "title": "ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation." + } + }, + { + "pmid": "26825173", + "pubmed": { + "ISODate": "2016-03-15T00:00:00.000Z", + "abstract": "Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.", + "authors": { + "abbreviation": "Tarah M Regan Anderson, Shi Hong Ma, Ganesh V Raj, ..., Carol A Lange", + "authorList": [ + { + "ForeName": "Tarah", + "LastName": "Regan Anderson", + "abbrevName": "Regan Anderson TM", + "email": null, + "isCollectiveName": false, + "name": "Tarah M Regan Anderson", + "orcid": null + }, + { + "ForeName": "Shi", + "LastName": "Ma", + "abbrevName": "Ma SH", + "email": null, + "isCollectiveName": false, + "name": "Shi Hong Ma", + "orcid": null + }, + { + "ForeName": "Ganesh", + "LastName": "Raj", + "abbrevName": "Raj GV", + "email": null, + "isCollectiveName": false, + "name": "Ganesh V Raj", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Cidlowski", + "abbrevName": "Cidlowski JA", + "email": null, + "isCollectiveName": false, + "name": "John A Cidlowski", + "orcid": null + }, + { + "ForeName": "Taylor", + "LastName": "Helle", + "abbrevName": "Helle TM", + "email": null, + "isCollectiveName": false, + "name": "Taylor M Helle", + "orcid": null + }, + { + "ForeName": "Todd", + "LastName": "Knutson", + "abbrevName": "Knutson TP", + "email": null, + "isCollectiveName": false, + "name": "Todd P Knutson", + "orcid": null + }, + { + "ForeName": "Raisa", + "LastName": "Krutilina", + "abbrevName": "Krutilina RI", + "email": null, + "isCollectiveName": false, + "name": "Raisa I Krutilina", + "orcid": null + }, + { + "ForeName": "Tiffany", + "LastName": "Seagroves", + "abbrevName": "Seagroves TN", + "email": null, + "isCollectiveName": false, + "name": "Tiffany N Seagroves", + "orcid": null + }, + { + "ForeName": "Carol", + "LastName": "Lange", + "abbrevName": "Lange CA", + "email": "lange047@umn.edu", + "isCollectiveName": false, + "name": "Carol A Lange", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Carol", + "LastName": "Lange", + "email": [ + "lange047@umn.edu" + ], + "name": "Carol A Lange" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-2510", + "pmid": "26825173", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "30964885", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "Triple-Negative Breast Cancers (TNBCs) are the most difficult to treat subtype of breast cancer and are often associated with high nuclear expression of Snail and Cathepsin L (Cat L) protease. We have previously shown that Snail can increase Cat L expression/activity in prostate and breast cancer cells. This study investigated the role of CUX1 (a downstream substrate of Cat L) in TNBC. We showed that Cat L and CUX1 were highly expressed in TNBC patient tissue/cell lines, as compared to ER-positive samples, using cBioportal data and western blot/zymography analyses. Additionally, luciferase reporter and chromatin immunoprecipitation assays showed that CUX1 directly bound to estrogen receptor-alpha (ER-α) promoter in MDA-MB-468, a representative TNBC cell line, and that CUX1 siRNA could restore ER-α transcription and protein expression. Furthermore, Snail and CUX1 expression in various TNBC cell lines was inhibited by muscadine grape skin extract (MSKE, a natural grape product rich in anthocyanins) or Cat L inhibitor (Z-FY-CHO) leading to decreased cell invasion and migration. MSKE decreased cell viability and increased expression of apoptotic markers in MDA-MB-468 cells, with no effect on non-tumorigenic MCF10A cells. MSKE also decreased CUX1 binding to ER-α promoter and restored ER-α expression in TNBC cells, while both MSKE and CUX1 siRNA restored sensitivity to estradiol and 4-hydoxytamoxifen as shown by increased cell viability. Therefore, CUX1 activated by Snail-Cat L signaling may contribute to TNBC via ER-α repression, and may be a viable target for TNBC using natural products such as MSKE that targets cancer and not normal cells.", + "authors": { + "abbreviation": "Liza J Burton, Ohuod Hawsawi, Janae Sweeney, ..., Valerie Odero-Marah", + "authorList": [ + { + "ForeName": "Liza", + "LastName": "Burton", + "abbrevName": "Burton LJ", + "email": null, + "isCollectiveName": false, + "name": "Liza J Burton", + "orcid": null + }, + { + "ForeName": "Ohuod", + "LastName": "Hawsawi", + "abbrevName": "Hawsawi O", + "email": null, + "isCollectiveName": false, + "name": "Ohuod Hawsawi", + "orcid": null + }, + { + "ForeName": "Janae", + "LastName": "Sweeney", + "abbrevName": "Sweeney J", + "email": null, + "isCollectiveName": false, + "name": "Janae Sweeney", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Bowen", + "abbrevName": "Bowen N", + "email": null, + "isCollectiveName": false, + "name": "Nathan Bowen", + "orcid": "0000-0002-1609-6698" + }, + { + "ForeName": "Tamaro", + "LastName": "Hudson", + "abbrevName": "Hudson T", + "email": null, + "isCollectiveName": false, + "name": "Tamaro Hudson", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Odero-Marah", + "abbrevName": "Odero-Marah V", + "email": null, + "isCollectiveName": false, + "name": "Valerie Odero-Marah", + "orcid": "0000-0002-5238-9914" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0214844", + "pmid": "30964885", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 14 2019", + "title": "CCAAT-displacement protein/cut homeobox transcription factor (CUX1) represses estrogen receptor-alpha (ER-α) in triple-negative breast cancer cells and can be antagonized by muscadine grape skin extract (MSKE)." + } + }, + { + "pmid": "36037364", + "pubmed": { + "ISODate": "2022-09-06T00:00:00.000Z", + "abstract": "Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.", + "authors": { + "abbreviation": "Haibiao Xie, Jin Zhou, Xijuan Liu, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Haibiao", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haibiao Xie", + "orcid": "0000-0001-6729-8479" + }, + { + "ForeName": "Jin", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zhou", + "orcid": null + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Yawei", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yawei Xu", + "orcid": null + }, + { + "ForeName": "Austin", + "LastName": "Hepperla", + "abbrevName": "Hepperla AJ", + "email": null, + "isCollectiveName": false, + "name": "Austin J Hepperla", + "orcid": "0000-0002-0107-2001" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Tao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Yao", + "abbrevName": "Yao H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Yao", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": "0000-0002-9073-3835" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Gong", + "abbrevName": "Gong K", + "email": null, + "isCollectiveName": false, + "name": "Kan Gong", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119854119", + "pmid": "36037364", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer." + } + }, + { + "pmid": "25920936", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.", + "authors": { + "abbreviation": "Shuang Li, Qingzhu Wei, Qin Li, ..., Qiang Xiao", + "authorList": [ + { + "ForeName": "Shuang", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuang Li", + "orcid": null + }, + { + "ForeName": "Qingzhu", + "LastName": "Wei", + "abbrevName": "Wei Q", + "email": null, + "isCollectiveName": false, + "name": "Qingzhu Wei", + "orcid": null + }, + { + "ForeName": "Qin", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qin Li", + "orcid": null + }, + { + "ForeName": "Bin", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bin Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Xiao", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2015.1040958", + "pmid": "25920936", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 16 2015", + "title": "Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer." + } + }, + { + "pmid": "25195714", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Glypican 3 (GPC3) has been paid particular attention owing to its potential as diagnosis marker for hepatocellular carcinoma (HCC). Identifying the mechanisms regulating the reactivation of GPC3 in HCC appears to be clinically meaningful. Previous study identified zinc-fingers and homeoboxes 2 (ZHX2) as transcriptional factor responsible for postnatal repression of GPC3 in mice. Here, in this study, we provided the first evidence that down regulated ZHX2 is responsible for GPC3 reactivation in HCC. First, inverse correlation of ZHX2 with GPC3 expression was shown in cultured liver cell lines. Second, ZHX2 overexpression significantly decreased GPC3 expression, while ZHX2 knockdown effectively increased GPC3 level in different HCC cell lines. Consistently, dual luciferase and ChIP assay showed that ZHX2 dose-dependently suppressed GPC3 promoter activity by binding with the core promoter. More importantly, immunohistochemical staining demonstrated the inverse correlation between nuclear ZHX2 with GPC3 expression in HCC tissues. Further in vitro analysis showed that nuclear translocation was crucial for ZHX2 mediated repression on GPC3 transcription. Taken together, our results prove that ZHX2 suppresses GPC3 transcription by binding with its core promoter and reduced nucleic ZHX2 expression may be involved in GPC3 reactivation in HCC.", + "authors": { + "abbreviation": "Fang Luan, Peng Liu, Hongxin Ma, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Fang", + "LastName": "Luan", + "abbrevName": "Luan F", + "email": null, + "isCollectiveName": false, + "name": "Fang Luan", + "orcid": null + }, + { + "ForeName": "Peng", + "LastName": "Liu", + "abbrevName": "Liu P", + "email": null, + "isCollectiveName": false, + "name": "Peng Liu", + "orcid": null + }, + { + "ForeName": "Hongxin", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Ma", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Liu", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.biocel.2014.08.021", + "pmid": "25195714", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Biochem Cell Biol 55 2014", + "title": "Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma." + } + }, + { + "pmid": "28054302", + "pubmed": { + "ISODate": "2017-04-01T00:00:00.000Z", + "abstract": "PURPOSE: Despite advances that have been made in systemic chemotherapy, the prognosis of advanced triple-negative breast cancer (TNBC) patients is still poor. The identification of key factors governing TNBC development is considered imperative for the development of novel effective therapeutic approaches. Previously, it has been reported that microRNA (miR)-761 may act as either a tumor suppressor or as an oncogene in different types of cancer. Here, we aimed at assessing the biological role of this miRNA in TNBC. METHODS: First, we measured the expression of miR-761 in primary breast cancer tissues and breast cancer-derived cell lines using qRT-PCR. Subsequently, over-expression and silencing experiments were performed to determine the role of miR-761 in TNBC cell proliferation, colony formation, migration and invasion in vitro. The in vivo role of miR-761 in TNBC growth and metastasis was determined in mouse models. Bioinformatics analyses, dual-luciferase reporter assays, Western blot analyses and rescue experiments were performed to identify miR-761 target gene(s). RESULTS: We found that miR-761 was up-regulated in primary breast cancer tissues and its derived cell lines and, particularly, in TNBC tissues and cell lines. We also found that exogenous miR-761 over-expression augmented in vitro TNBC cell proliferation, colony formation, migration and invasion, whereas miR-761 down-regulation impaired these features. In vivo, we found that miR-761 over-expression facilitated TNBC growth and lung metastasis. Mechanistically, miR-761 was found to negatively regulate the expression of tripartite motif-containing 29 (TRIM29) in TNBC cells by binding to the 3'-untranslated region of its mRNA. In conformity with these results, a significant negative correlation between miR-761 expression and TRIM29 protein expression was noted in primary TNBC tissues (r = -0.452, p = 0.0126). We also found that exogenous TRIM29 over-expression reversed the proliferative and invasive capacities of TNBC cells. CONCLUSIONS: Our data indicate that miR-761 acts as an oncogene in TNBC. This mode of action can, at least partially, be ascribed to the down-regulation of its target TRIM29. We suggest that miR-761 may serve as a promising therapeutic target for TNBC.", + "authors": { + "abbreviation": "Guang-Cheng Guo, Jia-Xiang Wang, Ming-Li Han, ..., Lin Li", + "authorList": [ + { + "ForeName": "Guang-Cheng", + "LastName": "Guo", + "abbrevName": "Guo GC", + "email": null, + "isCollectiveName": false, + "name": "Guang-Cheng Guo", + "orcid": null + }, + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "abbrevName": "Wang JX", + "email": "ggc503@126.com", + "isCollectiveName": false, + "name": "Jia-Xiang Wang", + "orcid": null + }, + { + "ForeName": "Ming-Li", + "LastName": "Han", + "abbrevName": "Han ML", + "email": null, + "isCollectiveName": false, + "name": "Ming-Li Han", + "orcid": null + }, + { + "ForeName": "Lian-Ping", + "LastName": "Zhang", + "abbrevName": "Zhang LP", + "email": null, + "isCollectiveName": false, + "name": "Lian-Ping Zhang", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Lin Li", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "email": [ + "ggc503@126.com" + ], + "name": "Jia-Xiang Wang" + } + ] + }, + "doi": "10.1007/s13402-016-0312-6", + "pmid": "28054302", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Oncol (Dordr) 40 2017", + "title": "microRNA-761 induces aggressive phenotypes in triple-negative breast cancer cells by repressing TRIM29 expression." + } + }, + { + "pmid": "28361350", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin β1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin β1 (ITGB1) gene expression have not been well elucidated. METHODS: Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin β1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin β1 gene and drives its expression. RESULTS: We demonstrated that FOXM1 directly binds to the promoter of integrin β1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells. CONCLUSION: Our study suggests that FOXM1 transcription factor regulates Integrin β1 gene expression and that FOXM1/ Integrin-β1/FAK axis may play an important role in the progression of TNBC.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Nermin Kahraman, Ahmed Ashour, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": "bozpolat@mdanderson.org", + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "email": [ + "bozpolat@mdanderson.org" + ], + "name": "Bulent Ozpolat" + } + ] + }, + "doi": "10.1007/s10549-017-4207-7", + "pmid": "28361350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res Treat 163 2017", + "title": "FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer." + } + }, + { + "pmid": "28423652", + "pubmed": { + "ISODate": "2017-04-25T00:00:00.000Z", + "abstract": "MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.", + "authors": { + "abbreviation": "Rosa Drago-Ferrante, Francesca Pentimalli, Daniela Carlisi, ..., Riccardo Di Fiore", + "authorList": [ + { + "ForeName": "Rosa", + "LastName": "Drago-Ferrante", + "abbrevName": "Drago-Ferrante R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Drago-Ferrante", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Pentimalli", + "abbrevName": "Pentimalli F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Pentimalli", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Carlisi", + "abbrevName": "Carlisi D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Carlisi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "De Blasio", + "abbrevName": "De Blasio A", + "email": null, + "isCollectiveName": false, + "name": "Anna De Blasio", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Saliba", + "abbrevName": "Saliba C", + "email": null, + "isCollectiveName": false, + "name": "Christian Saliba", + "orcid": null + }, + { + "ForeName": "Shawn", + "LastName": "Baldacchino", + "abbrevName": "Baldacchino S", + "email": null, + "isCollectiveName": false, + "name": "Shawn Baldacchino", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Degaetano", + "abbrevName": "Degaetano J", + "email": null, + "isCollectiveName": false, + "name": "James Degaetano", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Debono", + "abbrevName": "Debono J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Debono", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Caruana-Dingli", + "abbrevName": "Caruana-Dingli G", + "email": null, + "isCollectiveName": false, + "name": "Gordon Caruana-Dingli", + "orcid": null + }, + { + "ForeName": "Godfrey", + "LastName": "Grech", + "abbrevName": "Grech G", + "email": null, + "isCollectiveName": false, + "name": "Godfrey Grech", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Scerri", + "abbrevName": "Scerri C", + "email": null, + "isCollectiveName": false, + "name": "Christian Scerri", + "orcid": null + }, + { + "ForeName": "Giovanni", + "LastName": "Tesoriere", + "abbrevName": "Tesoriere G", + "email": null, + "isCollectiveName": false, + "name": "Giovanni Tesoriere", + "orcid": null + }, + { + "ForeName": "Antonio", + "LastName": "Giordano", + "abbrevName": "Giordano A", + "email": null, + "isCollectiveName": false, + "name": "Antonio Giordano", + "orcid": null + }, + { + "ForeName": "Renza", + "LastName": "Vento", + "abbrevName": "Vento R", + "email": null, + "isCollectiveName": false, + "name": "Renza Vento", + "orcid": null + }, + { + "ForeName": "Riccardo", + "LastName": "Di Fiore", + "abbrevName": "Di Fiore R", + "email": null, + "isCollectiveName": false, + "name": "Riccardo Di Fiore", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.15960", + "pmid": "28423652", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 8 2017", + "title": "Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation." + } + }, + { + "pmid": "36228375", + "pubmed": { + "ISODate": "2022-12-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly aggressive and hypoxic compared with other subtypes. The role of hypoxia inducible factor 1α (HIF-1α) as a key hypoxic transcription factor in oncogenic processes has been extensively studied. Recently, it has been shown that HIF-1α regulates the complex biological processes of TNBC, such as glycolysis, angiogenesis, invasion and metastasis, breast cancer stem cells (BCSCs) enrichment, and immune escape, to promote TNBC survival and development through the activation of downstream target genes. In addition, inflammatory mediators, oxygen levels, noncoding RNAs, complex signaling regulatory networks, epigenetic regulators are involved in the upstream regulatory expression of HIF-1α. However, further studies are needed to determine the potential and future directions of targeting HIF-1α in TNBC. This article discusses the expression of the HIF-1α transcription factor in TNBC. We also explored the mechanism by which HIF-1α drives TNBC progression. The potential significance of targeting HIF-1α for immunotherapy, chemotherapy, anti-angiogenic therapy, and photodynamic therapy is discussed. The intrinsic mechanism, existing problems and future directions of targeting HIF-1α are also studied.", + "authors": { + "abbreviation": "Qi Liu, Chengcheng Guan, Cui Liu, ..., Changgang Sun", + "authorList": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": "2020110892@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Qi Liu", + "orcid": null + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "abbrevName": "Guan C", + "email": "2020110896@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Chengcheng Guan", + "orcid": null + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": "2019101062@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Cui Liu", + "orcid": null + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "abbrevName": "Li H", + "email": "2019101020@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Huayao Li", + "orcid": null + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "2020111256@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Jibiao Wu", + "orcid": null + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "abbrevName": "Sun C", + "email": "zyxyscg@wfmc.edu.cn", + "isCollectiveName": false, + "name": "Changgang Sun", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "email": [ + "2020110892@sdutcm.edu.cn" + ], + "name": "Qi Liu" + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "email": [ + "2020110896@sdutcm.edu.cn" + ], + "name": "Chengcheng Guan" + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "email": [ + "2019101062@sdutcm.edu.cn" + ], + "name": "Cui Liu" + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "email": [ + "2019101020@sdutcm.edu.cn" + ], + "name": "Huayao Li" + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "email": [ + "2020111256@sdutcm.edu.cn" + ], + "name": "Jibiao Wu" + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "email": [ + "zyxyscg@wfmc.edu.cn" + ], + "name": "Changgang Sun" + } + ] + }, + "doi": "10.1016/j.biopha.2022.113861", + "pmid": "36228375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biomed Pharmacother 156 2022", + "title": "Targeting hypoxia-inducible factor-1alpha: A new strategy for triple-negative breast cancer therapy." + } + }, + { + "pmid": "28239645", + "pubmed": { + "ISODate": "2017-02-23T00:00:00.000Z", + "abstract": "Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.", + "authors": { + "abbreviation": "Manfredi Ponente, Letizia Campanini, Roberto Cuttano, ..., Rosa Bernardi", + "authorList": [ + { + "ForeName": "Manfredi", + "LastName": "Ponente", + "abbrevName": "Ponente M", + "email": null, + "isCollectiveName": false, + "name": "Manfredi Ponente", + "orcid": null + }, + { + "ForeName": "Letizia", + "LastName": "Campanini", + "abbrevName": "Campanini L", + "email": null, + "isCollectiveName": false, + "name": "Letizia Campanini", + "orcid": null + }, + { + "ForeName": "Roberto", + "LastName": "Cuttano", + "abbrevName": "Cuttano R", + "email": null, + "isCollectiveName": false, + "name": "Roberto Cuttano", + "orcid": null + }, + { + "ForeName": "Andrea", + "LastName": "Piunti", + "abbrevName": "Piunti A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Piunti", + "orcid": null + }, + { + "ForeName": "Giacomo", + "LastName": "Delledonne", + "abbrevName": "Delledonne GA", + "email": null, + "isCollectiveName": false, + "name": "Giacomo A Delledonne", + "orcid": null + }, + { + "ForeName": "Nadia", + "LastName": "Coltella", + "abbrevName": "Coltella N", + "email": null, + "isCollectiveName": false, + "name": "Nadia Coltella", + "orcid": null + }, + { + "ForeName": "Roberta", + "LastName": "Valsecchi", + "abbrevName": "Valsecchi R", + "email": null, + "isCollectiveName": false, + "name": "Roberta Valsecchi", + "orcid": null + }, + { + "ForeName": "Alessandra", + "LastName": "Villa", + "abbrevName": "Villa A", + "email": null, + "isCollectiveName": false, + "name": "Alessandra Villa", + "orcid": null + }, + { + "ForeName": "Ugo", + "LastName": "Cavallaro", + "abbrevName": "Cavallaro U", + "email": null, + "isCollectiveName": false, + "name": "Ugo Cavallaro", + "orcid": null + }, + { + "ForeName": "Linda", + "LastName": "Pattini", + "abbrevName": "Pattini L", + "email": null, + "isCollectiveName": false, + "name": "Linda Pattini", + "orcid": null + }, + { + "ForeName": "Claudio", + "LastName": "Doglioni", + "abbrevName": "Doglioni C", + "email": null, + "isCollectiveName": false, + "name": "Claudio Doglioni", + "orcid": null + }, + { + "ForeName": "Rosa", + "LastName": "Bernardi", + "abbrevName": "Bernardi R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Bernardi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/jci.insight.87380", + "pmid": "28239645", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "JCI Insight 2 2017", + "title": "PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes." + } + }, + { + "pmid": "32778144", + "pubmed": { + "ISODate": "2020-08-10T00:00:00.000Z", + "abstract": "BACKGROUND: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. METHODS: In order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation. RESULTS: We first determined that IL-1β expression correlates with the levels of HIF-1α as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1α, GPER and the IL-1β/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1β that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1β released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs. CONCLUSIONS: Our data shed new light on the role of hypoxia in the activation of the IL-1β/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.", + "authors": { + "abbreviation": "Rosamaria Lappano, Marianna Talia, Francesca Cirillo, ..., Marcello Maggiolini", + "authorList": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "abbrevName": "Lappano R", + "email": "rosamaria.lappano@unical.it", + "isCollectiveName": false, + "name": "Rosamaria Lappano", + "orcid": null + }, + { + "ForeName": "Marianna", + "LastName": "Talia", + "abbrevName": "Talia M", + "email": null, + "isCollectiveName": false, + "name": "Marianna Talia", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Cirillo", + "abbrevName": "Cirillo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Cirillo", + "orcid": null + }, + { + "ForeName": "Damiano", + "LastName": "Rigiracciolo", + "abbrevName": "Rigiracciolo DC", + "email": null, + "isCollectiveName": false, + "name": "Damiano Cosimo Rigiracciolo", + "orcid": null + }, + { + "ForeName": "Domenica", + "LastName": "Scordamaglia", + "abbrevName": "Scordamaglia D", + "email": null, + "isCollectiveName": false, + "name": "Domenica Scordamaglia", + "orcid": null + }, + { + "ForeName": "Rita", + "LastName": "Guzzi", + "abbrevName": "Guzzi R", + "email": null, + "isCollectiveName": false, + "name": "Rita Guzzi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Miglietta", + "abbrevName": "Miglietta AM", + "email": null, + "isCollectiveName": false, + "name": "Anna Maria Miglietta", + "orcid": null + }, + { + "ForeName": "Ernestina", + "LastName": "De Francesco", + "abbrevName": "De Francesco EM", + "email": null, + "isCollectiveName": false, + "name": "Ernestina Marianna De Francesco", + "orcid": null + }, + { + "ForeName": "Antonino", + "LastName": "Belfiore", + "abbrevName": "Belfiore A", + "email": null, + "isCollectiveName": false, + "name": "Antonino Belfiore", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "abbrevName": "Maggiolini M", + "email": "marcello.maggiolini@unical.it", + "isCollectiveName": false, + "name": "Marcello Maggiolini", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "email": [ + "rosamaria.lappano@unical.it" + ], + "name": "Rosamaria Lappano" + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "email": [ + "marcello.maggiolini@unical.it" + ], + "name": "Marcello Maggiolini" + } + ] + }, + "doi": "10.1186/s13046-020-01667-y", + "pmid": "32778144", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Exp Clin Cancer Res 39 2020", + "title": "The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)." + } + }, + { + "pmid": "27184798", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer.", + "authors": { + "abbreviation": "Min-Sun Jin, Hyebin Lee, In Ae Park, ..., Han Suk Ryu", + "authorList": [ + { + "ForeName": "Min-Sun", + "LastName": "Jin", + "abbrevName": "Jin MS", + "email": null, + "isCollectiveName": false, + "name": "Min-Sun Jin", + "orcid": null + }, + { + "ForeName": "Hyebin", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "Hyebin Lee", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Park", + "abbrevName": "Park IA", + "email": null, + "isCollectiveName": false, + "name": "In Ae Park", + "orcid": null + }, + { + "ForeName": "Yul", + "LastName": "Chung", + "abbrevName": "Chung YR", + "email": null, + "isCollectiveName": false, + "name": "Yul Ri Chung", + "orcid": null + }, + { + "ForeName": "Seock-Ah", + "LastName": "Im", + "abbrevName": "Im SA", + "email": null, + "isCollectiveName": false, + "name": "Seock-Ah Im", + "orcid": null + }, + { + "ForeName": "Kyung-Hun", + "LastName": "Lee", + "abbrevName": "Lee KH", + "email": null, + "isCollectiveName": false, + "name": "Kyung-Hun Lee", + "orcid": null + }, + { + "ForeName": "Hyeong-Gon", + "LastName": "Moon", + "abbrevName": "Moon HG", + "email": null, + "isCollectiveName": false, + "name": "Hyeong-Gon Moon", + "orcid": null + }, + { + "ForeName": "Wonshik", + "LastName": "Han", + "abbrevName": "Han W", + "email": null, + "isCollectiveName": false, + "name": "Wonshik Han", + "orcid": null + }, + { + "ForeName": "Kyubo", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyubo Kim", + "orcid": null + }, + { + "ForeName": "Tae-Yong", + "LastName": "Kim", + "abbrevName": "Kim TY", + "email": null, + "isCollectiveName": false, + "name": "Tae-Yong Kim", + "orcid": null + }, + { + "ForeName": "Dong-Young", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Young Noh", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Ryu", + "abbrevName": "Ryu HS", + "email": "karlnash@naver.com", + "isCollectiveName": false, + "name": "Han Suk Ryu", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Han", + "LastName": "Ryu", + "email": [ + "karlnash@naver.com" + ], + "name": "Han Suk Ryu" + } + ] + }, + "doi": "10.1007/s00428-016-1953-6", + "pmid": "27184798", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Virchows Arch 469 2016", + "title": "Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer." + } + }, + { + "pmid": "31683461", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "OBJECTIVE: To investigate the effect of ZHX2 on lung cancer cells proliferation and apoptosis. MATERIALS AND METHODS: The mRNA and protein expression of ZHX2 were detected by qRT-PCR and western blot, respectively. The human lung cancer cells were divided into Control, NC, ZHX2, SB, and ZHX2 + Ani groups. The cell proliferation was detected by CCK-8 assay and the cell migration and invasion were detected by Transwell assay. Cell apoptosis was detected by flow cytometry. Apoptosis and p38MAPK signaling pathway related proteins were detected by western blot. The nude mice model of lung cancer xenograft was constructed. The tumor volume and tumor weight were measured. The expression of PCNA protein in tumor tissues was detected by immunohistochemistry. The apoptosis of tumor cells was detected by TUNEL staining. The ZHX2 and p38MAPK signaling pathway related proteins in tumor tissues were detected by western blot. RESULTS: The expression of ZHX2 gene and protein in the cancer cell lines were significantly decreased. Compared with control and NC groups, the cells proliferation, migration and invasion were inhibited in ZHX2 and SB groups, while the apoptosis and apoptosis related proteins were increased (p< 0.05). Meanwhile, compared with ZHX2 group, the tumor growth rate, volume, weight, the percentage of PCNA-positive cells, and p-P38 MAPK/P38 MAPK were increased significantly in ZHX2 + Ani group, while the apoptotic index and the expression of MMP-9 protein were significantly decreased (p< 0.05). CONCLUSION: ZHX2 could inhibit proliferation and promote apoptosis of lung cancer cells by inhibiting p38MAPK signaling pathway.", + "authors": { + "abbreviation": "Xudong Tian, Yadong Wang, Shuhai Li, ..., Hui Tian", + "authorList": [ + { + "ForeName": "Xudong", + "LastName": "Tian", + "abbrevName": "Tian X", + "email": null, + "isCollectiveName": false, + "name": "Xudong Tian", + "orcid": null + }, + { + "ForeName": "Yadong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yadong Wang", + "orcid": null + }, + { + "ForeName": "Shuhai", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuhai Li", + "orcid": null + }, + { + "ForeName": "Weiming", + "LastName": "Yue", + "abbrevName": "Yue W", + "email": null, + "isCollectiveName": false, + "name": "Weiming Yue", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Tian", + "abbrevName": "Tian H", + "email": null, + "isCollectiveName": false, + "name": "Hui Tian", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3233/CBM-190514", + "pmid": "31683461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Biomark 27 2020", + "title": "ZHX2 inhibits proliferation and promotes apoptosis of human lung cancer cells through targeting p38MAPK pathway." + } + }, + { + "pmid": "34408002", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.", + "authors": { + "abbreviation": "Tian-Jian Yu, Ying-Ying Liu, Xiao-Guang Li, ..., Yi-Zhou Jiang", + "authorList": [ + { + "ForeName": "Tian-Jian", + "LastName": "Yu", + "abbrevName": "Yu TJ", + "email": null, + "isCollectiveName": false, + "name": "Tian-Jian Yu", + "orcid": null + }, + { + "ForeName": "Ying-Ying", + "LastName": "Liu", + "abbrevName": "Liu YY", + "email": null, + "isCollectiveName": false, + "name": "Ying-Ying Liu", + "orcid": null + }, + { + "ForeName": "Xiao-Guang", + "LastName": "Li", + "abbrevName": "Li XG", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Guang Li", + "orcid": null + }, + { + "ForeName": "Bi", + "LastName": "Lian", + "abbrevName": "Lian B", + "email": null, + "isCollectiveName": false, + "name": "Bi Lian", + "orcid": null + }, + { + "ForeName": "Xun-Xi", + "LastName": "Lu", + "abbrevName": "Lu XX", + "email": null, + "isCollectiveName": false, + "name": "Xun-Xi Lu", + "orcid": "0000-0002-5118-0377" + }, + { + "ForeName": "Xi", + "LastName": "Jin", + "abbrevName": "Jin X", + "email": null, + "isCollectiveName": false, + "name": "Xi Jin", + "orcid": null + }, + { + "ForeName": "Zhi-Ming", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Ming Shao", + "orcid": "0000-0001-8781-2455" + }, + { + "ForeName": "Xin", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Xin Hu", + "orcid": null + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "abbrevName": "Di GH", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Gen-Hong Di", + "orcid": null + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "abbrevName": "Jiang YZ", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Yi-Zhou Jiang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Hu", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Xin Hu" + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Gen-Hong Di" + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Yi-Zhou Jiang" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-21-0747", + "pmid": "34408002", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 81 2021", + "title": "PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "31529195", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype. Extended periods of lactation protect against breast cancer development, but the mechanisms underlying this protection are unknown. We examined the effects of the milk protein alpha-casein over expression in the triple negative MDA-MB-231 breast cancer cell line. The effects of recombinant alpha-casein added exogenously to MDA-MB-231 breast cancer cells, and immortalised human fibroblasts were also investigated. We used transcriptional reporters to understand the signalling pathways downstream of alpha-casein in breast cancer cells and these fibroblasts that were activated by breast cancer cells. To extend our findings to the clinical setting, we analysed public gene expression datasets to further understand the relevance of these signalling pathways in triple negative breast cancer cells and patient samples. Finally, we used small molecular inhibitors to target relevant pathways and highlight these as potential candidates for the treatment of TN breast cancer. High levels of alpha-casein gene expression were predictive of good prognosis across 263 TNBC patient tumour samples. Alpha-casein over expression or exogenous addition reduces cancer stem cell (CSC) activity. HIF-1alpha was identified to be a key downstream target of alpha-casein, in both breast cancer cells and activated fibroblasts, and STAT transcription factors to be upstream of HIF-1alpha. Interestingly, HIF-1alpha is regulated by STAT3 in breast cancer cells, but STAT1 is the regulator of HIF-1alpha in activated fibroblasts. In analysis of 573 TNBC patient samples, alpha-casein expression, inversely correlated to HIF-1alpha, STAT3 and STAT1. STAT1 and STAT3 inhibitors target HIF-1alpha signalling in activated fibroblasts and MDA-MB-231 breast cancer cells respectively, and also abrogate CSC activities. Our findings provide an explanation for the protective effects of lactation in TNBC. Clinical data correlates high alpha-casein expression with increased recurrence-free survival in TNBC patients. Mechanistically, alpha-casein reduces breast cancer stem cell activity in vitro, and STAT3 and STAT1 were identified as regulators of pro-tumorigenic HIF-1alpha signalling in breast cancer cells and fibroblasts respectively.", + "authors": { + "abbreviation": "Kirsten E L Garner, Nathan J Hull, Andrew H Sims, ..., Robert B Clarke", + "authorList": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "abbrevName": "Garner KEL", + "email": "Kirsten.garner@manchester.ac.uk", + "isCollectiveName": false, + "name": "Kirsten E L Garner", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Hull", + "abbrevName": "Hull NJ", + "email": null, + "isCollectiveName": false, + "name": "Nathan J Hull", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Lamb", + "abbrevName": "Lamb R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lamb", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Clarke", + "abbrevName": "Clarke RB", + "email": null, + "isCollectiveName": false, + "name": "Robert B Clarke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "email": [ + "Kirsten.garner@manchester.ac.uk" + ], + "name": "Kirsten E L Garner" + } + ] + }, + "doi": "10.1007/s10911-019-09435-1", + "pmid": "31529195", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mammary Gland Biol Neoplasia 24 2019", + "title": "The Milk Protein Alpha-Casein Suppresses Triple Negative Breast Cancer Stem Cell Activity Via STAT and HIF-1alpha Signalling Pathways in Breast Cancer Cells and Fibroblasts." + } + }, + { + "pmid": "24248265", + "pubmed": { + "ISODate": "2014-02-01T00:00:00.000Z", + "abstract": "UNLABELLED: Targeted therapy against triple-negative breast cancers, which lack expression of the estrogen, progesterone, and HER2 receptors, is not available and the overall response to cytotoxic chemotherapy is poor. One of the molecular hallmarks of triple-negative breast cancers is increased expression of genes that are transcriptionally activated by hypoxia-inducible factors (HIFs), which are implicated in many critical aspects of cancer progression including metabolism, angiogenesis, invasion, metastasis, and stem cell maintenance. Ganetespib is a second-generation inhibitor of heat shock protein 90 (HSP90), a molecular chaperone that is essential for the stability and function of multiple client proteins in cancer cells including HIF-1α. In this study, human MDA-MB-231 and MDA-MB-435 triple-negative breast cancer cells were injected into the mammary fat pad of immunodeficient mice that received weekly intravenous injections of ganetespib or vehicle following the development of palpable tumors. Ganetespib treatment markedly impaired primary tumor growth and vascularization, and eliminated local tissue invasion and distant metastasis to regional lymph nodes and lungs. Ganetespib treatment also significantly reduced the number of Aldefluor-positive cancer stem cells in the primary tumor. Primary tumors of ganetespib-treated mice had significantly reduced levels of HIF-1α (but not HIF-2α) protein and of HIF-1 target gene mRNAs encoding proteins that play key roles in angiogenesis, metabolism, invasion, and metastasis, thereby providing a molecular basis for observed effects of the drug on the growth and metastasis of triple-negative breast cancer. KEY MESSAGES: Triple-negative breast cancers (TNBCs) respond poorly to available chemotherapy. TNBCs overexpress genes regulated by hypoxia-inducible factors (HIFs). Ganetespib induces degradation of HSP90 client proteins, including HIF-1α. Ganetespib inhibited TNBC orthotopic tumor growth, invasion, and metastasis. Ganetespib inhibited expression of HIF-1 target genes involved in TNBC progression.", + "authors": { + "abbreviation": "Lisha Xiang, Daniele M Gilkes, Pallavi Chaturvedi, ..., Gregg L Semenza", + "authorList": [ + { + "ForeName": "Lisha", + "LastName": "Xiang", + "abbrevName": "Xiang L", + "email": null, + "isCollectiveName": false, + "name": "Lisha Xiang", + "orcid": null + }, + { + "ForeName": "Daniele", + "LastName": "Gilkes", + "abbrevName": "Gilkes DM", + "email": null, + "isCollectiveName": false, + "name": "Daniele M Gilkes", + "orcid": null + }, + { + "ForeName": "Pallavi", + "LastName": "Chaturvedi", + "abbrevName": "Chaturvedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Chaturvedi", + "orcid": null + }, + { + "ForeName": "Weibo", + "LastName": "Luo", + "abbrevName": "Luo W", + "email": null, + "isCollectiveName": false, + "name": "Weibo Luo", + "orcid": null + }, + { + "ForeName": "Hongxia", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Hongxia Hu", + "orcid": null + }, + { + "ForeName": "Naoharu", + "LastName": "Takano", + "abbrevName": "Takano N", + "email": null, + "isCollectiveName": false, + "name": "Naoharu Takano", + "orcid": null + }, + { + "ForeName": "Houjie", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Houjie Liang", + "orcid": null + }, + { + "ForeName": "Gregg", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": null, + "isCollectiveName": false, + "name": "Gregg L Semenza", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s00109-013-1102-5", + "pmid": "24248265", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Med (Berl) 92 2014", + "title": "Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer." + } + }, + { + "pmid": "31264274", + "pubmed": { + "ISODate": "2019-10-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.", + "authors": { + "abbreviation": "Chen Gong, Jin Zou, Mingsheng Zhang, ..., Yong Li", + "authorList": [ + { + "ForeName": "Chen", + "LastName": "Gong", + "abbrevName": "Gong C", + "email": null, + "isCollectiveName": false, + "name": "Chen Gong", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zou", + "abbrevName": "Zou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zou", + "orcid": null + }, + { + "ForeName": "Mingsheng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mingsheng Zhang", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Shanshan", + "LastName": "Xu", + "abbrevName": "Xu S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Xu", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Zhu", + "orcid": null + }, + { + "ForeName": "Mengqi", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mengqi Yang", + "orcid": null + }, + { + "ForeName": "Dongjia", + "LastName": "Li", + "abbrevName": "Li D", + "email": null, + "isCollectiveName": false, + "name": "Dongjia Li", + "orcid": null + }, + { + "ForeName": "Yun", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yun Wang", + "orcid": null + }, + { + "ForeName": "Jialu", + "LastName": "Shi", + "abbrevName": "Shi J", + "email": null, + "isCollectiveName": false, + "name": "Jialu Shi", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Li", + "orcid": "0000-0003-4681-263X" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23079", + "pmid": "31264274", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer." + } + }, + { + "pmid": "33824311", + "pubmed": { + "ISODate": "2021-04-06T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15-20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.", + "authors": { + "abbreviation": "Fengxia Chen, Qingqing Wang, Xiaoyan Yu, ..., Yunfeng Zhou", + "authorList": [ + { + "ForeName": "Fengxia", + "LastName": "Chen", + "abbrevName": "Chen F", + "email": null, + "isCollectiveName": false, + "name": "Fengxia Chen", + "orcid": null + }, + { + "ForeName": "Qingqing", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqing Wang", + "orcid": "0000-0002-6440-582X" + }, + { + "ForeName": "Xiaoyan", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyan Yu", + "orcid": null + }, + { + "ForeName": "Ningning", + "LastName": "Yang", + "abbrevName": "Yang N", + "email": null, + "isCollectiveName": false, + "name": "Ningning Yang", + "orcid": null + }, + { + "ForeName": "Yuan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Wang", + "orcid": "0000-0003-1894-0853" + }, + { + "ForeName": "Yangyang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yangyang Zeng", + "orcid": null + }, + { + "ForeName": "Zhewen", + "LastName": "Zheng", + "abbrevName": "Zheng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhewen Zheng", + "orcid": null + }, + { + "ForeName": "Fuxiang", + "LastName": "Zhou", + "abbrevName": "Zhou F", + "email": null, + "isCollectiveName": false, + "name": "Fuxiang Zhou", + "orcid": null + }, + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": "yfzhouwhu@163.com", + "isCollectiveName": false, + "name": "Yunfeng Zhou", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "email": [ + "yfzhouwhu@163.com" + ], + "name": "Yunfeng Zhou" + } + ] + }, + "doi": "10.1038/s41419-021-03661-4", + "pmid": "33824311", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis." + } + }, + { + "pmid": "35188449", + "pubmed": { + "ISODate": "2022-05-01T00:00:00.000Z", + "abstract": "There is no clear treatment guideline or individualized treatment plan for triple-negative breast cancer (TNBC). The aim of this study was to investigate more effective targets for TNBC-targeted therapy. MDA-MB-231 and BT549 cell lines were used to explore the function of LINC00649 on the proliferation, invasion, and migration of TNBC cells. A mice subcutaneous tumor model and a pulmonary metastasis model was established to identify the role of LINC00649 on the growth and metastasis of TNBC in vivo. LINC00649 was found to be a key molecule involved in the occurrence and development of TNBC by screening of public databases and detection of TNBC clinical samples. LINC00649 increased hypoxia-inducible factor 1α (HIF-1α) mRNA stability and protein expression by interacting with the nuclear factor 90 (NF90)/NF45 complex. In vitro, interference with LINC00649 inhibits MDA-MB-231 and BT549 cell proliferation, migration, and invasion, and the addition of HIF-1α revised this effect. In vivo experiments showed that LINC00649 promoted the growth and metastasis of TNBC. We demonstrated that LINC00649 interacts with the NF90/NF45 complex to increase the mRNA stability of HIF-1α and up-regulate HIF-1α expression, thereby inducing the proliferation, invasion, and migration of TNBC cells as well as tumor growth and metastasis.", + "authors": { + "abbreviation": "Jianhua Zhang, Chuang Du, Linfeng Zhang, ..., Jingruo Li", + "authorList": [ + { + "ForeName": "Jianhua", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jianhua Zhang", + "orcid": null + }, + { + "ForeName": "Chuang", + "LastName": "Du", + "abbrevName": "Du C", + "email": null, + "isCollectiveName": false, + "name": "Chuang Du", + "orcid": null + }, + { + "ForeName": "Linfeng", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Linfeng Zhang", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Wang", + "orcid": null + }, + { + "ForeName": "Yingying", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingying Zhang", + "orcid": null + }, + { + "ForeName": "Jingruo", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jingruo Li", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2022.2040283", + "pmid": "35188449", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Cycle 21 2022", + "title": "LncRNA LINC00649 promotes the growth and metastasis of triple-negative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex." + } + }, + { + "pmid": "30784286", + "pubmed": { + "ISODate": "2019-05-23T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The unclear molecular mechanisms underlying could provide important theoretical basis for the prevention and control of HCC. This study performed chromatin immunoprecipitation-sequencing (ChIP-seq) to analyze the binding sites between zinc fingers and homeoboxes 2 (ZHX2) and its genome-wide target genes, and bioinformatics was used to analyze their gene transcription regulation network. Immunohistochemistry was used to detect the ZHX2 expression in HCC, and its association with the clinicopathological characteristics of HCC. Results of RT-PCR and western blot showed the expression of ZHX2 in HepG2 cells was obviously lower compared with normal liver cells. ZHX2 could be amplified in ChIP products, then ChIP-seq reveals there were 232 genes binding in promoter regions. GO analysis of functions revealed these genes were mainly associated with biological processes (BP), cellular components (CC), and molecular functions (MF). In addition, PTEN was found enriched in certain biological functions in BP analysis. Then, four pathways of these genes based on Kyoto Encyclopedia of Genes and Genomes (KEGG) were found P<0.05. Last analysis of immunohistochemistry showed the rates of ZHX2 expression and PTEN expression in paracancerous tissues both were significantly higher than that in HCC tissues (P=0.042; P<0.001), with negative correlations with AFP values (r=-0.246, P=0.040; r=-0.263, P=0.028). Further, PTEN expression was positively correlated with the differentiation level in HCC tissues (r=0.267, P=0.025). Spearman correlation analysis revealed that the expression profiles of ZHX2 and PTEN were positively correlated in HCC tissues (r=0.258, P=0.031). This study is the first to use ChIP-seq technology to analyze the specific regulatory mechanisms of the transcription suppressor ZHX2 in the context of HCC at the genome level.", + "authors": { + "abbreviation": "Z Lv, R He, M Huang, ..., G Chen", + "authorList": [ + { + "ForeName": "Z", + "LastName": "Lv", + "abbrevName": "Lv Z", + "email": null, + "isCollectiveName": false, + "name": "Z Lv", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "He", + "abbrevName": "He R", + "email": null, + "isCollectiveName": false, + "name": "R He", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Huang", + "abbrevName": "Huang M", + "email": null, + "isCollectiveName": false, + "name": "M Huang", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Zhao", + "abbrevName": "Zhao G", + "email": null, + "isCollectiveName": false, + "name": "G Zhao", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Ma", + "abbrevName": "Ma J", + "email": null, + "isCollectiveName": false, + "name": "J Ma", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": null, + "isCollectiveName": false, + "name": "G Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.4149/neo_2018_180806N593", + "pmid": "30784286", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Neoplasma 66 2019", + "title": "Targeting genes and signaling pathways of transcriptional suppressor ZHX2 in hepatocellular carcinoma: a Chromatin Immunoprecipitation-sequencing (ChIP-seq) investigation." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-12-10T08:46:24.367Z", + "_newestOpId": "86b98413-ceb6-4d6d-8b1b-9ba64b977913", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "13f57ee3-df7d-4ec8-b8ca-0efdd62f99d5" + }, + { + "id": "3295573e-31b2-40c4-99f1-4dbf6a34990a" + } + ], + "id": "3fd6a28f-483e-4eb4-ab6f-0a9025bd9cd1", + "liveId": "4684fd14-2146-4c30-b96c-31440207b731", + "lock": null, + "locked": false, + "name": "", + "position": { + "x": -190.08016877637147, + "y": -157.6436517069429 + }, + "relatedPapers": [ + { + "pmid": "26918606", + "pubmed": { + "ISODate": "2016-03-29T00:00:00.000Z", + "abstract": "Eukaryotic elongation factor 2 kinase (eEF2K), an emerging molecular target for cancer therapy, contributes to cancer proliferation, cell survival, tumorigenesis, and invasion, disease progression and drug resistance. Although eEF2K is highly up-regulated in various cancers, the mechanism of gene regulation has not been elucidated. In this study, we examined the role of Forkhead Box M1 (FOXM1) proto-oncogenic transcription factor in triple negative breast cancer (TNBC) cells and the regulation of eEF2K. We found that FOXM1 is highly upregulated in TNBC and its knockdown by RNA interference (siRNA) significantly inhibited eEF2K expression and suppressed cell proliferation, colony formation, migration, invasion and induced apoptotic cell death, recapitulating the effects of eEF2K inhibition. Knockdown of FOXM1 inhibited regulators of cell cycle, migration/invasion and survival, including cyclin D1, Src and MAPK-ERK signaling pathways, respectively. We also demonstrated that FOXM1 (1B and 1C isoforms) directly binds to and transcriptionally regulates eEF2K gene expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. Furthermore, in vivo inhibition of FOXM1 by liposomal siRNA-nanoparticles suppressed growth of MDA-MB-231 TNBC tumor xenografts in orthotopic models. In conclusion, our study provides the first evidence about the transcriptional regulation of eEF2K in TNBC and the role of FOXM1 in mediating breast cancer cell proliferation, survival, migration/invasion, progression and tumorgenesis and highlighting the potential of FOXM1/eEF2K axis as a molecular target in breast and other cancers.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Ahmed Ashour, Nermin Kahraman, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": null, + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.7672", + "pmid": "26918606", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 7 2016", + "title": "FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells." + } + }, + { + "pmid": "26751287", + "pubmed": { + "ISODate": "2016-02-01T00:00:00.000Z", + "abstract": "Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.", + "authors": { + "abbreviation": "Aifu Lin, Chunlai Li, Zhen Xing, ..., Liuqing Yang", + "authorList": [ + { + "ForeName": "Aifu", + "LastName": "Lin", + "abbrevName": "Lin A", + "email": null, + "isCollectiveName": false, + "name": "Aifu Lin", + "orcid": null + }, + { + "ForeName": "Chunlai", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunlai Li", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Xing", + "abbrevName": "Xing Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Xing", + "orcid": null + }, + { + "ForeName": "Qingsong", + "LastName": "Hu", + "abbrevName": "Hu Q", + "email": null, + "isCollectiveName": false, + "name": "Qingsong Hu", + "orcid": null + }, + { + "ForeName": "Ke", + "LastName": "Liang", + "abbrevName": "Liang K", + "email": null, + "isCollectiveName": false, + "name": "Ke Liang", + "orcid": null + }, + { + "ForeName": "Leng", + "LastName": "Han", + "abbrevName": "Han L", + "email": null, + "isCollectiveName": false, + "name": "Leng Han", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Wang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Hawke", + "abbrevName": "Hawke DH", + "email": null, + "isCollectiveName": false, + "name": "David H Hawke", + "orcid": "0000-0002-6102-7843" + }, + { + "ForeName": "Shouyu", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shouyu Wang", + "orcid": null + }, + { + "ForeName": "Yanyan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhang", + "orcid": null + }, + { + "ForeName": "Yongkun", + "LastName": "Wei", + "abbrevName": "Wei Y", + "email": null, + "isCollectiveName": false, + "name": "Yongkun Wei", + "orcid": null + }, + { + "ForeName": "Guolin", + "LastName": "Ma", + "abbrevName": "Ma G", + "email": null, + "isCollectiveName": false, + "name": "Guolin Ma", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Park", + "abbrevName": "Park PK", + "email": null, + "isCollectiveName": false, + "name": "Peter K Park", + "orcid": null + }, + { + "ForeName": "Jianwei", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jianwei Zhou", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Zhou", + "orcid": null + }, + { + "ForeName": "Zhibin", + "LastName": "Hu", + "abbrevName": "Hu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhibin Hu", + "orcid": null + }, + { + "ForeName": "Yubin", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": null, + "isCollectiveName": false, + "name": "Yubin Zhou", + "orcid": null + }, + { + "ForeName": "Jeffery", + "LastName": "Marks", + "abbrevName": "Marks JR", + "email": null, + "isCollectiveName": false, + "name": "Jeffery R Marks", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Han Liang", + "orcid": "0000-0001-7633-286X" + }, + { + "ForeName": "Mien-Chie", + "LastName": "Hung", + "abbrevName": "Hung MC", + "email": null, + "isCollectiveName": false, + "name": "Mien-Chie Hung", + "orcid": null + }, + { + "ForeName": "Chunru", + "LastName": "Lin", + "abbrevName": "Lin C", + "email": null, + "isCollectiveName": false, + "name": "Chunru Lin", + "orcid": null + }, + { + "ForeName": "Liuqing", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Liuqing Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3295", + "pmid": "26751287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer." + } + }, + { + "pmid": "28361350", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin β1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin β1 (ITGB1) gene expression have not been well elucidated. METHODS: Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin β1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin β1 gene and drives its expression. RESULTS: We demonstrated that FOXM1 directly binds to the promoter of integrin β1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells. CONCLUSION: Our study suggests that FOXM1 transcription factor regulates Integrin β1 gene expression and that FOXM1/ Integrin-β1/FAK axis may play an important role in the progression of TNBC.", + "authors": { + "abbreviation": "Zuhal Hamurcu, Nermin Kahraman, Ahmed Ashour, Bulent Ozpolat", + "authorList": [ + { + "ForeName": "Zuhal", + "LastName": "Hamurcu", + "abbrevName": "Hamurcu Z", + "email": null, + "isCollectiveName": false, + "name": "Zuhal Hamurcu", + "orcid": null + }, + { + "ForeName": "Nermin", + "LastName": "Kahraman", + "abbrevName": "Kahraman N", + "email": null, + "isCollectiveName": false, + "name": "Nermin Kahraman", + "orcid": null + }, + { + "ForeName": "Ahmed", + "LastName": "Ashour", + "abbrevName": "Ashour A", + "email": null, + "isCollectiveName": false, + "name": "Ahmed Ashour", + "orcid": null + }, + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "abbrevName": "Ozpolat B", + "email": "bozpolat@mdanderson.org", + "isCollectiveName": false, + "name": "Bulent Ozpolat", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bulent", + "LastName": "Ozpolat", + "email": [ + "bozpolat@mdanderson.org" + ], + "name": "Bulent Ozpolat" + } + ] + }, + "doi": "10.1007/s10549-017-4207-7", + "pmid": "28361350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res Treat 163 2017", + "title": "FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer." + } + }, + { + "pmid": "30964885", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "Triple-Negative Breast Cancers (TNBCs) are the most difficult to treat subtype of breast cancer and are often associated with high nuclear expression of Snail and Cathepsin L (Cat L) protease. We have previously shown that Snail can increase Cat L expression/activity in prostate and breast cancer cells. This study investigated the role of CUX1 (a downstream substrate of Cat L) in TNBC. We showed that Cat L and CUX1 were highly expressed in TNBC patient tissue/cell lines, as compared to ER-positive samples, using cBioportal data and western blot/zymography analyses. Additionally, luciferase reporter and chromatin immunoprecipitation assays showed that CUX1 directly bound to estrogen receptor-alpha (ER-α) promoter in MDA-MB-468, a representative TNBC cell line, and that CUX1 siRNA could restore ER-α transcription and protein expression. Furthermore, Snail and CUX1 expression in various TNBC cell lines was inhibited by muscadine grape skin extract (MSKE, a natural grape product rich in anthocyanins) or Cat L inhibitor (Z-FY-CHO) leading to decreased cell invasion and migration. MSKE decreased cell viability and increased expression of apoptotic markers in MDA-MB-468 cells, with no effect on non-tumorigenic MCF10A cells. MSKE also decreased CUX1 binding to ER-α promoter and restored ER-α expression in TNBC cells, while both MSKE and CUX1 siRNA restored sensitivity to estradiol and 4-hydoxytamoxifen as shown by increased cell viability. Therefore, CUX1 activated by Snail-Cat L signaling may contribute to TNBC via ER-α repression, and may be a viable target for TNBC using natural products such as MSKE that targets cancer and not normal cells.", + "authors": { + "abbreviation": "Liza J Burton, Ohuod Hawsawi, Janae Sweeney, ..., Valerie Odero-Marah", + "authorList": [ + { + "ForeName": "Liza", + "LastName": "Burton", + "abbrevName": "Burton LJ", + "email": null, + "isCollectiveName": false, + "name": "Liza J Burton", + "orcid": null + }, + { + "ForeName": "Ohuod", + "LastName": "Hawsawi", + "abbrevName": "Hawsawi O", + "email": null, + "isCollectiveName": false, + "name": "Ohuod Hawsawi", + "orcid": null + }, + { + "ForeName": "Janae", + "LastName": "Sweeney", + "abbrevName": "Sweeney J", + "email": null, + "isCollectiveName": false, + "name": "Janae Sweeney", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Bowen", + "abbrevName": "Bowen N", + "email": null, + "isCollectiveName": false, + "name": "Nathan Bowen", + "orcid": "0000-0002-1609-6698" + }, + { + "ForeName": "Tamaro", + "LastName": "Hudson", + "abbrevName": "Hudson T", + "email": null, + "isCollectiveName": false, + "name": "Tamaro Hudson", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Odero-Marah", + "abbrevName": "Odero-Marah V", + "email": null, + "isCollectiveName": false, + "name": "Valerie Odero-Marah", + "orcid": "0000-0002-5238-9914" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0214844", + "pmid": "30964885", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 14 2019", + "title": "CCAAT-displacement protein/cut homeobox transcription factor (CUX1) represses estrogen receptor-alpha (ER-α) in triple-negative breast cancer cells and can be antagonized by muscadine grape skin extract (MSKE)." + } + }, + { + "pmid": "27184798", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer.", + "authors": { + "abbreviation": "Min-Sun Jin, Hyebin Lee, In Ae Park, ..., Han Suk Ryu", + "authorList": [ + { + "ForeName": "Min-Sun", + "LastName": "Jin", + "abbrevName": "Jin MS", + "email": null, + "isCollectiveName": false, + "name": "Min-Sun Jin", + "orcid": null + }, + { + "ForeName": "Hyebin", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "Hyebin Lee", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Park", + "abbrevName": "Park IA", + "email": null, + "isCollectiveName": false, + "name": "In Ae Park", + "orcid": null + }, + { + "ForeName": "Yul", + "LastName": "Chung", + "abbrevName": "Chung YR", + "email": null, + "isCollectiveName": false, + "name": "Yul Ri Chung", + "orcid": null + }, + { + "ForeName": "Seock-Ah", + "LastName": "Im", + "abbrevName": "Im SA", + "email": null, + "isCollectiveName": false, + "name": "Seock-Ah Im", + "orcid": null + }, + { + "ForeName": "Kyung-Hun", + "LastName": "Lee", + "abbrevName": "Lee KH", + "email": null, + "isCollectiveName": false, + "name": "Kyung-Hun Lee", + "orcid": null + }, + { + "ForeName": "Hyeong-Gon", + "LastName": "Moon", + "abbrevName": "Moon HG", + "email": null, + "isCollectiveName": false, + "name": "Hyeong-Gon Moon", + "orcid": null + }, + { + "ForeName": "Wonshik", + "LastName": "Han", + "abbrevName": "Han W", + "email": null, + "isCollectiveName": false, + "name": "Wonshik Han", + "orcid": null + }, + { + "ForeName": "Kyubo", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyubo Kim", + "orcid": null + }, + { + "ForeName": "Tae-Yong", + "LastName": "Kim", + "abbrevName": "Kim TY", + "email": null, + "isCollectiveName": false, + "name": "Tae-Yong Kim", + "orcid": null + }, + { + "ForeName": "Dong-Young", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Young Noh", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Ryu", + "abbrevName": "Ryu HS", + "email": "karlnash@naver.com", + "isCollectiveName": false, + "name": "Han Suk Ryu", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Han", + "LastName": "Ryu", + "email": [ + "karlnash@naver.com" + ], + "name": "Han Suk Ryu" + } + ] + }, + "doi": "10.1007/s00428-016-1953-6", + "pmid": "27184798", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Virchows Arch 469 2016", + "title": "Overexpression of HIF1α and CAXI predicts poor outcome in early-stage triple negative breast cancer." + } + }, + { + "pmid": "31529195", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype. Extended periods of lactation protect against breast cancer development, but the mechanisms underlying this protection are unknown. We examined the effects of the milk protein alpha-casein over expression in the triple negative MDA-MB-231 breast cancer cell line. The effects of recombinant alpha-casein added exogenously to MDA-MB-231 breast cancer cells, and immortalised human fibroblasts were also investigated. We used transcriptional reporters to understand the signalling pathways downstream of alpha-casein in breast cancer cells and these fibroblasts that were activated by breast cancer cells. To extend our findings to the clinical setting, we analysed public gene expression datasets to further understand the relevance of these signalling pathways in triple negative breast cancer cells and patient samples. Finally, we used small molecular inhibitors to target relevant pathways and highlight these as potential candidates for the treatment of TN breast cancer. High levels of alpha-casein gene expression were predictive of good prognosis across 263 TNBC patient tumour samples. Alpha-casein over expression or exogenous addition reduces cancer stem cell (CSC) activity. HIF-1alpha was identified to be a key downstream target of alpha-casein, in both breast cancer cells and activated fibroblasts, and STAT transcription factors to be upstream of HIF-1alpha. Interestingly, HIF-1alpha is regulated by STAT3 in breast cancer cells, but STAT1 is the regulator of HIF-1alpha in activated fibroblasts. In analysis of 573 TNBC patient samples, alpha-casein expression, inversely correlated to HIF-1alpha, STAT3 and STAT1. STAT1 and STAT3 inhibitors target HIF-1alpha signalling in activated fibroblasts and MDA-MB-231 breast cancer cells respectively, and also abrogate CSC activities. Our findings provide an explanation for the protective effects of lactation in TNBC. Clinical data correlates high alpha-casein expression with increased recurrence-free survival in TNBC patients. Mechanistically, alpha-casein reduces breast cancer stem cell activity in vitro, and STAT3 and STAT1 were identified as regulators of pro-tumorigenic HIF-1alpha signalling in breast cancer cells and fibroblasts respectively.", + "authors": { + "abbreviation": "Kirsten E L Garner, Nathan J Hull, Andrew H Sims, ..., Robert B Clarke", + "authorList": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "abbrevName": "Garner KEL", + "email": "Kirsten.garner@manchester.ac.uk", + "isCollectiveName": false, + "name": "Kirsten E L Garner", + "orcid": null + }, + { + "ForeName": "Nathan", + "LastName": "Hull", + "abbrevName": "Hull NJ", + "email": null, + "isCollectiveName": false, + "name": "Nathan J Hull", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Lamb", + "abbrevName": "Lamb R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lamb", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Clarke", + "abbrevName": "Clarke RB", + "email": null, + "isCollectiveName": false, + "name": "Robert B Clarke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Kirsten", + "LastName": "Garner", + "email": [ + "Kirsten.garner@manchester.ac.uk" + ], + "name": "Kirsten E L Garner" + } + ] + }, + "doi": "10.1007/s10911-019-09435-1", + "pmid": "31529195", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mammary Gland Biol Neoplasia 24 2019", + "title": "The Milk Protein Alpha-Casein Suppresses Triple Negative Breast Cancer Stem Cell Activity Via STAT and HIF-1alpha Signalling Pathways in Breast Cancer Cells and Fibroblasts." + } + }, + { + "pmid": "35867755", + "pubmed": { + "ISODate": "2022-07-12T00:00:00.000Z", + "abstract": "Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Zhaoping Qiu, Weijie Guo, Bo Dong, ..., Yadi Wu", + "authorList": [ + { + "ForeName": "Zhaoping", + "LastName": "Qiu", + "abbrevName": "Qiu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaoping Qiu", + "orcid": null + }, + { + "ForeName": "Weijie", + "LastName": "Guo", + "abbrevName": "Guo W", + "email": null, + "isCollectiveName": false, + "name": "Weijie Guo", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bo Dong", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Wang", + "orcid": null + }, + { + "ForeName": "Pan", + "LastName": "Deng", + "abbrevName": "Deng P", + "email": null, + "isCollectiveName": false, + "name": "Pan Deng", + "orcid": "0000-0003-2974-7389" + }, + { + "ForeName": "Chi", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Chi Wang", + "orcid": null + }, + { + "ForeName": "Jinpeng", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jinpeng Liu", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + }, + { + "ForeName": "Rudolf", + "LastName": "Grosschedl", + "abbrevName": "Grosschedl R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Grosschedl", + "orcid": null + }, + { + "ForeName": "Zhiyong", + "LastName": "Yu", + "abbrevName": "Yu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyong Yu", + "orcid": null + }, + { + "ForeName": "Jiong", + "LastName": "Deng", + "abbrevName": "Deng J", + "email": null, + "isCollectiveName": false, + "name": "Jiong Deng", + "orcid": null + }, + { + "ForeName": "Yadi", + "LastName": "Wu", + "abbrevName": "Wu Y", + "email": null, + "isCollectiveName": false, + "name": "Yadi Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119518119", + "pmid": "35867755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "EBF1 promotes triple-negative breast cancer progression by surveillance of the HIF1α pathway." + } + }, + { + "pmid": "26825173", + "pubmed": { + "ISODate": "2016-03-15T00:00:00.000Z", + "abstract": "Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.", + "authors": { + "abbreviation": "Tarah M Regan Anderson, Shi Hong Ma, Ganesh V Raj, ..., Carol A Lange", + "authorList": [ + { + "ForeName": "Tarah", + "LastName": "Regan Anderson", + "abbrevName": "Regan Anderson TM", + "email": null, + "isCollectiveName": false, + "name": "Tarah M Regan Anderson", + "orcid": null + }, + { + "ForeName": "Shi", + "LastName": "Ma", + "abbrevName": "Ma SH", + "email": null, + "isCollectiveName": false, + "name": "Shi Hong Ma", + "orcid": null + }, + { + "ForeName": "Ganesh", + "LastName": "Raj", + "abbrevName": "Raj GV", + "email": null, + "isCollectiveName": false, + "name": "Ganesh V Raj", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Cidlowski", + "abbrevName": "Cidlowski JA", + "email": null, + "isCollectiveName": false, + "name": "John A Cidlowski", + "orcid": null + }, + { + "ForeName": "Taylor", + "LastName": "Helle", + "abbrevName": "Helle TM", + "email": null, + "isCollectiveName": false, + "name": "Taylor M Helle", + "orcid": null + }, + { + "ForeName": "Todd", + "LastName": "Knutson", + "abbrevName": "Knutson TP", + "email": null, + "isCollectiveName": false, + "name": "Todd P Knutson", + "orcid": null + }, + { + "ForeName": "Raisa", + "LastName": "Krutilina", + "abbrevName": "Krutilina RI", + "email": null, + "isCollectiveName": false, + "name": "Raisa I Krutilina", + "orcid": null + }, + { + "ForeName": "Tiffany", + "LastName": "Seagroves", + "abbrevName": "Seagroves TN", + "email": null, + "isCollectiveName": false, + "name": "Tiffany N Seagroves", + "orcid": null + }, + { + "ForeName": "Carol", + "LastName": "Lange", + "abbrevName": "Lange CA", + "email": "lange047@umn.edu", + "isCollectiveName": false, + "name": "Carol A Lange", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Carol", + "LastName": "Lange", + "email": [ + "lange047@umn.edu" + ], + "name": "Carol A Lange" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-2510", + "pmid": "26825173", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "24248265", + "pubmed": { + "ISODate": "2014-02-01T00:00:00.000Z", + "abstract": "UNLABELLED: Targeted therapy against triple-negative breast cancers, which lack expression of the estrogen, progesterone, and HER2 receptors, is not available and the overall response to cytotoxic chemotherapy is poor. One of the molecular hallmarks of triple-negative breast cancers is increased expression of genes that are transcriptionally activated by hypoxia-inducible factors (HIFs), which are implicated in many critical aspects of cancer progression including metabolism, angiogenesis, invasion, metastasis, and stem cell maintenance. Ganetespib is a second-generation inhibitor of heat shock protein 90 (HSP90), a molecular chaperone that is essential for the stability and function of multiple client proteins in cancer cells including HIF-1α. In this study, human MDA-MB-231 and MDA-MB-435 triple-negative breast cancer cells were injected into the mammary fat pad of immunodeficient mice that received weekly intravenous injections of ganetespib or vehicle following the development of palpable tumors. Ganetespib treatment markedly impaired primary tumor growth and vascularization, and eliminated local tissue invasion and distant metastasis to regional lymph nodes and lungs. Ganetespib treatment also significantly reduced the number of Aldefluor-positive cancer stem cells in the primary tumor. Primary tumors of ganetespib-treated mice had significantly reduced levels of HIF-1α (but not HIF-2α) protein and of HIF-1 target gene mRNAs encoding proteins that play key roles in angiogenesis, metabolism, invasion, and metastasis, thereby providing a molecular basis for observed effects of the drug on the growth and metastasis of triple-negative breast cancer. KEY MESSAGES: Triple-negative breast cancers (TNBCs) respond poorly to available chemotherapy. TNBCs overexpress genes regulated by hypoxia-inducible factors (HIFs). Ganetespib induces degradation of HSP90 client proteins, including HIF-1α. Ganetespib inhibited TNBC orthotopic tumor growth, invasion, and metastasis. Ganetespib inhibited expression of HIF-1 target genes involved in TNBC progression.", + "authors": { + "abbreviation": "Lisha Xiang, Daniele M Gilkes, Pallavi Chaturvedi, ..., Gregg L Semenza", + "authorList": [ + { + "ForeName": "Lisha", + "LastName": "Xiang", + "abbrevName": "Xiang L", + "email": null, + "isCollectiveName": false, + "name": "Lisha Xiang", + "orcid": null + }, + { + "ForeName": "Daniele", + "LastName": "Gilkes", + "abbrevName": "Gilkes DM", + "email": null, + "isCollectiveName": false, + "name": "Daniele M Gilkes", + "orcid": null + }, + { + "ForeName": "Pallavi", + "LastName": "Chaturvedi", + "abbrevName": "Chaturvedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Chaturvedi", + "orcid": null + }, + { + "ForeName": "Weibo", + "LastName": "Luo", + "abbrevName": "Luo W", + "email": null, + "isCollectiveName": false, + "name": "Weibo Luo", + "orcid": null + }, + { + "ForeName": "Hongxia", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Hongxia Hu", + "orcid": null + }, + { + "ForeName": "Naoharu", + "LastName": "Takano", + "abbrevName": "Takano N", + "email": null, + "isCollectiveName": false, + "name": "Naoharu Takano", + "orcid": null + }, + { + "ForeName": "Houjie", + "LastName": "Liang", + "abbrevName": "Liang H", + "email": null, + "isCollectiveName": false, + "name": "Houjie Liang", + "orcid": null + }, + { + "ForeName": "Gregg", + "LastName": "Semenza", + "abbrevName": "Semenza GL", + "email": null, + "isCollectiveName": false, + "name": "Gregg L Semenza", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s00109-013-1102-5", + "pmid": "24248265", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Med (Berl) 92 2014", + "title": "Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer." + } + }, + { + "pmid": "30784286", + "pubmed": { + "ISODate": "2019-05-23T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The unclear molecular mechanisms underlying could provide important theoretical basis for the prevention and control of HCC. This study performed chromatin immunoprecipitation-sequencing (ChIP-seq) to analyze the binding sites between zinc fingers and homeoboxes 2 (ZHX2) and its genome-wide target genes, and bioinformatics was used to analyze their gene transcription regulation network. Immunohistochemistry was used to detect the ZHX2 expression in HCC, and its association with the clinicopathological characteristics of HCC. Results of RT-PCR and western blot showed the expression of ZHX2 in HepG2 cells was obviously lower compared with normal liver cells. ZHX2 could be amplified in ChIP products, then ChIP-seq reveals there were 232 genes binding in promoter regions. GO analysis of functions revealed these genes were mainly associated with biological processes (BP), cellular components (CC), and molecular functions (MF). In addition, PTEN was found enriched in certain biological functions in BP analysis. Then, four pathways of these genes based on Kyoto Encyclopedia of Genes and Genomes (KEGG) were found P<0.05. Last analysis of immunohistochemistry showed the rates of ZHX2 expression and PTEN expression in paracancerous tissues both were significantly higher than that in HCC tissues (P=0.042; P<0.001), with negative correlations with AFP values (r=-0.246, P=0.040; r=-0.263, P=0.028). Further, PTEN expression was positively correlated with the differentiation level in HCC tissues (r=0.267, P=0.025). Spearman correlation analysis revealed that the expression profiles of ZHX2 and PTEN were positively correlated in HCC tissues (r=0.258, P=0.031). This study is the first to use ChIP-seq technology to analyze the specific regulatory mechanisms of the transcription suppressor ZHX2 in the context of HCC at the genome level.", + "authors": { + "abbreviation": "Z Lv, R He, M Huang, ..., G Chen", + "authorList": [ + { + "ForeName": "Z", + "LastName": "Lv", + "abbrevName": "Lv Z", + "email": null, + "isCollectiveName": false, + "name": "Z Lv", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "He", + "abbrevName": "He R", + "email": null, + "isCollectiveName": false, + "name": "R He", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Huang", + "abbrevName": "Huang M", + "email": null, + "isCollectiveName": false, + "name": "M Huang", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Zhao", + "abbrevName": "Zhao G", + "email": null, + "isCollectiveName": false, + "name": "G Zhao", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Ma", + "abbrevName": "Ma J", + "email": null, + "isCollectiveName": false, + "name": "J Ma", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": null, + "isCollectiveName": false, + "name": "G Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.4149/neo_2018_180806N593", + "pmid": "30784286", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Neoplasma 66 2019", + "title": "Targeting genes and signaling pathways of transcriptional suppressor ZHX2 in hepatocellular carcinoma: a Chromatin Immunoprecipitation-sequencing (ChIP-seq) investigation." + } + }, + { + "pmid": "32114388", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Liver cancer stem cells (CSCs) are critical determinants of HCC relapse and therapeutic resistance, but the mechanisms underlying the maintenance of CSCs are poorly understood. We aimed to explore the role of tumor repressor Zinc-fingers and homeoboxes 2 (ZHX2) in liver CSCs. METHODS: CD133+ or EPCAM+ stem-like liver cancer cells were sorted from tumor tissues of HCC patients and HCC cell lines by flow cytometry. In addition, sorafenib-resistant cells, tumor-sphere forming cells and side population (SP) cells were respectively cultured and isolated as hepatic CSCs. The tumor-initiating and chemoresistance properties of ZHX2-overexpressing and ZHX2-knockdown cells were analyzed in vivo and in vitro. Microarray, luciferase reporter assay, chromatin immunoprecipitation (ChIP) and ChIP-on-chip analyses were performed to explore ZHX2 target genes. The expression of ZHX2 and its target gene were determined by quantitative RT-PCR, western blot, immunofluorescence and immunohistochemical staining in hepatoma cells and tumor and adjacent tissues from HCC patients. RESULTS: ZHX2 expression was significantly reduced in liver CSCs from different origins. ZHX2 deficiency led to enhanced liver tumor progression and expansion of CSC populations in vitro and in vivo. Re-expression of ZHX2 restricted capabilities of hepatic CSCs in supporting tumor initiation, self-renewal and sorafenib-resistance. Mechanically, ZHX2 suppressed liver CSCs via inhibiting KDM2A-mediated demethylation of histone H3 lysine 36 (H3K36) at the promoter regions of stemness-associated transcription factors, such as NANOG, SOX4 and OCT4. Moreover, patients with lower expression of ZHX2 and higher expression of KDM2A in tumor tissues showed significantly poorer survival. CONCLUSION: ZHX2 counteracts stem cell traits through transcriptionally repressing KDM2A in HCC. Our data will aid in a better understanding of molecular mechanisms underlying HCC relapse and drug resistance.", + "authors": { + "abbreviation": "Qinghai Lin, Zhuanchang Wu, Xuetian Yue, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Ying He", + "orcid": null + }, + { + "ForeName": "Yutong", + "LastName": "Ge", + "abbrevName": "Ge Y", + "email": null, + "isCollectiveName": false, + "name": "Yutong Ge", + "orcid": null + }, + { + "ForeName": "Siyu", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Siyu Tan", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Song", + "abbrevName": "Song H", + "email": null, + "isCollectiveName": false, + "name": "Hui Song", + "orcid": null + }, + { + "ForeName": "Detian", + "LastName": "Yuan", + "abbrevName": "Yuan D", + "email": null, + "isCollectiveName": false, + "name": "Detian Yuan", + "orcid": null + }, + { + "ForeName": "Yaoqin", + "LastName": "Gong", + "abbrevName": "Gong Y", + "email": null, + "isCollectiveName": false, + "name": "Yaoqin Gong", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.ebiom.2020.102676", + "pmid": "32114388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EBioMedicine 53 2020", + "title": "ZHX2 restricts hepatocellular carcinoma by suppressing stem cell-like traits through KDM2A-mediated H3K36 demethylation." + } + }, + { + "pmid": "32382017", + "pubmed": { + "ISODate": "2020-05-07T00:00:00.000Z", + "abstract": "Zinc fingers and homeoboxes 2 (ZHX2) was found as a novel VHL substrate target, and acted as an oncogenic driver in ccRCC. However, the detailed mechanism of ZHX2 in ccRCC development remains elusive, and no research has focused on studying ZHX2 in drug resistance yet. A tissue microarray with 358 ccRCC samples was used to determine the expression of ZHX2 in ccRCC patients. VHL-deficient cell line 786-O and VHL-normal cell line CAKI-1 was used for lineage reprogramming by transfecting with lentivirus. The in vitro and in vivo experiments were performed with these new cell lines to determine the mechanism of ZHX2 in ccRCC development and drug resistance. Immunohistochemistry analysis showed that ZHX2 was not highly expressed in ccRCC tumor tissues, only 33.2% (119/358) patients have high ZHX2 expression. However, high ZHX2 was significantly associated with advanced Fuhrman grade (p = 0.004), and proved to be an independent prognosis factor for progression-free survival (p = 0.0003), while there is no significant correlation with overall survival. We further discovered that ZHX2 overexpression could increase VEGF secretion and transcriptional activate the MEK/ERK1/2 and promote its downstream targets. We also found ZHX2 overexpression induce Sunitinib resistance though activating autophagy and the combination treatment of Sunitinib and Chloroquine could significantly rescue the phenomenon. In summary, these results indicate that ZHX2 drivers cell growth, migration though increase VEGF expression, and transcriptional activate MEK/ERK1/2 signaling pathway, and could induce Sunitinib resistance by regulating self-protective autophagy, these may provide new insight in advanced ccRCC treatment.", + "authors": { + "abbreviation": "Liangsong Zhu, Rong Ding, Hao Yan, ..., Zongming Lin", + "authorList": [ + { + "ForeName": "Liangsong", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liangsong Zhu", + "orcid": null + }, + { + "ForeName": "Rong", + "LastName": "Ding", + "abbrevName": "Ding R", + "email": null, + "isCollectiveName": false, + "name": "Rong Ding", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Yan", + "abbrevName": "Yan H", + "email": null, + "isCollectiveName": false, + "name": "Hao Yan", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "med-zhangjin@vip.sina.com", + "isCollectiveName": false, + "name": "Jin Zhang", + "orcid": null + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "abbrevName": "Lin Z", + "email": "lin.zongming@zs-hospital.sh.cn", + "isCollectiveName": false, + "name": "Zongming Lin", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jin", + "LastName": "Zhang", + "email": [ + "med-zhangjin@vip.sina.com" + ], + "name": "Jin Zhang" + }, + { + "ForeName": "Zongming", + "LastName": "Lin", + "email": [ + "lin.zongming@zs-hospital.sh.cn" + ], + "name": "Zongming Lin" + } + ] + }, + "doi": "10.1038/s41419-020-2541-x", + "pmid": "32382017", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 11 2020", + "title": "ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma." + } + }, + { + "pmid": "36228375", + "pubmed": { + "ISODate": "2022-12-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly aggressive and hypoxic compared with other subtypes. The role of hypoxia inducible factor 1α (HIF-1α) as a key hypoxic transcription factor in oncogenic processes has been extensively studied. Recently, it has been shown that HIF-1α regulates the complex biological processes of TNBC, such as glycolysis, angiogenesis, invasion and metastasis, breast cancer stem cells (BCSCs) enrichment, and immune escape, to promote TNBC survival and development through the activation of downstream target genes. In addition, inflammatory mediators, oxygen levels, noncoding RNAs, complex signaling regulatory networks, epigenetic regulators are involved in the upstream regulatory expression of HIF-1α. However, further studies are needed to determine the potential and future directions of targeting HIF-1α in TNBC. This article discusses the expression of the HIF-1α transcription factor in TNBC. We also explored the mechanism by which HIF-1α drives TNBC progression. The potential significance of targeting HIF-1α for immunotherapy, chemotherapy, anti-angiogenic therapy, and photodynamic therapy is discussed. The intrinsic mechanism, existing problems and future directions of targeting HIF-1α are also studied.", + "authors": { + "abbreviation": "Qi Liu, Chengcheng Guan, Cui Liu, ..., Changgang Sun", + "authorList": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": "2020110892@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Qi Liu", + "orcid": null + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "abbrevName": "Guan C", + "email": "2020110896@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Chengcheng Guan", + "orcid": null + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": "2019101062@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Cui Liu", + "orcid": null + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "abbrevName": "Li H", + "email": "2019101020@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Huayao Li", + "orcid": null + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "2020111256@sdutcm.edu.cn", + "isCollectiveName": false, + "name": "Jibiao Wu", + "orcid": null + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "abbrevName": "Sun C", + "email": "zyxyscg@wfmc.edu.cn", + "isCollectiveName": false, + "name": "Changgang Sun", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Qi", + "LastName": "Liu", + "email": [ + "2020110892@sdutcm.edu.cn" + ], + "name": "Qi Liu" + }, + { + "ForeName": "Chengcheng", + "LastName": "Guan", + "email": [ + "2020110896@sdutcm.edu.cn" + ], + "name": "Chengcheng Guan" + }, + { + "ForeName": "Cui", + "LastName": "Liu", + "email": [ + "2019101062@sdutcm.edu.cn" + ], + "name": "Cui Liu" + }, + { + "ForeName": "Huayao", + "LastName": "Li", + "email": [ + "2019101020@sdutcm.edu.cn" + ], + "name": "Huayao Li" + }, + { + "ForeName": "Jibiao", + "LastName": "Wu", + "email": [ + "2020111256@sdutcm.edu.cn" + ], + "name": "Jibiao Wu" + }, + { + "ForeName": "Changgang", + "LastName": "Sun", + "email": [ + "zyxyscg@wfmc.edu.cn" + ], + "name": "Changgang Sun" + } + ] + }, + "doi": "10.1016/j.biopha.2022.113861", + "pmid": "36228375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biomed Pharmacother 156 2022", + "title": "Targeting hypoxia-inducible factor-1alpha: A new strategy for triple-negative breast cancer therapy." + } + }, + { + "pmid": "33824311", + "pubmed": { + "ISODate": "2021-04-06T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15-20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.", + "authors": { + "abbreviation": "Fengxia Chen, Qingqing Wang, Xiaoyan Yu, ..., Yunfeng Zhou", + "authorList": [ + { + "ForeName": "Fengxia", + "LastName": "Chen", + "abbrevName": "Chen F", + "email": null, + "isCollectiveName": false, + "name": "Fengxia Chen", + "orcid": null + }, + { + "ForeName": "Qingqing", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqing Wang", + "orcid": "0000-0002-6440-582X" + }, + { + "ForeName": "Xiaoyan", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyan Yu", + "orcid": null + }, + { + "ForeName": "Ningning", + "LastName": "Yang", + "abbrevName": "Yang N", + "email": null, + "isCollectiveName": false, + "name": "Ningning Yang", + "orcid": null + }, + { + "ForeName": "Yuan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Wang", + "orcid": "0000-0003-1894-0853" + }, + { + "ForeName": "Yangyang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yangyang Zeng", + "orcid": null + }, + { + "ForeName": "Zhewen", + "LastName": "Zheng", + "abbrevName": "Zheng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhewen Zheng", + "orcid": null + }, + { + "ForeName": "Fuxiang", + "LastName": "Zhou", + "abbrevName": "Zhou F", + "email": null, + "isCollectiveName": false, + "name": "Fuxiang Zhou", + "orcid": null + }, + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "abbrevName": "Zhou Y", + "email": "yfzhouwhu@163.com", + "isCollectiveName": false, + "name": "Yunfeng Zhou", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Yunfeng", + "LastName": "Zhou", + "email": [ + "yfzhouwhu@163.com" + ], + "name": "Yunfeng Zhou" + } + ] + }, + "doi": "10.1038/s41419-021-03661-4", + "pmid": "33824311", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis." + } + }, + { + "pmid": "28239645", + "pubmed": { + "ISODate": "2017-02-23T00:00:00.000Z", + "abstract": "Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.", + "authors": { + "abbreviation": "Manfredi Ponente, Letizia Campanini, Roberto Cuttano, ..., Rosa Bernardi", + "authorList": [ + { + "ForeName": "Manfredi", + "LastName": "Ponente", + "abbrevName": "Ponente M", + "email": null, + "isCollectiveName": false, + "name": "Manfredi Ponente", + "orcid": null + }, + { + "ForeName": "Letizia", + "LastName": "Campanini", + "abbrevName": "Campanini L", + "email": null, + "isCollectiveName": false, + "name": "Letizia Campanini", + "orcid": null + }, + { + "ForeName": "Roberto", + "LastName": "Cuttano", + "abbrevName": "Cuttano R", + "email": null, + "isCollectiveName": false, + "name": "Roberto Cuttano", + "orcid": null + }, + { + "ForeName": "Andrea", + "LastName": "Piunti", + "abbrevName": "Piunti A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Piunti", + "orcid": null + }, + { + "ForeName": "Giacomo", + "LastName": "Delledonne", + "abbrevName": "Delledonne GA", + "email": null, + "isCollectiveName": false, + "name": "Giacomo A Delledonne", + "orcid": null + }, + { + "ForeName": "Nadia", + "LastName": "Coltella", + "abbrevName": "Coltella N", + "email": null, + "isCollectiveName": false, + "name": "Nadia Coltella", + "orcid": null + }, + { + "ForeName": "Roberta", + "LastName": "Valsecchi", + "abbrevName": "Valsecchi R", + "email": null, + "isCollectiveName": false, + "name": "Roberta Valsecchi", + "orcid": null + }, + { + "ForeName": "Alessandra", + "LastName": "Villa", + "abbrevName": "Villa A", + "email": null, + "isCollectiveName": false, + "name": "Alessandra Villa", + "orcid": null + }, + { + "ForeName": "Ugo", + "LastName": "Cavallaro", + "abbrevName": "Cavallaro U", + "email": null, + "isCollectiveName": false, + "name": "Ugo Cavallaro", + "orcid": null + }, + { + "ForeName": "Linda", + "LastName": "Pattini", + "abbrevName": "Pattini L", + "email": null, + "isCollectiveName": false, + "name": "Linda Pattini", + "orcid": null + }, + { + "ForeName": "Claudio", + "LastName": "Doglioni", + "abbrevName": "Doglioni C", + "email": null, + "isCollectiveName": false, + "name": "Claudio Doglioni", + "orcid": null + }, + { + "ForeName": "Rosa", + "LastName": "Bernardi", + "abbrevName": "Bernardi R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Bernardi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/jci.insight.87380", + "pmid": "28239645", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "JCI Insight 2 2017", + "title": "PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes." + } + }, + { + "pmid": "34408002", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease.", + "authors": { + "abbreviation": "Tian-Jian Yu, Ying-Ying Liu, Xiao-Guang Li, ..., Yi-Zhou Jiang", + "authorList": [ + { + "ForeName": "Tian-Jian", + "LastName": "Yu", + "abbrevName": "Yu TJ", + "email": null, + "isCollectiveName": false, + "name": "Tian-Jian Yu", + "orcid": null + }, + { + "ForeName": "Ying-Ying", + "LastName": "Liu", + "abbrevName": "Liu YY", + "email": null, + "isCollectiveName": false, + "name": "Ying-Ying Liu", + "orcid": null + }, + { + "ForeName": "Xiao-Guang", + "LastName": "Li", + "abbrevName": "Li XG", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Guang Li", + "orcid": null + }, + { + "ForeName": "Bi", + "LastName": "Lian", + "abbrevName": "Lian B", + "email": null, + "isCollectiveName": false, + "name": "Bi Lian", + "orcid": null + }, + { + "ForeName": "Xun-Xi", + "LastName": "Lu", + "abbrevName": "Lu XX", + "email": null, + "isCollectiveName": false, + "name": "Xun-Xi Lu", + "orcid": "0000-0002-5118-0377" + }, + { + "ForeName": "Xi", + "LastName": "Jin", + "abbrevName": "Jin X", + "email": null, + "isCollectiveName": false, + "name": "Xi Jin", + "orcid": null + }, + { + "ForeName": "Zhi-Ming", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Ming Shao", + "orcid": "0000-0001-8781-2455" + }, + { + "ForeName": "Xin", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Xin Hu", + "orcid": null + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "abbrevName": "Di GH", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Gen-Hong Di", + "orcid": null + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "abbrevName": "Jiang YZ", + "email": "yizhoujiang@fudan.edu.cn", + "isCollectiveName": false, + "name": "Yi-Zhou Jiang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Hu", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Xin Hu" + }, + { + "ForeName": "Gen-Hong", + "LastName": "Di", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Gen-Hong Di" + }, + { + "ForeName": "Yi-Zhou", + "LastName": "Jiang", + "email": [ + "yizhoujiang@fudan.edu.cn", + "genhongdi@163.com", + "xinhu@fudan.edu.cn" + ], + "name": "Yi-Zhou Jiang" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-21-0747", + "pmid": "34408002", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 81 2021", + "title": "PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer." + } + }, + { + "pmid": "27137755", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": "The aggressiveness of triple-negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self-renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia-inducible factor-1α (HIF-1α) expression is associated with aggressiveness of cancer. Nonetheless, how HIF-1α expression is regulated and how HIF-1α induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF-1α expression has not yet been studied. Here, we show that clinically relevant low-dose FTI, tipifarnib (300 nM), decreased HIF-1α expression, migration and tumorsphere formation in human MDA-MB-231 TNBC cells under a normoxic condition. In contrast, the low-dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA-MB 231 cells. Tipifarnib-induced decrease in HIF-1α expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E-cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF-1α-Snail pathway. J. Cell. Physiol. 232: 192-201, 2017. © 2016 Wiley Periodicals, Inc.", + "authors": { + "abbreviation": "Tomokazu Tanaka, Yuichi Ikegami, Harumasa Nakazawa, ..., Masao Kaneki", + "authorList": [ + { + "ForeName": "Tomokazu", + "LastName": "Tanaka", + "abbrevName": "Tanaka T", + "email": null, + "isCollectiveName": false, + "name": "Tomokazu Tanaka", + "orcid": null + }, + { + "ForeName": "Yuichi", + "LastName": "Ikegami", + "abbrevName": "Ikegami Y", + "email": null, + "isCollectiveName": false, + "name": "Yuichi Ikegami", + "orcid": null + }, + { + "ForeName": "Harumasa", + "LastName": "Nakazawa", + "abbrevName": "Nakazawa H", + "email": null, + "isCollectiveName": false, + "name": "Harumasa Nakazawa", + "orcid": null + }, + { + "ForeName": "Naohide", + "LastName": "Kuriyama", + "abbrevName": "Kuriyama N", + "email": null, + "isCollectiveName": false, + "name": "Naohide Kuriyama", + "orcid": null + }, + { + "ForeName": "Miwa", + "LastName": "Oki", + "abbrevName": "Oki M", + "email": null, + "isCollectiveName": false, + "name": "Miwa Oki", + "orcid": null + }, + { + "ForeName": "Jun-Ichi", + "LastName": "Hanai", + "abbrevName": "Hanai J", + "email": null, + "isCollectiveName": false, + "name": "Jun-Ichi Hanai", + "orcid": null + }, + { + "ForeName": "Vikas", + "LastName": "Sukhatme", + "abbrevName": "Sukhatme VP", + "email": null, + "isCollectiveName": false, + "name": "Vikas P Sukhatme", + "orcid": null + }, + { + "ForeName": "Masao", + "LastName": "Kaneki", + "abbrevName": "Kaneki M", + "email": "mkaneki@helix.mgh.harvard.edu", + "isCollectiveName": false, + "name": "Masao Kaneki", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masao", + "LastName": "Kaneki", + "email": [ + "mkaneki@helix.mgh.harvard.edu" + ], + "name": "Masao Kaneki" + } + ] + }, + "doi": "10.1002/jcp.25411", + "pmid": "27137755", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Physiol 232 2017", + "title": "Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1α and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro." + } + }, + { + "pmid": "31264274", + "pubmed": { + "ISODate": "2019-10-01T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.", + "authors": { + "abbreviation": "Chen Gong, Jin Zou, Mingsheng Zhang, ..., Yong Li", + "authorList": [ + { + "ForeName": "Chen", + "LastName": "Gong", + "abbrevName": "Gong C", + "email": null, + "isCollectiveName": false, + "name": "Chen Gong", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Zou", + "abbrevName": "Zou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zou", + "orcid": null + }, + { + "ForeName": "Mingsheng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mingsheng Zhang", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Shanshan", + "LastName": "Xu", + "abbrevName": "Xu S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Xu", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Zhu", + "orcid": null + }, + { + "ForeName": "Mengqi", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mengqi Yang", + "orcid": null + }, + { + "ForeName": "Dongjia", + "LastName": "Li", + "abbrevName": "Li D", + "email": null, + "isCollectiveName": false, + "name": "Dongjia Li", + "orcid": null + }, + { + "ForeName": "Yun", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yun Wang", + "orcid": null + }, + { + "ForeName": "Jialu", + "LastName": "Shi", + "abbrevName": "Shi J", + "email": null, + "isCollectiveName": false, + "name": "Jialu Shi", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Li", + "orcid": "0000-0003-4681-263X" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23079", + "pmid": "31264274", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer." + } + }, + { + "pmid": "31683461", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "OBJECTIVE: To investigate the effect of ZHX2 on lung cancer cells proliferation and apoptosis. MATERIALS AND METHODS: The mRNA and protein expression of ZHX2 were detected by qRT-PCR and western blot, respectively. The human lung cancer cells were divided into Control, NC, ZHX2, SB, and ZHX2 + Ani groups. The cell proliferation was detected by CCK-8 assay and the cell migration and invasion were detected by Transwell assay. Cell apoptosis was detected by flow cytometry. Apoptosis and p38MAPK signaling pathway related proteins were detected by western blot. The nude mice model of lung cancer xenograft was constructed. The tumor volume and tumor weight were measured. The expression of PCNA protein in tumor tissues was detected by immunohistochemistry. The apoptosis of tumor cells was detected by TUNEL staining. The ZHX2 and p38MAPK signaling pathway related proteins in tumor tissues were detected by western blot. RESULTS: The expression of ZHX2 gene and protein in the cancer cell lines were significantly decreased. Compared with control and NC groups, the cells proliferation, migration and invasion were inhibited in ZHX2 and SB groups, while the apoptosis and apoptosis related proteins were increased (p< 0.05). Meanwhile, compared with ZHX2 group, the tumor growth rate, volume, weight, the percentage of PCNA-positive cells, and p-P38 MAPK/P38 MAPK were increased significantly in ZHX2 + Ani group, while the apoptotic index and the expression of MMP-9 protein were significantly decreased (p< 0.05). CONCLUSION: ZHX2 could inhibit proliferation and promote apoptosis of lung cancer cells by inhibiting p38MAPK signaling pathway.", + "authors": { + "abbreviation": "Xudong Tian, Yadong Wang, Shuhai Li, ..., Hui Tian", + "authorList": [ + { + "ForeName": "Xudong", + "LastName": "Tian", + "abbrevName": "Tian X", + "email": null, + "isCollectiveName": false, + "name": "Xudong Tian", + "orcid": null + }, + { + "ForeName": "Yadong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yadong Wang", + "orcid": null + }, + { + "ForeName": "Shuhai", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuhai Li", + "orcid": null + }, + { + "ForeName": "Weiming", + "LastName": "Yue", + "abbrevName": "Yue W", + "email": null, + "isCollectiveName": false, + "name": "Weiming Yue", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "Tian", + "abbrevName": "Tian H", + "email": null, + "isCollectiveName": false, + "name": "Hui Tian", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3233/CBM-190514", + "pmid": "31683461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Biomark 27 2020", + "title": "ZHX2 inhibits proliferation and promotes apoptosis of human lung cancer cells through targeting p38MAPK pathway." + } + }, + { + "pmid": "36037364", + "pubmed": { + "ISODate": "2022-09-06T00:00:00.000Z", + "abstract": "Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.", + "authors": { + "abbreviation": "Haibiao Xie, Jin Zhou, Xijuan Liu, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Haibiao", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haibiao Xie", + "orcid": "0000-0001-6729-8479" + }, + { + "ForeName": "Jin", + "LastName": "Zhou", + "abbrevName": "Zhou J", + "email": null, + "isCollectiveName": false, + "name": "Jin Zhou", + "orcid": null + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Yawei", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yawei Xu", + "orcid": null + }, + { + "ForeName": "Austin", + "LastName": "Hepperla", + "abbrevName": "Hepperla AJ", + "email": null, + "isCollectiveName": false, + "name": "Austin J Hepperla", + "orcid": "0000-0002-0107-2001" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon JM", + "email": null, + "isCollectiveName": false, + "name": "Jeremy M Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Tao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Yao", + "abbrevName": "Yao H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Yao", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": "0000-0002-9073-3835" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Gong", + "abbrevName": "Gong K", + "email": null, + "isCollectiveName": false, + "name": "Kan Gong", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.2119854119", + "pmid": "36037364", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 119 2022", + "title": "USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer." + } + }, + { + "pmid": "25195714", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Glypican 3 (GPC3) has been paid particular attention owing to its potential as diagnosis marker for hepatocellular carcinoma (HCC). Identifying the mechanisms regulating the reactivation of GPC3 in HCC appears to be clinically meaningful. Previous study identified zinc-fingers and homeoboxes 2 (ZHX2) as transcriptional factor responsible for postnatal repression of GPC3 in mice. Here, in this study, we provided the first evidence that down regulated ZHX2 is responsible for GPC3 reactivation in HCC. First, inverse correlation of ZHX2 with GPC3 expression was shown in cultured liver cell lines. Second, ZHX2 overexpression significantly decreased GPC3 expression, while ZHX2 knockdown effectively increased GPC3 level in different HCC cell lines. Consistently, dual luciferase and ChIP assay showed that ZHX2 dose-dependently suppressed GPC3 promoter activity by binding with the core promoter. More importantly, immunohistochemical staining demonstrated the inverse correlation between nuclear ZHX2 with GPC3 expression in HCC tissues. Further in vitro analysis showed that nuclear translocation was crucial for ZHX2 mediated repression on GPC3 transcription. Taken together, our results prove that ZHX2 suppresses GPC3 transcription by binding with its core promoter and reduced nucleic ZHX2 expression may be involved in GPC3 reactivation in HCC.", + "authors": { + "abbreviation": "Fang Luan, Peng Liu, Hongxin Ma, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Fang", + "LastName": "Luan", + "abbrevName": "Luan F", + "email": null, + "isCollectiveName": false, + "name": "Fang Luan", + "orcid": null + }, + { + "ForeName": "Peng", + "LastName": "Liu", + "abbrevName": "Liu P", + "email": null, + "isCollectiveName": false, + "name": "Peng Liu", + "orcid": null + }, + { + "ForeName": "Hongxin", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Ma", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Liu", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": "machunhong@sdu.edu.cn", + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Chunhong", + "LastName": "Ma", + "email": [ + "machunhong@sdu.edu.cn" + ], + "name": "Chunhong Ma" + } + ] + }, + "doi": "10.1016/j.biocel.2014.08.021", + "pmid": "25195714", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Biochem Cell Biol 55 2014", + "title": "Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma." + } + }, + { + "pmid": "29333926", + "pubmed": { + "ISODate": "2018-04-03T00:00:00.000Z", + "abstract": "Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by poor patient prognosis and for which no targeted therapies are currently available. TNBC can be further categorized as either basal-like (BLBC) or quintuple-negative breast cancer (QNBC). In the present study, we aimed to identify novel molecular therapeutic targets for TNBC by analyzing the mRNA expression of TNBC-related genes in publicly available microarray data sets. We found that Engrailed 1 (EN1) was significantly overexpressed in TNBC. Using breast cancer cell lines, we found that EN1 was more highly expressed in TNBC than in other breast cancer subtypes. EN1 expression was analyzed in 199 TNBC paraffin-embedded tissue samples by immunohistochemistry. EN1 protein expression was positively associated with reduced overall survival (OS) rate in patients with QNBC, but not those with BLBC. The importance of EN1 expression in QNBC cell viability and tumorigenicity was evaluated using the QNBC cell lines, HCC38 and HCC1395. Based on our data, EN1 may promote the proliferation, migration, and multinucleation of QNBC cells, likely via the transcriptional activation of HDAC8, UTP11L, and ZIC3. We also demonstrated that actinomycin D effectively inhibits EN1 activity in QNBC cells. The results of the present study suggest that EN1 activity is highly clinically relevant to the survival prognosis of patients with QNBC and EN1 is a promising potential therapeutic target for future QNBC treatment.", + "authors": { + "abbreviation": "Yu Jin Kim, Minjung Sung, Ensel Oh, ..., Yoon-La Choi", + "authorList": [ + { + "ForeName": "Yu", + "LastName": "Kim", + "abbrevName": "Kim YJ", + "email": null, + "isCollectiveName": false, + "name": "Yu Jin Kim", + "orcid": null + }, + { + "ForeName": "Minjung", + "LastName": "Sung", + "abbrevName": "Sung M", + "email": null, + "isCollectiveName": false, + "name": "Minjung Sung", + "orcid": null + }, + { + "ForeName": "Ensel", + "LastName": "Oh", + "abbrevName": "Oh E", + "email": null, + "isCollectiveName": false, + "name": "Ensel Oh", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Vrancken", + "abbrevName": "Vrancken MV", + "email": null, + "isCollectiveName": false, + "name": "Michael Van Vrancken", + "orcid": null + }, + { + "ForeName": "Ji-Young", + "LastName": "Song", + "abbrevName": "Song JY", + "email": null, + "isCollectiveName": false, + "name": "Ji-Young Song", + "orcid": null + }, + { + "ForeName": "Kyungsoo", + "LastName": "Jung", + "abbrevName": "Jung K", + "email": null, + "isCollectiveName": false, + "name": "Kyungsoo Jung", + "orcid": null + }, + { + "ForeName": "Yoon-La", + "LastName": "Choi", + "abbrevName": "Choi YL", + "email": null, + "isCollectiveName": false, + "name": "Yoon-La Choi", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2018.1423913", + "pmid": "29333926", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 19 2018", + "title": "Engrailed 1 overexpression as a potential prognostic marker in quintuple-negative breast cancer." + } + }, + { + "pmid": "32770671", + "pubmed": { + "ISODate": "2020-12-01T00:00:00.000Z", + "abstract": "Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.", + "authors": { + "abbreviation": "Xiangguo Yu, Qinghai Lin, Zhuanchang Wu, ..., Chunhong Ma", + "authorList": [ + { + "ForeName": "Xiangguo", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiangguo Yu", + "orcid": null + }, + { + "ForeName": "Qinghai", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghai Lin", + "orcid": null + }, + { + "ForeName": "Zhuanchang", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuanchang Wu", + "orcid": null + }, + { + "ForeName": "Yankun", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yankun Zhang", + "orcid": null + }, + { + "ForeName": "Tixiao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tixiao Wang", + "orcid": null + }, + { + "ForeName": "Songbai", + "LastName": "Zhao", + "abbrevName": "Zhao S", + "email": null, + "isCollectiveName": false, + "name": "Songbai Zhao", + "orcid": null + }, + { + "ForeName": "Xiaojia", + "LastName": "Song", + "abbrevName": "Song X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojia Song", + "orcid": null + }, + { + "ForeName": "Chaojia", + "LastName": "Chen", + "abbrevName": "Chen C", + "email": null, + "isCollectiveName": false, + "name": "Chaojia Chen", + "orcid": null + }, + { + "ForeName": "Zehua", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zehua Wang", + "orcid": null + }, + { + "ForeName": "Leiqi", + "LastName": "Xu", + "abbrevName": "Xu L", + "email": null, + "isCollectiveName": false, + "name": "Leiqi Xu", + "orcid": null + }, + { + "ForeName": "Chunyang", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunyang Li", + "orcid": null + }, + { + "ForeName": "Lifen", + "LastName": "Gao", + "abbrevName": "Gao L", + "email": null, + "isCollectiveName": false, + "name": "Lifen Gao", + "orcid": null + }, + { + "ForeName": "Xiaohong", + "LastName": "Liang", + "abbrevName": "Liang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Liang", + "orcid": null + }, + { + "ForeName": "Xuetian", + "LastName": "Yue", + "abbrevName": "Yue X", + "email": null, + "isCollectiveName": false, + "name": "Xuetian Yue", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Ma", + "orcid": "0000-0002-8121-4718" + } + ], + "contacts": [] + }, + "doi": "10.1002/path.5530", + "pmid": "32770671", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Pathol 252 2020", + "title": "ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p." + } + }, + { + "pmid": "28423652", + "pubmed": { + "ISODate": "2017-04-25T00:00:00.000Z", + "abstract": "MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.", + "authors": { + "abbreviation": "Rosa Drago-Ferrante, Francesca Pentimalli, Daniela Carlisi, ..., Riccardo Di Fiore", + "authorList": [ + { + "ForeName": "Rosa", + "LastName": "Drago-Ferrante", + "abbrevName": "Drago-Ferrante R", + "email": null, + "isCollectiveName": false, + "name": "Rosa Drago-Ferrante", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Pentimalli", + "abbrevName": "Pentimalli F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Pentimalli", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Carlisi", + "abbrevName": "Carlisi D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Carlisi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "De Blasio", + "abbrevName": "De Blasio A", + "email": null, + "isCollectiveName": false, + "name": "Anna De Blasio", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Saliba", + "abbrevName": "Saliba C", + "email": null, + "isCollectiveName": false, + "name": "Christian Saliba", + "orcid": null + }, + { + "ForeName": "Shawn", + "LastName": "Baldacchino", + "abbrevName": "Baldacchino S", + "email": null, + "isCollectiveName": false, + "name": "Shawn Baldacchino", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Degaetano", + "abbrevName": "Degaetano J", + "email": null, + "isCollectiveName": false, + "name": "James Degaetano", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Debono", + "abbrevName": "Debono J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Debono", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Caruana-Dingli", + "abbrevName": "Caruana-Dingli G", + "email": null, + "isCollectiveName": false, + "name": "Gordon Caruana-Dingli", + "orcid": null + }, + { + "ForeName": "Godfrey", + "LastName": "Grech", + "abbrevName": "Grech G", + "email": null, + "isCollectiveName": false, + "name": "Godfrey Grech", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Scerri", + "abbrevName": "Scerri C", + "email": null, + "isCollectiveName": false, + "name": "Christian Scerri", + "orcid": null + }, + { + "ForeName": "Giovanni", + "LastName": "Tesoriere", + "abbrevName": "Tesoriere G", + "email": null, + "isCollectiveName": false, + "name": "Giovanni Tesoriere", + "orcid": null + }, + { + "ForeName": "Antonio", + "LastName": "Giordano", + "abbrevName": "Giordano A", + "email": null, + "isCollectiveName": false, + "name": "Antonio Giordano", + "orcid": null + }, + { + "ForeName": "Renza", + "LastName": "Vento", + "abbrevName": "Vento R", + "email": null, + "isCollectiveName": false, + "name": "Renza Vento", + "orcid": null + }, + { + "ForeName": "Riccardo", + "LastName": "Di Fiore", + "abbrevName": "Di Fiore R", + "email": null, + "isCollectiveName": false, + "name": "Riccardo Di Fiore", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.15960", + "pmid": "28423652", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Oncotarget 8 2017", + "title": "Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation." + } + }, + { + "pmid": "35188449", + "pubmed": { + "ISODate": "2022-05-01T00:00:00.000Z", + "abstract": "There is no clear treatment guideline or individualized treatment plan for triple-negative breast cancer (TNBC). The aim of this study was to investigate more effective targets for TNBC-targeted therapy. MDA-MB-231 and BT549 cell lines were used to explore the function of LINC00649 on the proliferation, invasion, and migration of TNBC cells. A mice subcutaneous tumor model and a pulmonary metastasis model was established to identify the role of LINC00649 on the growth and metastasis of TNBC in vivo. LINC00649 was found to be a key molecule involved in the occurrence and development of TNBC by screening of public databases and detection of TNBC clinical samples. LINC00649 increased hypoxia-inducible factor 1α (HIF-1α) mRNA stability and protein expression by interacting with the nuclear factor 90 (NF90)/NF45 complex. In vitro, interference with LINC00649 inhibits MDA-MB-231 and BT549 cell proliferation, migration, and invasion, and the addition of HIF-1α revised this effect. In vivo experiments showed that LINC00649 promoted the growth and metastasis of TNBC. We demonstrated that LINC00649 interacts with the NF90/NF45 complex to increase the mRNA stability of HIF-1α and up-regulate HIF-1α expression, thereby inducing the proliferation, invasion, and migration of TNBC cells as well as tumor growth and metastasis.", + "authors": { + "abbreviation": "Jianhua Zhang, Chuang Du, Linfeng Zhang, ..., Jingruo Li", + "authorList": [ + { + "ForeName": "Jianhua", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jianhua Zhang", + "orcid": null + }, + { + "ForeName": "Chuang", + "LastName": "Du", + "abbrevName": "Du C", + "email": null, + "isCollectiveName": false, + "name": "Chuang Du", + "orcid": null + }, + { + "ForeName": "Linfeng", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Linfeng Zhang", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Wang", + "orcid": null + }, + { + "ForeName": "Yingying", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingying Zhang", + "orcid": null + }, + { + "ForeName": "Jingruo", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jingruo Li", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2022.2040283", + "pmid": "35188449", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Cycle 21 2022", + "title": "LncRNA LINC00649 promotes the growth and metastasis of triple-negative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex." + } + }, + { + "pmid": "32778144", + "pubmed": { + "ISODate": "2020-08-10T00:00:00.000Z", + "abstract": "BACKGROUND: Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1β (IL-β) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1α (HIF-1α) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1β induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. METHODS: In order to ascertain the correlation of IL-β with HIF-1α and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1β by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation. RESULTS: We first determined that IL-1β expression correlates with the levels of HIF-1α as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1α, GPER and the IL-1β/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1β that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1β released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs. CONCLUSIONS: Our data shed new light on the role of hypoxia in the activation of the IL-1β/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.", + "authors": { + "abbreviation": "Rosamaria Lappano, Marianna Talia, Francesca Cirillo, ..., Marcello Maggiolini", + "authorList": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "abbrevName": "Lappano R", + "email": "rosamaria.lappano@unical.it", + "isCollectiveName": false, + "name": "Rosamaria Lappano", + "orcid": null + }, + { + "ForeName": "Marianna", + "LastName": "Talia", + "abbrevName": "Talia M", + "email": null, + "isCollectiveName": false, + "name": "Marianna Talia", + "orcid": null + }, + { + "ForeName": "Francesca", + "LastName": "Cirillo", + "abbrevName": "Cirillo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Cirillo", + "orcid": null + }, + { + "ForeName": "Damiano", + "LastName": "Rigiracciolo", + "abbrevName": "Rigiracciolo DC", + "email": null, + "isCollectiveName": false, + "name": "Damiano Cosimo Rigiracciolo", + "orcid": null + }, + { + "ForeName": "Domenica", + "LastName": "Scordamaglia", + "abbrevName": "Scordamaglia D", + "email": null, + "isCollectiveName": false, + "name": "Domenica Scordamaglia", + "orcid": null + }, + { + "ForeName": "Rita", + "LastName": "Guzzi", + "abbrevName": "Guzzi R", + "email": null, + "isCollectiveName": false, + "name": "Rita Guzzi", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Miglietta", + "abbrevName": "Miglietta AM", + "email": null, + "isCollectiveName": false, + "name": "Anna Maria Miglietta", + "orcid": null + }, + { + "ForeName": "Ernestina", + "LastName": "De Francesco", + "abbrevName": "De Francesco EM", + "email": null, + "isCollectiveName": false, + "name": "Ernestina Marianna De Francesco", + "orcid": null + }, + { + "ForeName": "Antonino", + "LastName": "Belfiore", + "abbrevName": "Belfiore A", + "email": null, + "isCollectiveName": false, + "name": "Antonino Belfiore", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Sims", + "abbrevName": "Sims AH", + "email": null, + "isCollectiveName": false, + "name": "Andrew H Sims", + "orcid": null + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "abbrevName": "Maggiolini M", + "email": "marcello.maggiolini@unical.it", + "isCollectiveName": false, + "name": "Marcello Maggiolini", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rosamaria", + "LastName": "Lappano", + "email": [ + "rosamaria.lappano@unical.it" + ], + "name": "Rosamaria Lappano" + }, + { + "ForeName": "Marcello", + "LastName": "Maggiolini", + "email": [ + "marcello.maggiolini@unical.it" + ], + "name": "Marcello Maggiolini" + } + ] + }, + "doi": "10.1186/s13046-020-01667-y", + "pmid": "32778144", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Exp Clin Cancer Res 39 2020", + "title": "The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)." + } + }, + { + "pmid": "25920936", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.", + "authors": { + "abbreviation": "Shuang Li, Qingzhu Wei, Qin Li, ..., Qiang Xiao", + "authorList": [ + { + "ForeName": "Shuang", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shuang Li", + "orcid": null + }, + { + "ForeName": "Qingzhu", + "LastName": "Wei", + "abbrevName": "Wei Q", + "email": null, + "isCollectiveName": false, + "name": "Qingzhu Wei", + "orcid": null + }, + { + "ForeName": "Qin", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qin Li", + "orcid": null + }, + { + "ForeName": "Bin", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bin Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Xiao", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/15384047.2015.1040958", + "pmid": "25920936", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Biol Ther 16 2015", + "title": "Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer." + } + }, + { + "pmid": "30026228", + "pubmed": { + "ISODate": "2018-07-20T00:00:00.000Z", + "abstract": "Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.", + "authors": { + "abbreviation": "Jing Zhang, Tao Wu, Jeremy Simon, ..., Qing Zhang", + "authorList": [ + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang", + "orcid": "0000-0001-6438-9113" + }, + { + "ForeName": "Tao", + "LastName": "Wu", + "abbrevName": "Wu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wu", + "orcid": "0000-0001-5380-3905" + }, + { + "ForeName": "Jeremy", + "LastName": "Simon", + "abbrevName": "Simon J", + "email": null, + "isCollectiveName": false, + "name": "Jeremy Simon", + "orcid": "0000-0003-3906-1663" + }, + { + "ForeName": "Mamoru", + "LastName": "Takada", + "abbrevName": "Takada M", + "email": null, + "isCollectiveName": false, + "name": "Mamoru Takada", + "orcid": "0000-0002-3961-9009" + }, + { + "ForeName": "Ryoichi", + "LastName": "Saito", + "abbrevName": "Saito R", + "email": null, + "isCollectiveName": false, + "name": "Ryoichi Saito", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Fan", + "abbrevName": "Fan C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Fan", + "orcid": null + }, + { + "ForeName": "Xian-De", + "LastName": "Liu", + "abbrevName": "Liu XD", + "email": null, + "isCollectiveName": false, + "name": "Xian-De Liu", + "orcid": "0000-0002-9639-0458" + }, + { + "ForeName": "Eric", + "LastName": "Jonasch", + "abbrevName": "Jonasch E", + "email": null, + "isCollectiveName": false, + "name": "Eric Jonasch", + "orcid": "0000-0003-0943-2806" + }, + { + "ForeName": "Ling", + "LastName": "Xie", + "abbrevName": "Xie L", + "email": null, + "isCollectiveName": false, + "name": "Ling Xie", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xian Chen", + "orcid": null + }, + { + "ForeName": "Xiaosai", + "LastName": "Yao", + "abbrevName": "Yao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaosai Yao", + "orcid": "0000-0001-9729-0726" + }, + { + "ForeName": "Bin", + "LastName": "Teh", + "abbrevName": "Teh BT", + "email": null, + "isCollectiveName": false, + "name": "Bin Tean Teh", + "orcid": "0000-0003-1514-1124" + }, + { + "ForeName": "Patrick", + "LastName": "Tan", + "abbrevName": "Tan P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Tan", + "orcid": null + }, + { + "ForeName": "Xingnan", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xingnan Zheng", + "orcid": "0000-0003-3034-4421" + }, + { + "ForeName": "Mingjie", + "LastName": "Li", + "abbrevName": "Li M", + "email": null, + "isCollectiveName": false, + "name": "Mingjie Li", + "orcid": "0000-0001-5337-4901" + }, + { + "ForeName": "Cortney", + "LastName": "Lawrence", + "abbrevName": "Lawrence C", + "email": null, + "isCollectiveName": false, + "name": "Cortney Lawrence", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Fan", + "abbrevName": "Fan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Fan", + "orcid": "0000-0003-3842-2391" + }, + { + "ForeName": "Jiang", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiang Geng", + "orcid": "0000-0002-7202-2167" + }, + { + "ForeName": "Xijuan", + "LastName": "Liu", + "abbrevName": "Liu X", + "email": null, + "isCollectiveName": false, + "name": "Xijuan Liu", + "orcid": null + }, + { + "ForeName": "Lianxin", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Lianxin Hu", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Chengheng", + "LastName": "Liao", + "abbrevName": "Liao C", + "email": null, + "isCollectiveName": false, + "name": "Chengheng Liao", + "orcid": null + }, + { + "ForeName": "Kai", + "LastName": "Hong", + "abbrevName": "Hong K", + "email": null, + "isCollectiveName": false, + "name": "Kai Hong", + "orcid": null + }, + { + "ForeName": "Giada", + "LastName": "Zurlo", + "abbrevName": "Zurlo G", + "email": null, + "isCollectiveName": false, + "name": "Giada Zurlo", + "orcid": null + }, + { + "ForeName": "Joel", + "LastName": "Parker", + "abbrevName": "Parker JS", + "email": null, + "isCollectiveName": false, + "name": "Joel S Parker", + "orcid": "0000-0003-2080-6901" + }, + { + "ForeName": "J", + "LastName": "Auman", + "abbrevName": "Auman JT", + "email": null, + "isCollectiveName": false, + "name": "J Todd Auman", + "orcid": "0000-0002-9328-8829" + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou", + "orcid": "0000-0001-9827-2247" + }, + { + "ForeName": "W", + "LastName": "Rathmell", + "abbrevName": "Rathmell WK", + "email": null, + "isCollectiveName": false, + "name": "W Kimryn Rathmell", + "orcid": "0000-0002-4984-0225" + }, + { + "ForeName": "William", + "LastName": "Kim", + "abbrevName": "Kim WY", + "email": null, + "isCollectiveName": false, + "name": "William Y Kim", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Kirschner", + "abbrevName": "Kirschner MW", + "email": null, + "isCollectiveName": false, + "name": "Marc W Kirschner", + "orcid": "0000-0001-6540-6130" + }, + { + "ForeName": "William", + "LastName": "Kaelin", + "abbrevName": "Kaelin WG", + "email": null, + "isCollectiveName": false, + "name": "William G Kaelin", + "orcid": "0000-0002-0574-4856" + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": "0000-0003-1246-1333" + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": "qing_zhang@med.unc.edu", + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": "0000-0002-6595-8995" + } + ], + "contacts": [ + { + "ForeName": "Qing", + "LastName": "Zhang", + "email": [ + "qing_zhang@med.unc.edu" + ], + "name": "Qing Zhang" + } + ] + }, + "doi": "10.1126/science.aap8411", + "pmid": "30026228", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 361 2018", + "title": "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma." + } + }, + { + "pmid": "24670641", + "pubmed": { + "ISODate": "2014-04-03T00:00:00.000Z", + "abstract": "Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.", + "authors": { + "abbreviation": "Xi Chen, Dimitrios Iliopoulos, Qing Zhang, ..., Laurie H Glimcher", + "authorList": [ + { + "ForeName": "Xi", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xi Chen", + "orcid": null + }, + { + "ForeName": "Dimitrios", + "LastName": "Iliopoulos", + "abbrevName": "Iliopoulos D", + "email": null, + "isCollectiveName": false, + "name": "Dimitrios Iliopoulos", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhang", + "orcid": null + }, + { + "ForeName": "Qianzi", + "LastName": "Tang", + "abbrevName": "Tang Q", + "email": null, + "isCollectiveName": false, + "name": "Qianzi Tang", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Greenblatt", + "abbrevName": "Greenblatt MB", + "email": null, + "isCollectiveName": false, + "name": "Matthew B Greenblatt", + "orcid": null + }, + { + "ForeName": "Maria", + "LastName": "Hatziapostolou", + "abbrevName": "Hatziapostolou M", + "email": null, + "isCollectiveName": false, + "name": "Maria Hatziapostolou", + "orcid": null + }, + { + "ForeName": "Elgene", + "LastName": "Lim", + "abbrevName": "Lim E", + "email": null, + "isCollectiveName": false, + "name": "Elgene Lim", + "orcid": null + }, + { + "ForeName": "Wai", + "LastName": "Tam", + "abbrevName": "Tam WL", + "email": null, + "isCollectiveName": false, + "name": "Wai Leong Tam", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ni", + "abbrevName": "Ni M", + "email": null, + "isCollectiveName": false, + "name": "Min Ni", + "orcid": null + }, + { + "ForeName": "Yiwen", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yiwen Chen", + "orcid": null + }, + { + "ForeName": "Junhua", + "LastName": "Mai", + "abbrevName": "Mai J", + "email": null, + "isCollectiveName": false, + "name": "Junhua Mai", + "orcid": null + }, + { + "ForeName": "Haifa", + "LastName": "Shen", + "abbrevName": "Shen H", + "email": null, + "isCollectiveName": false, + "name": "Haifa Shen", + "orcid": null + }, + { + "ForeName": "Dorothy", + "LastName": "Hu", + "abbrevName": "Hu DZ", + "email": null, + "isCollectiveName": false, + "name": "Dorothy Z Hu", + "orcid": null + }, + { + "ForeName": "Stanley", + "LastName": "Adoro", + "abbrevName": "Adoro S", + "email": null, + "isCollectiveName": false, + "name": "Stanley Adoro", + "orcid": null + }, + { + "ForeName": "Bella", + "LastName": "Hu", + "abbrevName": "Hu B", + "email": null, + "isCollectiveName": false, + "name": "Bella Hu", + "orcid": null + }, + { + "ForeName": "Minkyung", + "LastName": "Song", + "abbrevName": "Song M", + "email": null, + "isCollectiveName": false, + "name": "Minkyung Song", + "orcid": null + }, + { + "ForeName": "Chen", + "LastName": "Tan", + "abbrevName": "Tan C", + "email": null, + "isCollectiveName": false, + "name": "Chen Tan", + "orcid": null + }, + { + "ForeName": "Melissa", + "LastName": "Landis", + "abbrevName": "Landis MD", + "email": null, + "isCollectiveName": false, + "name": "Melissa D Landis", + "orcid": null + }, + { + "ForeName": "Mauro", + "LastName": "Ferrari", + "abbrevName": "Ferrari M", + "email": null, + "isCollectiveName": false, + "name": "Mauro Ferrari", + "orcid": null + }, + { + "ForeName": "Sandra", + "LastName": "Shin", + "abbrevName": "Shin SJ", + "email": null, + "isCollectiveName": false, + "name": "Sandra J Shin", + "orcid": null + }, + { + "ForeName": "Myles", + "LastName": "Brown", + "abbrevName": "Brown M", + "email": null, + "isCollectiveName": false, + "name": "Myles Brown", + "orcid": null + }, + { + "ForeName": "Jenny", + "LastName": "Chang", + "abbrevName": "Chang JC", + "email": null, + "isCollectiveName": false, + "name": "Jenny C Chang", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XS", + "email": null, + "isCollectiveName": false, + "name": "X Shirley Liu", + "orcid": null + }, + { + "ForeName": "Laurie", + "LastName": "Glimcher", + "abbrevName": "Glimcher LH", + "email": null, + "isCollectiveName": false, + "name": "Laurie H Glimcher", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13119", + "pmid": "24670641", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 508 2014", + "title": "XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway." + } + }, + { + "pmid": "28054302", + "pubmed": { + "ISODate": "2017-04-01T00:00:00.000Z", + "abstract": "PURPOSE: Despite advances that have been made in systemic chemotherapy, the prognosis of advanced triple-negative breast cancer (TNBC) patients is still poor. The identification of key factors governing TNBC development is considered imperative for the development of novel effective therapeutic approaches. Previously, it has been reported that microRNA (miR)-761 may act as either a tumor suppressor or as an oncogene in different types of cancer. Here, we aimed at assessing the biological role of this miRNA in TNBC. METHODS: First, we measured the expression of miR-761 in primary breast cancer tissues and breast cancer-derived cell lines using qRT-PCR. Subsequently, over-expression and silencing experiments were performed to determine the role of miR-761 in TNBC cell proliferation, colony formation, migration and invasion in vitro. The in vivo role of miR-761 in TNBC growth and metastasis was determined in mouse models. Bioinformatics analyses, dual-luciferase reporter assays, Western blot analyses and rescue experiments were performed to identify miR-761 target gene(s). RESULTS: We found that miR-761 was up-regulated in primary breast cancer tissues and its derived cell lines and, particularly, in TNBC tissues and cell lines. We also found that exogenous miR-761 over-expression augmented in vitro TNBC cell proliferation, colony formation, migration and invasion, whereas miR-761 down-regulation impaired these features. In vivo, we found that miR-761 over-expression facilitated TNBC growth and lung metastasis. Mechanistically, miR-761 was found to negatively regulate the expression of tripartite motif-containing 29 (TRIM29) in TNBC cells by binding to the 3'-untranslated region of its mRNA. In conformity with these results, a significant negative correlation between miR-761 expression and TRIM29 protein expression was noted in primary TNBC tissues (r = -0.452, p = 0.0126). We also found that exogenous TRIM29 over-expression reversed the proliferative and invasive capacities of TNBC cells. CONCLUSIONS: Our data indicate that miR-761 acts as an oncogene in TNBC. This mode of action can, at least partially, be ascribed to the down-regulation of its target TRIM29. We suggest that miR-761 may serve as a promising therapeutic target for TNBC.", + "authors": { + "abbreviation": "Guang-Cheng Guo, Jia-Xiang Wang, Ming-Li Han, ..., Lin Li", + "authorList": [ + { + "ForeName": "Guang-Cheng", + "LastName": "Guo", + "abbrevName": "Guo GC", + "email": null, + "isCollectiveName": false, + "name": "Guang-Cheng Guo", + "orcid": null + }, + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "abbrevName": "Wang JX", + "email": "ggc503@126.com", + "isCollectiveName": false, + "name": "Jia-Xiang Wang", + "orcid": null + }, + { + "ForeName": "Ming-Li", + "LastName": "Han", + "abbrevName": "Han ML", + "email": null, + "isCollectiveName": false, + "name": "Ming-Li Han", + "orcid": null + }, + { + "ForeName": "Lian-Ping", + "LastName": "Zhang", + "abbrevName": "Zhang LP", + "email": null, + "isCollectiveName": false, + "name": "Lian-Ping Zhang", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Lin Li", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Jia-Xiang", + "LastName": "Wang", + "email": [ + "ggc503@126.com" + ], + "name": "Jia-Xiang Wang" + } + ] + }, + "doi": "10.1007/s13402-016-0312-6", + "pmid": "28054302", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Oncol (Dordr) 40 2017", + "title": "microRNA-761 induces aggressive phenotypes in triple-negative breast cancer cells by repressing TRIM29 expression." + } + } + ], + "secret": "read-only", + "type": "complex" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/complex_tests_2.json b/neo4j-test/document/complex_tests_2.json new file mode 100644 index 000000000..9401bce41 --- /dev/null +++ b/neo4j-test/document/complex_tests_2.json @@ -0,0 +1,7702 @@ +{ + "document": [ + { + "_creationTimestamp": "2020-10-02T11:02:50.418Z", + "_newestOpId": "ca4a59ac-1a01-419d-bacd-6d61b6034592", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "p53, the guardian of the genome, requires chaperoning by Hsp70 and Hsp90. However, how the two chaperone machineries affect p53 conformation and regulate its function remains elusive. We found that Hsp70, together with Hsp40, unfolds p53 in an ATP-dependent reaction. This unfolded state of p53 is susceptible to aggregation after release induced by the nucleotide exchange factor Bag-1. However, when Hsp90 and the adaptor protein Hop are present, p53 is transferred from Hsp70 to Hsp90, allowing restoration of the native state upon ATP hydrolysis. Our results suggest that the p53 conformation is constantly remodeled by the two major chaperone machineries. This connects p53 activity to stress, and the levels of free molecular chaperones are important factors regulating p53 activity. Together, our findings reveal an intricate interplay and cooperation of Hsp70 and Hsp90 in regulating the conformation of a client.", + "ArticleTitle": "Coordinated Conformational Processing of the Tumor Suppressor Protein p53 by the Hsp70 and Hsp90 Chaperone Machineries.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Center for Integrated Protein Science Munich CIPSM at the Department Chemie, Technische Universität München, Garching, Germany.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Vinay", + "Identifier": [], + "Initials": "V", + "LastName": "Dahiya" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Chemistry, Center for NanoScience, Nanosystems Initiative Munich (NIM) and Center for Integrated Protein Science Munich (CiPSM), Ludwig Maximilians University Munich, Munich, Germany.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ganesh", + "Identifier": [], + "Initials": "G", + "LastName": "Agam" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Center for Integrated Protein Science Munich CIPSM at the Department Chemie, Technische Universität München, Garching, Germany.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jannis", + "Identifier": [], + "Initials": "J", + "LastName": "Lawatscheck" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Center for Integrated Protein Science Munich CIPSM at the Department Chemie, Technische Universität München, Garching, Germany.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Daniel Andreas", + "Identifier": [], + "Initials": "DA", + "LastName": "Rutz" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Chemistry, Center for NanoScience, Nanosystems Initiative Munich (NIM) and Center for Integrated Protein Science Munich (CiPSM), Ludwig Maximilians University Munich, Munich, Germany. Electronic address: d.lamb@lmu.de.", + "email": [ + "d.lamb@lmu.de" + ] + } + ], + "CollectiveName": null, + "ForeName": "Don C", + "Identifier": [], + "Initials": "DC", + "LastName": "Lamb" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Center for Integrated Protein Science Munich CIPSM at the Department Chemie, Technische Universität München, Garching, Germany. Electronic address: johannes.buchner@tum.de.", + "email": [ + "johannes.buchner@tum.de" + ] + } + ], + "CollectiveName": null, + "ForeName": "Johannes", + "Identifier": [], + "Initials": "J", + "LastName": "Buchner" + } + ], + "Journal": { + "ISOAbbreviation": "Mol Cell", + "ISSN": { + "IssnType": "Electronic", + "value": "1097-4164" + }, + "JournalIssue": { + "Issue": "4", + "PubDate": { + "Day": "16", + "Month": "May", + "Year": "2019" + }, + "Volume": "74" + }, + "Title": "Molecular cell" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "C091732", + "value": "BCL2-associated athanogene 1 protein" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D004268", + "value": "DNA-Binding Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D018840", + "value": "HSP70 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1601638023.018, + "liveId": "d57db9b6-3fc3-481d-a545-6fc7ac632f83", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [], + "relatedPapers": [ + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + } + ], + "secret": "read-only", + "status": "public", + "tweet": null, + "verified": true + } + ], + "element": [ + { + "_creationTimestamp": "2020-10-02T11:16:34.314Z", + "_newestOpId": "4a1dc050-0ad8-48e7-babb-1107ee984c87", + "_ops": [], + "association": { + "charge": 0, + "combinedOrganismIndex": 1, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "191170" + }, + { + "db": "HGNC", + "id": "HGNC:11998" + }, + { + "db": "Ensembl", + "id": "ENSG00000141510" + } + ], + "defaultOrganismIndex": 1, + "distance": 0, + "esScore": 10.016931, + "formulae": [ + "C9H12N2O6" + ], + "id": "7157", + "inchi": "InChI=1S/C9H12N2O6/c12-2-4-5(13)6(14)7(17-4)3-1-10-9(16)11-8(3)15/h1,4-7,12-14H,2H2,(H2,10,11,15,16)/t4-,5-,6-,7+/m1/s1", + "inchiKey": "PTJWIQPHWPFNBW-GBNDHIKLSA-N", + "mass": 244.20146, + "monoisotopicMass": 244.06954, + "name": "TP53", + "nameDistance": 0.19999999999999996, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100020, + "shortSynonyms": [ + "BCC7", + "BMFS5", + "LFS1", + "P53", + "TRP53", + "tumor protein p53", + "phosphoprotein p53", + "tumor supressor p53", + "p53 tumor suppressor", + "cellular tumor antigen p53" + ], + "summary": "A C-glycosyl pyrimidine that consists of uracil having a beta-D-ribofuranosyl residue attached at position 5. The C-glycosyl isomer of the nucleoside uridine.", + "synonyms": [ + "BCC7", + "BMFS5", + "LFS1", + "P53", + "TRP53", + "cellular tumor antigen p53", + "antigen NY-CO-13", + "mutant tumor protein 53", + "p53 tumor suppressor", + "phosphoprotein p53", + "transformation-related protein 53", + "tumor protein 53", + "tumor supressor p53", + "tumor protein p53" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "087b104d-5ce7-46ac-9ecf-5a8bc7a0f12b", + "liveId": "f3c05768-3266-49d3-8bb0-43b3ba3ab966", + "lock": null, + "locked": false, + "name": "p53", + "parentId": "abf851cd-f8ba-4c2a-a085-4b1394a3d291", + "position": { + "x": 74.43037974683541, + "y": 104.8101265822785 + }, + "relatedPapers": [ + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + }, + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2020-10-02T11:26:15.231Z", + "_newestOpId": "a5b45fba-613f-4060-a6c6-ea7c1de6f162", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "6519b9a7-9a21-4280-a6e5-f487c8017f95" + }, + { + "group": "negative", + "id": "087b104d-5ce7-46ac-9ecf-5a8bc7a0f12b" + } + ], + "id": "b6e4c90d-4870-4c64-8abf-b6e16b0738f7", + "liveId": "ad59c7a4-ed76-4c54-829a-e5e5b0505cc5", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2020-10-02T11:16:58.958Z", + "_newestOpId": "a5f58033-0022-4be8-b1c2-df2d0563582f", + "_ops": [], + "association": { + "charge": 0, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "140550" + }, + { + "db": "HGNC", + "id": "HGNC:5232" + }, + { + "db": "Ensembl", + "id": "ENSG00000204389" + } + ], + "defaultOrganismIndex": 1, + "distance": 0.11111111111111116, + "esScore": 47.790237, + "formulae": [ + "C9H14N4O4" + ], + "id": "3303", + "inchi": "InChI=1S/C9H14N4O4/c10-6(1-5-2-11-4-12-5)8(15)13-7(3-14)9(16)17/h2,4,6-7,14H,1,3,10H2,(H,11,12)(H,13,15)(H,16,17)/t6-,7-/m0/s1", + "inchiKey": "KRBMQYPTDYSENE-BQBZGAKWSA-N", + "mass": 242.2319, + "monoisotopicMass": 242.1015, + "name": "HSPA1A", + "nameDistance": 0.5555555555555556, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 1100000056, + "shortSynonyms": [ + "HEL-S-103", + "HSP70-1", + "HSP70-1A", + "HSP70-2", + "HSP70.1", + "HSP70I", + "HSP70.2", + "HSP72", + "HSPA1", + "HSP70.1/HSP70.2" + ], + "summary": "A dipeptide formed from L-histidine and L-serine residues.", + "synonyms": [ + "HEL-S-103", + "HSP70-1", + "HSP70-1A", + "HSP70-2", + "HSP70.1", + "HSP70.2", + "HSP70I", + "HSP72", + "HSPA1", + "heat shock 70 kDa protein 1A", + "HSP70-1/HSP70-2", + "HSP70.1/HSP70.2", + "Heat shock 70 kDa protein 1B", + "Heat shock 70 kDa protein 2", + "dnaK-type molecular chaperone HSP70-1", + "epididymis secretory protein Li 103", + "epididymis secretory sperm binding protein", + "heat shock 70 kDa protein 1", + "heat shock 70 kDa protein 1/2", + "heat shock 70 kDa protein 1A/1B", + "heat shock 70kD protein 1A", + "heat shock 70kDa protein 1A", + "heat shock-induced protein", + "heat shock protein family A (Hsp70) member 1A" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "6519b9a7-9a21-4280-a6e5-f487c8017f95", + "liveId": "3579fa3e-8a20-456a-a254-770b4cbef870", + "lock": null, + "locked": false, + "name": "Hsp70", + "parentId": "abf851cd-f8ba-4c2a-a085-4b1394a3d291", + "position": { + "x": 103.79746835443039, + "y": 57.21518987341772 + }, + "relatedPapers": [ + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2020-10-02T11:27:01.903Z", + "_newestOpId": "cc546532-a6da-4d2d-8878-dfc24324e863", + "_ops": [], + "association": "interaction", + "completed": false, + "description": "", + "entries": [ + { + "group": null, + "id": "5e02b559-c27b-4a05-9aa4-269251eaaf5f" + }, + { + "group": "unsigned", + "id": "6519b9a7-9a21-4280-a6e5-f487c8017f95" + } + ], + "id": "7ba76f35-faaa-4622-ae37-5aff0d802eed", + "liveId": "882a9808-6738-4751-b26b-5f1c4eeada79", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + }, + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + } + ], + "secret": "read-only", + "type": "interaction" + }, + { + "_creationTimestamp": "2020-10-02T11:23:57.069Z", + "_newestOpId": "bdac9740-a057-4e3a-84f9-8d6a8b3ffb78", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "6519b9a7-9a21-4280-a6e5-f487c8017f95" + }, + { + "id": "087b104d-5ce7-46ac-9ecf-5a8bc7a0f12b" + }, + { + "id": "5e02b559-c27b-4a05-9aa4-269251eaaf5f" + } + ], + "id": "abf851cd-f8ba-4c2a-a085-4b1394a3d291", + "liveId": "6ea88a8d-9e6b-462b-8d66-30e2e90d9239", + "lock": null, + "locked": false, + "name": "", + "position": { + "x": 80, + "y": 81.0126582278481 + }, + "relatedPapers": [ + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + } + ], + "secret": "read-only", + "type": "complex" + }, + { + "_creationTimestamp": "2020-10-02T11:23:58.183Z", + "_newestOpId": "ff11168e-7429-45c7-9bd2-dd3de6494693", + "_ops": [], + "association": { + "charge": 0, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "140572" + }, + { + "db": "HGNC", + "id": "HGNC:5258" + }, + { + "db": "Ensembl", + "id": "ENSG00000096384" + } + ], + "defaultOrganismIndex": 1, + "distance": 0.11111111111111116, + "esScore": 25.380903, + "formulae": [ + "H" + ], + "id": "3326", + "mass": 1.00794, + "monoisotopicMass": 1.00783, + "name": "HSP90AB1", + "nameDistance": 0.2727272727272727, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 1100000027, + "shortSynonyms": [ + "D6S182", + "HSP84", + "HSP90B", + "HSPC2", + "HSPCB", + "HSP90-beta", + "heat shock protein HSP 90-beta", + "heat shock protein 90 kDa", + "heat shock 90kD protein 1, beta", + "heat shock protein 90 alpha family class B member 1" + ], + "synonyms": [ + "D6S182", + "HSP84", + "HSP90B", + "HSPC2", + "HSPCB", + "heat shock protein HSP 90-beta", + "HSP90-beta", + "heat shock 84 kDa", + "heat shock 90kD protein 1, beta", + "heat shock protein 90 kDa", + "heat shock protein 90kDa alpha (cytosolic), class B member 1", + "heat shock protein 90kDa alpha family class B member 1", + "heat shock protein 90 alpha family class B member 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "5e02b559-c27b-4a05-9aa4-269251eaaf5f", + "liveId": "f13d6d40-2396-421d-97a9-9253825f70a5", + "lock": null, + "locked": false, + "name": "Hsp90", + "parentId": "abf851cd-f8ba-4c2a-a085-4b1394a3d291", + "position": { + "x": 56.202531645569614, + "y": 57.721518987341774 + }, + "relatedPapers": [ + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2020-10-02T11:26:44.433Z", + "_newestOpId": "6bd35b29-9393-4b21-94a1-0486c1d0ded9", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "5e02b559-c27b-4a05-9aa4-269251eaaf5f" + }, + { + "group": "positive", + "id": "087b104d-5ce7-46ac-9ecf-5a8bc7a0f12b" + } + ], + "id": "eb40318c-9a0e-45f6-a81e-21836fd9e9e3", + "liveId": "c04f113b-98ad-4c86-ab6b-b6a4ffc19e03", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 60.75949367088607, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "21700222", + "pubmed": { + "ISODate": "2011-06-24T00:00:00.000Z", + "abstract": "Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular \"client\" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.", + "authors": { + "abbreviation": "Daniel R Southworth, David A Agard", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Southworth", + "abbrevName": "Southworth DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Southworth" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard DA", + "email": null, + "isCollectiveName": false, + "name": "David A Agard" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2011.04.023", + "pmid": "21700222", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex." + } + }, + { + "pmid": "31665549", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.", + "authors": { + "abbreviation": "Jesús García-Cano, Susana Sánchez-Tena, Joan Sala-Gaston, ..., Jose Luis Rosa", + "authorList": [ + { + "ForeName": "Jesús", + "LastName": "García-Cano", + "abbrevName": "García-Cano J", + "email": null, + "isCollectiveName": false, + "name": "Jesús García-Cano" + }, + { + "ForeName": "Susana", + "LastName": "Sánchez-Tena", + "abbrevName": "Sánchez-Tena S", + "email": null, + "isCollectiveName": false, + "name": "Susana Sánchez-Tena" + }, + { + "ForeName": "Joan", + "LastName": "Sala-Gaston", + "abbrevName": "Sala-Gaston J", + "email": null, + "isCollectiveName": false, + "name": "Joan Sala-Gaston" + }, + { + "ForeName": "Agnès", + "LastName": "Figueras", + "abbrevName": "Figueras A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Figueras" + }, + { + "ForeName": "Francesc", + "LastName": "Viñals", + "abbrevName": "Viñals F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Viñals" + }, + { + "ForeName": "Ramon", + "LastName": "Bartrons", + "abbrevName": "Bartrons R", + "email": null, + "isCollectiveName": false, + "name": "Ramon Bartrons" + }, + { + "ForeName": "Francesc", + "LastName": "Ventura", + "abbrevName": "Ventura F", + "email": null, + "isCollectiveName": false, + "name": "Francesc Ventura" + }, + { + "ForeName": "Jose", + "LastName": "Rosa", + "abbrevName": "Rosa JL", + "email": null, + "isCollectiveName": false, + "name": "Jose Luis Rosa" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12592", + "pmid": "31665549", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Oncol 14 2020", + "title": "Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2." + } + }, + { + "pmid": "31027880", + "pubmed": { + "ISODate": "2019-05-16T00:00:00.000Z", + "abstract": "The activity of the tumor suppressor p53 has to be timed and balanced closely to prevent untimely induction of cell death. The stability of p53 depends on the ubiquitin ligase Mdm2 but also on Hsp70 and Hsp90 chaperones that interact with its DNA binding domain (DBD). Using hydrogen exchange mass spectrometry and biochemical methods, we analyzed conformational states of wild-type p53-DBD at physiological temperatures and conformational perturbations in three frequent p53 cancer mutants. We demonstrate that the Hsp70/Hdj1 system shifts the conformational equilibrium of p53 toward a flexible, more mutant-like, DNA binding inactive state by binding to the DNA binding loop. The analyzed cancer mutants are likewise destabilized by interaction with the Hsp70/Hdj1 system. In contrast, Hsp90 protects the DBD of p53 wild-type and mutant proteins from unfolding. We propose that the Hsp70 and Hsp90 chaperone systems assume complementary functions to optimally balance conformational plasticity with conformational stability.", + "authors": { + "abbreviation": "Marta Boysen, Roman Kityk, Matthias P Mayer", + "authorList": [ + { + "ForeName": "Marta", + "LastName": "Boysen", + "abbrevName": "Boysen M", + "email": null, + "isCollectiveName": false, + "name": "Marta Boysen" + }, + { + "ForeName": "Roman", + "LastName": "Kityk", + "abbrevName": "Kityk R", + "email": null, + "isCollectiveName": false, + "name": "Roman Kityk" + }, + { + "ForeName": "Matthias", + "LastName": "Mayer", + "abbrevName": "Mayer MP", + "email": "m.mayer@zmbh.uni-heidelberg.de", + "isCollectiveName": false, + "name": "Matthias P Mayer" + } + ], + "contacts": [ + { + "ForeName": "Matthias", + "LastName": "Mayer", + "email": [ + "m.mayer@zmbh.uni-heidelberg.de" + ], + "name": "Matthias P Mayer" + } + ] + }, + "doi": "10.1016/j.molcel.2019.03.032", + "pmid": "31027880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 74 2019", + "title": "Hsp70- and Hsp90-Mediated Regulation of the Conformation of p53 DNA Binding Domain and p53 Cancer Variants." + } + }, + { + "pmid": "32198203", + "pubmed": { + "ISODate": "2020-04-07T00:00:00.000Z", + "abstract": "Hsp70 is a conserved molecular chaperone that plays an indispensable role in regulating protein folding, translocation, and degradation. The conformational dynamics of Hsp70 and its regulation by cochaperones are vital to its function. Using bulk and single-molecule fluorescence resonance energy transfer (smFRET) techniques, we studied the interdomain conformational distribution of human stress-inducible Hsp70A1 and the kinetics of conformational changes induced by nucleotide and the Hsp40 cochaperone Hdj1. We found that the conformations between and within the nucleotide- and substrate-binding domains show heterogeneity. The conformational distribution in the ATP-bound state can be induced by Hdj1 to form an \"ADP-like\" undocked conformation, which is an ATPase-stimulated state. Kinetic measurements indicate that Hdj1 binds to monomeric Hsp70 as the first step, then induces undocking of the two domains and closing of the substrate-binding cleft. Dimeric Hdj1 then facilitates dimerization of Hsp70 and formation of a heterotetrameric Hsp70-Hsp40 complex. Our results provide a kinetic view of the conformational cycle of Hsp70 and reveal the importance of the dynamic nature of Hsp70 for its function.", + "authors": { + "abbreviation": "Si Wu, Liu Hong, Yuqing Wang, ..., Sarah Perrett", + "authorList": [ + { + "ForeName": "Si", + "LastName": "Wu", + "abbrevName": "Wu S", + "email": null, + "isCollectiveName": false, + "name": "Si Wu" + }, + { + "ForeName": "Liu", + "LastName": "Hong", + "abbrevName": "Hong L", + "email": null, + "isCollectiveName": false, + "name": "Liu Hong" + }, + { + "ForeName": "Yuqing", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuqing Wang" + }, + { + "ForeName": "Jieqiong", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jieqiong Yu" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang" + }, + { + "ForeName": "Hong", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhang" + }, + { + "ForeName": "Sarah", + "LastName": "Perrett", + "abbrevName": "Perrett S", + "email": "sarah.perrett@cantab.net", + "isCollectiveName": false, + "name": "Sarah Perrett" + } + ], + "contacts": [ + { + "ForeName": "Sarah", + "LastName": "Perrett", + "email": [ + "sarah.perrett@cantab.net" + ], + "name": "Sarah Perrett" + } + ] + }, + "doi": "10.1073/pnas.1914376117", + "pmid": "32198203", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "Kinetics of the conformational cycle of Hsp70 reveals the importance of the dynamic and heterogeneous nature of Hsp70 for its function." + } + }, + { + "pmid": "20688913", + "pubmed": { + "ISODate": "2010-10-15T00:00:00.000Z", + "abstract": "Hsp90 is a ubiquitous, ATP-dependent chaperone, essential for eukaryotes. It possesses a broad spectrum of substrates, among which is the p53 transcription factor, encoded by a tumor-suppressor gene. Here, we elucidate the role of the adenine nucleotide in the Hsp90 chaperone cycle, by taking advantage of a unique in vitro assay measuring Hsp90-dependent p53 binding to the promoter sequence. E42A and D88N Hsp90β variants bind but do not hydrolyze ATP, whereas E42A has increased and D88N decreased ATP affinity, compared with WT Hsp90β. Nevertheless, both of these mutants interact with WT p53 with a similar affinity. Surprisingly, in the case of WT, but also E42A Hsp90β, the presence of ATP stimulates dissociation of Hsp90-p53 complexes and results in p53 binding to the promoter sequence. D88N Hsp90β is not efficient in both of these reactions. Using a trap version of the chaperonin GroEL, which irreversibly captures unfolded proteins, we show that Hsp90 chaperone action on WT p53 results in a partial unfolding of the substrate. The ATP-dependent dissociation of p53-Hsp90 complex allows further folding of p53 protein to an active conformation, able to bind to the promoter sequence. Furthermore, in support of these results, the overproduction of WT or E42A Hsp90β stimulates transcription from the WAF1 gene promoter in H1299 cells. Altogether, our research indicates that ATP binding to Hsp90β is a sufficient step for effective WT p53 client protein chaperoning.", + "authors": { + "abbreviation": "Dawid Walerych, Malgorzata Gutkowska, Marcin P Klejman, ..., Alicja Zylicz", + "authorList": [ + { + "ForeName": "Dawid", + "LastName": "Walerych", + "abbrevName": "Walerych D", + "email": null, + "isCollectiveName": false, + "name": "Dawid Walerych" + }, + { + "ForeName": "Malgorzata", + "LastName": "Gutkowska", + "abbrevName": "Gutkowska M", + "email": null, + "isCollectiveName": false, + "name": "Malgorzata Gutkowska" + }, + { + "ForeName": "Marcin", + "LastName": "Klejman", + "abbrevName": "Klejman MP", + "email": null, + "isCollectiveName": false, + "name": "Marcin P Klejman" + }, + { + "ForeName": "Bartosz", + "LastName": "Wawrzynow", + "abbrevName": "Wawrzynow B", + "email": null, + "isCollectiveName": false, + "name": "Bartosz Wawrzynow" + }, + { + "ForeName": "Zuzanna", + "LastName": "Tracz", + "abbrevName": "Tracz Z", + "email": null, + "isCollectiveName": false, + "name": "Zuzanna Tracz" + }, + { + "ForeName": "Milena", + "LastName": "Wiech", + "abbrevName": "Wiech M", + "email": null, + "isCollectiveName": false, + "name": "Milena Wiech" + }, + { + "ForeName": "Maciej", + "LastName": "Zylicz", + "abbrevName": "Zylicz M", + "email": null, + "isCollectiveName": false, + "name": "Maciej Zylicz" + }, + { + "ForeName": "Alicja", + "LastName": "Zylicz", + "abbrevName": "Zylicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Zylicz" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.112110", + "pmid": "20688913", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "ATP binding to Hsp90 is sufficient for effective chaperoning of p53 protein." + } + }, + { + "pmid": "15911628", + "pubmed": { + "ISODate": "2005-07-22T00:00:00.000Z", + "abstract": "The cellular level of the tumor suppressor p53 is tightly regulated through induced degradation via the ubiquitin/proteasome system. The ubiquitin ligase Mdm2 plays a pivotal role in stimulating p53 turnover. However, recently additional ubiquitin ligases have been identified that participate in the degradation of the tumor suppressor. Apparently, multiple degradation pathways are employed to ensure proper destruction of p53. Here we show that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53. CHIP-induced degradation was observed for mutant p53, which was previously shown to associate with the chaperones Hsc70 and Hsp90, and for the wild-type form of the tumor suppressor. Our data reveal that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association.", + "authors": { + "abbreviation": "Claudia Esser, Martin Scheffner, Jörg Höhfeld", + "authorList": [ + { + "ForeName": "Claudia", + "LastName": "Esser", + "abbrevName": "Esser C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Esser" + }, + { + "ForeName": "Martin", + "LastName": "Scheffner", + "abbrevName": "Scheffner M", + "email": null, + "isCollectiveName": false, + "name": "Martin Scheffner" + }, + { + "ForeName": "Jörg", + "LastName": "Höhfeld", + "abbrevName": "Höhfeld J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Höhfeld" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M501574200", + "pmid": "15911628", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation." + } + }, + { + "pmid": "26482100", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. ", + "authors": { + "abbreviation": "Olivier Genest, Joel R Hoskins, Andrea N Kravats, ..., Sue Wickner", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Genest", + "abbrevName": "Genest O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Genest" + }, + { + "ForeName": "Joel", + "LastName": "Hoskins", + "abbrevName": "Hoskins JR", + "email": null, + "isCollectiveName": false, + "name": "Joel R Hoskins" + }, + { + "ForeName": "Andrea", + "LastName": "Kravats", + "abbrevName": "Kravats AN", + "email": null, + "isCollectiveName": false, + "name": "Andrea N Kravats" + }, + { + "ForeName": "Shannon", + "LastName": "Doyle", + "abbrevName": "Doyle SM", + "email": "doyles@mail.nih.gov", + "isCollectiveName": false, + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "abbrevName": "Wickner S", + "email": "wickners@mail.nih.gov", + "isCollectiveName": false, + "name": "Sue Wickner" + } + ], + "contacts": [ + { + "ForeName": "Shannon", + "LastName": "Doyle", + "email": [ + "doyles@mail.nih.gov" + ], + "name": "Shannon M Doyle" + }, + { + "ForeName": "Sue", + "LastName": "Wickner", + "email": [ + "wickners@mail.nih.gov" + ], + "name": "Sue Wickner" + } + ] + }, + "doi": "10.1016/j.jmb.2015.10.010", + "pmid": "26482100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Mol Biol 427 2015", + "title": "Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling." + } + }, + { + "pmid": "24535459", + "pubmed": { + "ISODate": "2014-04-04T00:00:00.000Z", + "abstract": "Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change. ", + "authors": { + "abbreviation": "Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, ..., Hideaki Itoh", + "authorList": [ + { + "ForeName": "Soh", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto S", + "email": null, + "isCollectiveName": false, + "name": "Soh Yamamoto" + }, + { + "ForeName": "Ganesh", + "LastName": "Subedi", + "abbrevName": "Subedi GP", + "email": null, + "isCollectiveName": false, + "name": "Ganesh Prasad Subedi" + }, + { + "ForeName": "Shinya", + "LastName": "Hanashima", + "abbrevName": "Hanashima S", + "email": null, + "isCollectiveName": false, + "name": "Shinya Hanashima" + }, + { + "ForeName": "Tadashi", + "LastName": "Satoh", + "abbrevName": "Satoh T", + "email": null, + "isCollectiveName": false, + "name": "Tadashi Satoh" + }, + { + "ForeName": "Michiro", + "LastName": "Otaka", + "abbrevName": "Otaka M", + "email": null, + "isCollectiveName": false, + "name": "Michiro Otaka" + }, + { + "ForeName": "Hideki", + "LastName": "Wakui", + "abbrevName": "Wakui H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Wakui" + }, + { + "ForeName": "Ken-ichi", + "LastName": "Sawada", + "abbrevName": "Sawada K", + "email": null, + "isCollectiveName": false, + "name": "Ken-ichi Sawada" + }, + { + "ForeName": "Shin-ichi", + "LastName": "Yokota", + "abbrevName": "Yokota S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Yokota" + }, + { + "ForeName": "Yoshiki", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshiki Yamaguchi" + }, + { + "ForeName": "Hiroshi", + "LastName": "Kubota", + "abbrevName": "Kubota H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Kubota" + }, + { + "ForeName": "Hideaki", + "LastName": "Itoh", + "abbrevName": "Itoh H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Itoh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M114.553255", + "pmid": "24535459", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "ATPase activity and ATP-dependent conformational change in the co-chaperone HSP70/HSP90-organizing protein (HOP)." + } + }, + { + "pmid": "25921532", + "pubmed": { + "ISODate": "2015-05-05T00:00:00.000Z", + "abstract": "Protein folding in cells is regulated by networks of chaperones, including the heat shock protein 70 (Hsp70) system, which consists of the Hsp40 cochaperone and a nucleotide exchange factor. Hsp40 mediates complex formation between Hsp70 and client proteins prior to interaction with Hsp90. We used mass spectrometry (MS) to monitor assemblies formed between eukaryotic Hsp90/Hsp70/Hsp40, Hop, p23, and a client protein, a fragment of the glucocorticoid receptor (GR). We found that Hsp40 promotes interactions between the client and Hsp70, and facilitates dimerization of monomeric Hsp70. This dimerization is antiparallel, stabilized by post-translational modifications (PTMs), and maintained in the stable heterohexameric client-loading complex Hsp902Hsp702HopGR identified here. Addition of p23 to this client-loading complex induces transfer of GR onto Hsp90 and leads to expulsion of Hop and Hsp70. Based on these results, we propose that Hsp70 antiparallel dimerization, stabilized by PTMs, positions the client for transfer from Hsp70 to Hsp90.", + "authors": { + "abbreviation": "Nina Morgner, Carla Schmidt, Victoria Beilsten-Edmands, ..., Carol V Robinson", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "abbrevName": "Morgner N", + "email": "morgner@chemie.uni-frankfurt.de", + "isCollectiveName": false, + "name": "Nina Morgner" + }, + { + "ForeName": "Carla", + "LastName": "Schmidt", + "abbrevName": "Schmidt C", + "email": null, + "isCollectiveName": false, + "name": "Carla Schmidt" + }, + { + "ForeName": "Victoria", + "LastName": "Beilsten-Edmands", + "abbrevName": "Beilsten-Edmands V", + "email": null, + "isCollectiveName": false, + "name": "Victoria Beilsten-Edmands" + }, + { + "ForeName": "Ima-Obong", + "LastName": "Ebong", + "abbrevName": "Ebong IO", + "email": null, + "isCollectiveName": false, + "name": "Ima-Obong Ebong" + }, + { + "ForeName": "Nisha", + "LastName": "Patel", + "abbrevName": "Patel NA", + "email": null, + "isCollectiveName": false, + "name": "Nisha A Patel" + }, + { + "ForeName": "Eugenia", + "LastName": "Clerico", + "abbrevName": "Clerico EM", + "email": null, + "isCollectiveName": false, + "name": "Eugenia M Clerico" + }, + { + "ForeName": "Elaine", + "LastName": "Kirschke", + "abbrevName": "Kirschke E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Kirschke" + }, + { + "ForeName": "Soumya", + "LastName": "Daturpalli", + "abbrevName": "Daturpalli S", + "email": null, + "isCollectiveName": false, + "name": "Soumya Daturpalli" + }, + { + "ForeName": "Sophie", + "LastName": "Jackson", + "abbrevName": "Jackson SE", + "email": null, + "isCollectiveName": false, + "name": "Sophie E Jackson" + }, + { + "ForeName": "David", + "LastName": "Agard", + "abbrevName": "Agard D", + "email": null, + "isCollectiveName": false, + "name": "David Agard" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "abbrevName": "Robinson CV", + "email": "carol.robinson@chem.ox.ac.uk", + "isCollectiveName": false, + "name": "Carol V Robinson" + } + ], + "contacts": [ + { + "ForeName": "Nina", + "LastName": "Morgner", + "email": [ + "morgner@chemie.uni-frankfurt.de" + ], + "name": "Nina Morgner" + }, + { + "ForeName": "Carol", + "LastName": "Robinson", + "email": [ + "carol.robinson@chem.ox.ac.uk" + ], + "name": "Carol V Robinson" + } + ] + }, + "doi": "10.1016/j.celrep.2015.03.063", + "pmid": "25921532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 11 2015", + "title": "Hsp70 forms antiparallel dimers stabilized by post-translational modifications to position clients for transfer to Hsp90." + } + }, + { + "pmid": "12853476", + "pubmed": { + "ISODate": "2003-07-15T00:00:00.000Z", + "abstract": "In the eukaryotic cytosol, Hsp70 and Hsp90 cooperate with various co-chaperone proteins in the folding of a growing set of substrates, including the glucocorticoid receptor (GR). Here, we analyse the function of the co-chaperone Tpr2, which contains two chaperone-binding TPR domains and a DnaJ homologous J domain. In vivo, an increase or decrease in Tpr2 expression reduces GR activation, suggesting that Tpr2 is required at a narrowly defined expression level. As shown in vitro, Tpr2 recognizes both Hsp70 and Hsp90 through its TPR domains, and its J domain stimulates ATP hydrolysis and polypeptide binding by Hsp70. Furthermore, unlike other co-chaperones, Tpr2 induces ATP-independent dissociation of Hsp90 but not of Hsp70 from chaperone-substrate complexes. Excess Tpr2 inhibits the Hsp90-dependent folding of GR in cell lysates. We propose a novel mechanism in which Tpr2 mediates the retrograde transfer of substrates from Hsp90 onto Hsp70. At normal levels substoichiometric to Hsp90 and Hsp70, this activity optimizes the function of the multichaperone machinery.", + "authors": { + "abbreviation": "Alexander Brychzy, Theo Rein, Konstanze F Winklhofer, ..., Wolfgang M J Obermann", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Brychzy", + "abbrevName": "Brychzy A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Brychzy" + }, + { + "ForeName": "Theo", + "LastName": "Rein", + "abbrevName": "Rein T", + "email": null, + "isCollectiveName": false, + "name": "Theo Rein" + }, + { + "ForeName": "Konstanze", + "LastName": "Winklhofer", + "abbrevName": "Winklhofer KF", + "email": null, + "isCollectiveName": false, + "name": "Konstanze F Winklhofer" + }, + { + "ForeName": "F", + "LastName": "Hartl", + "abbrevName": "Hartl FU", + "email": null, + "isCollectiveName": false, + "name": "F Ulrich Hartl" + }, + { + "ForeName": "Jason", + "LastName": "Young", + "abbrevName": "Young JC", + "email": null, + "isCollectiveName": false, + "name": "Jason C Young" + }, + { + "ForeName": "Wolfgang", + "LastName": "Obermann", + "abbrevName": "Obermann WM", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang M J Obermann" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/cdg362", + "pmid": "12853476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 22 2003", + "title": "Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system." + } + } + ], + "secret": "read-only", + "type": "binding" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/complex_tests_3.json b/neo4j-test/document/complex_tests_3.json new file mode 100644 index 000000000..b03a34b45 --- /dev/null +++ b/neo4j-test/document/complex_tests_3.json @@ -0,0 +1,6854 @@ +{ + "document": [ + { + "_creationTimestamp": "2020-10-31T17:19:35.027Z", + "_newestOpId": "6d8018f4-4c18-4a4d-858e-d4db0be87893", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "ArticleTitle": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul 02841, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Hyo Min", + "Identifier": [], + "Initials": "HM", + "LastName": "Cho" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul 02841, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jae Ryun", + "Identifier": [], + "Initials": "JR", + "LastName": "Ryu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul 02841, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Youhwa", + "Identifier": [], + "Initials": "Y", + "LastName": "Jo" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biology, Kyung Hee University, Seoul 02447, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Tae Woong", + "Identifier": [], + "Initials": "TW", + "LastName": "Seo" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biology, Kyung Hee University, Seoul 02447, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ye Na", + "Identifier": [], + "Initials": "YN", + "LastName": "Choi" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul 02841, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "June Hoan", + "Identifier": [], + "Initials": "JH", + "LastName": "Kim" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Physiology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jee Min", + "Identifier": [], + "Initials": "JM", + "LastName": "Chung" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu 42988, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Bongki", + "Identifier": [], + "Initials": "B", + "LastName": "Cho" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Physiology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ho Chul", + "Identifier": [], + "Initials": "HC", + "LastName": "Kang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu 42988, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Seong-Woon", + "Identifier": [], + "Initials": "SW", + "LastName": "Yu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biology, Kyung Hee University, Seoul 02447, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Soon Ji", + "Identifier": [], + "Initials": "SJ", + "LastName": "Yoo" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul 02841, Republic of Korea.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Hyun", + "Identifier": [], + "Initials": "H", + "LastName": "Kim" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul 02841, Republic of Korea. Electronic address: woongsun@korea.ac.kr.", + "email": [ + "woongsun@korea.ac.kr" + ] + } + ], + "CollectiveName": null, + "ForeName": "Woong", + "Identifier": [], + "Initials": "W", + "LastName": "Sun" + } + ], + "Journal": { + "ISOAbbreviation": "Mol Cell", + "ISSN": { + "IssnType": "Electronic", + "value": "1097-4164" + }, + "JournalIssue": { + "Issue": "2", + "PubDate": { + "Day": "17", + "Month": "Jan", + "Year": "2019" + }, + "Volume": "73" + }, + "Title": "Molecular cell" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "D015220", + "value": "Calcium Channels" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D027682", + "value": "Cation Transport Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D008869", + "value": "Microtubule-Associated Proteins" + }, 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null, + "isCollectiveName": false, + "name": "Jee Min Chung", + "orcid": "0000-0003-1725-0770" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho", + "orcid": null + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang", + "orcid": null + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu", + "orcid": null + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo", + "orcid": null + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim", + "orcid": "0000-0002-7210-5798" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun", + "orcid": null + } + ], + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1604164775.031, + "entries": [ + { + "id": "3ed4ad3e-dab8-4b6d-b488-5c0299421da1" + }, + { + "id": "12e5cc51-1be3-4ea7-8d24-af343658668e" + }, + { + "id": "fa615793-b1ec-410a-a426-75a4a1d34cff" + }, + { + "id": "01b1b41a-db22-4247-a2b9-4c24bee7f4c4" + }, + { + "id": "abce49de-663c-4a5b-8bc5-de1ec79a63d7" + } + ], + "id": "c164dd79-2351-4a88-b7f4-7a48245735ef", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1604937879.702, + "liveId": "9dc5dce4-7b66-4d80-8b6c-0eec454c4e88", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [], + "relatedPapers": [ + { + "pmid": "30581142", + "pubmed": { + "ISODate": "2019-01-17T00:00:00.000Z", + "abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "authors": { + "abbreviation": "Hyo Min Cho, Jae Ryun Ryu, Youhwa Jo, ..., Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Jae", + "LastName": "Ryu", + "abbrevName": "Ryu JR", + "email": null, + "isCollectiveName": false, + "name": "Jae Ryun Ryu" + }, + { + "ForeName": "Youhwa", + "LastName": "Jo", + "abbrevName": "Jo Y", + "email": null, + "isCollectiveName": false, + "name": "Youhwa Jo" + }, + { + "ForeName": "Tae", + "LastName": "Seo", + "abbrevName": "Seo TW", + "email": null, + "isCollectiveName": false, + "name": "Tae Woong Seo" + }, + { + "ForeName": "Ye", + "LastName": "Choi", + "abbrevName": "Choi YN", + "email": null, + "isCollectiveName": false, + "name": "Ye Na Choi" + }, + { + "ForeName": "June", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": null, + "isCollectiveName": false, + "name": "June Hoan Kim" + }, + { + "ForeName": "Jee", + "LastName": "Chung", + "abbrevName": "Chung JM", + "email": null, + "isCollectiveName": false, + "name": "Jee Min Chung" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho" + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo" + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [ + { + "ForeName": "Woong", + "LastName": "Sun", + "email": [ + "woongsun@korea.ac.kr" + ], + "name": "Woong Sun" + } + ] + }, + "doi": "10.1016/j.molcel.2018.11.009", + "pmid": "30581142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 73 2019", + "title": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System." + } + }, + { + "pmid": "27050458", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact \"coupling\" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the \"coupling\" across the double membrane for mitochondrial dynamics and quality control. ", + "authors": { + "abbreviation": "Ming Chen, Ziheng Chen, Yueying Wang, ..., Quan Chen", + "authorList": [ + { + "ForeName": "Ming", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Ming Chen" + }, + { + "ForeName": "Ziheng", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Ziheng Chen" + }, + { + "ForeName": "Yueying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yueying Wang" + }, + { + "ForeName": "Zheng", + "LastName": "Tan", + "abbrevName": "Tan Z", + "email": null, + "isCollectiveName": false, + "name": "Zheng Tan" + }, + { + "ForeName": "Chongzhuo", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Chongzhuo Zhu" + }, + { + "ForeName": "Yanjun", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanjun Li" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Linbo", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Linbo Chen" + }, + { + "ForeName": "Ruize", + "LastName": "Gao", + "abbrevName": "Gao R", + "email": null, + "isCollectiveName": false, + "name": "Ruize Gao" + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu" + }, + { + "ForeName": "Quan", + "LastName": "Chen", + "abbrevName": "Chen Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Chen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2016.1151580", + "pmid": "27050458", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 12 2016", + "title": "Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy." + } + }, + { + "pmid": "33851959", + "pubmed": { + "ISODate": "2021-06-07T00:00:00.000Z", + "abstract": "Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (\"mosaic distribution\"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.", + "authors": { + "abbreviation": "Yumiko Oshima, Etienne Cartier, Liron Boyman, ..., Mariusz Karbowski", + "authorList": [ + { + "ForeName": "Yumiko", + "LastName": "Oshima", + "abbrevName": "Oshima Y", + "email": null, + "isCollectiveName": false, + "name": "Yumiko Oshima" + }, + { + "ForeName": "Etienne", + "LastName": "Cartier", + "abbrevName": "Cartier E", + "email": null, + "isCollectiveName": false, + "name": "Etienne Cartier" + }, + { + "ForeName": "Liron", + "LastName": "Boyman", + "abbrevName": "Boyman L", + "email": null, + "isCollectiveName": false, + "name": "Liron Boyman" + }, + { + "ForeName": "Nicolas", + "LastName": "Verhoeven", + "abbrevName": "Verhoeven N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Verhoeven" + }, + { + "ForeName": "Brian", + "LastName": "Polster", + "abbrevName": "Polster BM", + "email": null, + "isCollectiveName": false, + "name": "Brian M Polster" + }, + { + "ForeName": "Weiliang", + "LastName": "Huang", + "abbrevName": "Huang W", + "email": null, + "isCollectiveName": false, + "name": "Weiliang Huang" + }, + { + "ForeName": "Maureen", + "LastName": "Kane", + "abbrevName": "Kane M", + "email": null, + "isCollectiveName": false, + "name": "Maureen Kane" + }, + { + "ForeName": "W", + "LastName": "Lederer", + "abbrevName": "Lederer WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jonathan Lederer" + }, + { + "ForeName": "Mariusz", + "LastName": "Karbowski", + "abbrevName": "Karbowski M", + "email": null, + "isCollectiveName": false, + "name": "Mariusz Karbowski" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202006043", + "pmid": "33851959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination." + } + }, + { + "pmid": "32529373", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Dynamin-like protein 1 (Drp1) is the master regulator of mitochondrial fission. Drp1 translocates from the cytosol to the mitochondrial outer membrane to execute the scission process. Here we describe an immunofluorescence-based method to measure the mitochondrial translocation of Drp1 and quantify Drp1-related mitochondrial fission by labeling the mitochondrial import receptor subunit TOM20 in fixed cell culture.", + "authors": { + "abbreviation": "Di Hu, Xin Qi", + "authorList": [ + { + "ForeName": "Di", + "LastName": "Hu", + "abbrevName": "Hu D", + "email": null, + "isCollectiveName": false, + "name": "Di Hu" + }, + { + "ForeName": "Xin", + "LastName": "Qi", + "abbrevName": "Qi X", + "email": "xxq38@case.edu", + "isCollectiveName": false, + "name": "Xin Qi" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Qi", + "email": [ + "xxq38@case.edu" + ], + "name": "Xin Qi" + } + ] + }, + "doi": "10.1007/978-1-0716-0676-6_15", + "pmid": "32529373", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Methods Mol Biol 2159 2020", + "title": "Quantifying Drp1-Mediated Mitochondrial Fission by Immunostaining in Fixed Cells." + } + }, + { + "pmid": "23284813", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.", + "authors": { + "abbreviation": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, ..., Taiichi Katayama", + "authorList": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "abbrevName": "Takamura H", + "email": "takamura@ugscd.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Hironori Takamura" + }, + { + "ForeName": "Yoshihisa", + "LastName": "Koyama", + "abbrevName": "Koyama Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshihisa Koyama" + }, + { + "ForeName": "Shinsuke", + "LastName": "Matsuzaki", + "abbrevName": "Matsuzaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinsuke Matsuzaki" + }, + { + "ForeName": "Kohei", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kohei Yamada" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Hattori" + }, + { + "ForeName": "Shingo", + "LastName": "Miyata", + "abbrevName": "Miyata S", + "email": null, + "isCollectiveName": false, + "name": "Shingo Miyata" + }, + { + "ForeName": "Kana", + "LastName": "Takemoto", + "abbrevName": "Takemoto K", + "email": null, + "isCollectiveName": false, + "name": "Kana Takemoto" + }, + { + "ForeName": "Masaya", + "LastName": "Tohyama", + "abbrevName": "Tohyama M", + "email": null, + "isCollectiveName": false, + "name": "Masaya Tohyama" + }, + { + "ForeName": "Taiichi", + "LastName": "Katayama", + "abbrevName": "Katayama T", + "email": null, + "isCollectiveName": false, + "name": "Taiichi Katayama" + } + ], + "contacts": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "email": [ + "takamura@ugscd.osaka-u.ac.jp" + ], + "name": "Hironori Takamura" + } + ] + }, + "doi": "10.1371/journal.pone.0051912", + "pmid": "23284813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression." + } + }, + { + "pmid": "30760382", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].", + "authors": { + "abbreviation": "Hyo Min Cho, Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": null, + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "30760382", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "BMB Rep 52 2019", + "title": "The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance." + } + }, + { + "pmid": "27288452", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.", + "authors": { + "abbreviation": "Teisha Y Bradshaw, Lisa E L Romano, Emma J Duncan, ..., J Paul Chapple", + "authorList": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "abbrevName": "Bradshaw TY", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "Lisa", + "LastName": "Romano", + "abbrevName": "Romano LE", + "email": null, + "isCollectiveName": false, + "name": "Lisa E L Romano" + }, + { + "ForeName": "Emma", + "LastName": "Duncan", + "abbrevName": "Duncan EJ", + "email": null, + "isCollectiveName": false, + "name": "Emma J Duncan" + }, + { + "ForeName": "Suran", + "LastName": "Nethisinghe", + "abbrevName": "Nethisinghe S", + "email": null, + "isCollectiveName": false, + "name": "Suran Nethisinghe" + }, + { + "ForeName": "Rosella", + "LastName": "Abeti", + "abbrevName": "Abeti R", + "email": null, + "isCollectiveName": false, + "name": "Rosella Abeti" + }, + { + "ForeName": "Gregory", + "LastName": "Michael", + "abbrevName": "Michael GJ", + "email": null, + "isCollectiveName": false, + "name": "Gregory J Michael" + }, + { + "ForeName": "Paola", + "LastName": "Giunti", + "abbrevName": "Giunti P", + "email": null, + "isCollectiveName": false, + "name": "Paola Giunti" + }, + { + "ForeName": "Sascha", + "LastName": "Vermeer", + "abbrevName": "Vermeer S", + "email": null, + "isCollectiveName": false, + "name": "Sascha Vermeer" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "abbrevName": "Chapple JP", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "J Paul Chapple" + } + ], + "contacts": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "J Paul Chapple" + } + ] + }, + "doi": "10.1093/hmg/ddw173", + "pmid": "27288452", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay." + } + }, + { + "pmid": "28363867", + "pubmed": { + "ISODate": "2017-05-13T00:00:00.000Z", + "abstract": "Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin-related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1.", + "authors": { + "abbreviation": "Mai-Tram Vo, Myoung Seok Ko, Unn Hwa Lee, ..., Jeong Woo Park", + "authorList": [ + { + "ForeName": "Mai-Tram", + "LastName": "Vo", + "abbrevName": "Vo MT", + "email": null, + "isCollectiveName": false, + "name": "Mai-Tram Vo" + }, + { + "ForeName": "Myoung", + "LastName": "Ko", + "abbrevName": "Ko MS", + "email": null, + "isCollectiveName": false, + "name": "Myoung Seok Ko" + }, + { + "ForeName": "Unn", + "LastName": "Lee", + "abbrevName": "Lee UH", + "email": null, + "isCollectiveName": false, + "name": "Unn Hwa Lee" + }, + { + "ForeName": "Eun", + "LastName": "Yoon", + "abbrevName": "Yoon EH", + "email": null, + "isCollectiveName": false, + "name": "Eun Hye Yoon" + }, + { + "ForeName": "Byung", + "LastName": "Lee", + "abbrevName": "Lee BJ", + "email": null, + "isCollectiveName": false, + "name": "Byung Ju Lee" + }, + { + "ForeName": "Wha", + "LastName": "Cho", + "abbrevName": "Cho WJ", + "email": null, + "isCollectiveName": false, + "name": "Wha Ja Cho" + }, + { + "ForeName": "Chang", + "LastName": "Ha", + "abbrevName": "Ha CM", + "email": null, + "isCollectiveName": false, + "name": "Chang Man Ha" + }, + { + "ForeName": "Kyungjin", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyungjin Kim" + }, + { + "ForeName": "Jeong", + "LastName": "Park", + "abbrevName": "Park JW", + "email": "jwpark@ulsan.ac.kr", + "isCollectiveName": false, + "name": "Jeong Woo Park" + } + ], + "contacts": [ + { + "ForeName": "Jeong", + "LastName": "Park", + "email": [ + "jwpark@ulsan.ac.kr" + ], + "name": "Jeong Woo Park" + } + ] + }, + "doi": "10.1016/j.bbrc.2017.03.154", + "pmid": "28363867", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochem Biophys Res Commun 486 2017", + "title": "Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1." + } + }, + { + "pmid": "18838687", + "pubmed": { + "ISODate": "2008-10-14T00:00:00.000Z", + "abstract": "Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.", + "authors": { + "abbreviation": "G M Cereghetti, A Stangherlin, O Martins de Brito, ..., L Scorrano", + "authorList": [ + { + "ForeName": "G", + "LastName": "Cereghetti", + "abbrevName": "Cereghetti GM", + "email": null, + "isCollectiveName": false, + "name": "G M Cereghetti" + }, + { + "ForeName": "A", + "LastName": "Stangherlin", + "abbrevName": "Stangherlin A", + "email": null, + "isCollectiveName": false, + "name": "A Stangherlin" + }, + { + "ForeName": "O", + "LastName": "Martins de Brito", + "abbrevName": "Martins de Brito O", + "email": null, + "isCollectiveName": false, + "name": "O Martins de Brito" + }, + { + "ForeName": "C", + "LastName": "Chang", + "abbrevName": "Chang CR", + "email": null, + "isCollectiveName": false, + "name": "C R Chang" + }, + { + "ForeName": "C", + "LastName": "Blackstone", + "abbrevName": "Blackstone C", + "email": null, + "isCollectiveName": false, + "name": "C Blackstone" + }, + { + "ForeName": "P", + "LastName": "Bernardi", + "abbrevName": "Bernardi P", + "email": null, + "isCollectiveName": false, + "name": "P Bernardi" + }, + { + "ForeName": "L", + "LastName": "Scorrano", + "abbrevName": "Scorrano L", + "email": null, + "isCollectiveName": false, + "name": "L Scorrano" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0808249105", + "pmid": "18838687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 105 2008", + "title": "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." + } + }, + { + "pmid": "33734301", + "pubmed": { + "ISODate": "2021-04-05T00:00:00.000Z", + "abstract": "Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.", + "authors": { + "abbreviation": "Yanfang Chen, Romane Leboutet, Céline Largeau, ..., Renaud Legouis", + "authorList": [ + { + "ForeName": "Yanfang", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfang Chen" + }, + { + "ForeName": "Romane", + "LastName": "Leboutet", + "abbrevName": "Leboutet R", + "email": null, + "isCollectiveName": false, + "name": "Romane Leboutet" + }, + { + "ForeName": "Céline", + "LastName": "Largeau", + "abbrevName": "Largeau C", + "email": null, + "isCollectiveName": false, + "name": "Céline Largeau" + }, + { + "ForeName": "Siham", + "LastName": "Zentout", + "abbrevName": "Zentout S", + "email": null, + "isCollectiveName": false, + "name": "Siham Zentout" + }, + { + "ForeName": "Christophe", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Lefebvre" + }, + { + "ForeName": "Agnès", + "LastName": "Delahodde", + "abbrevName": "Delahodde A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Delahodde" + }, + { + "ForeName": "Emmanuel", + "LastName": "Culetto", + "abbrevName": "Culetto E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Culetto" + }, + { + "ForeName": "Renaud", + "LastName": "Legouis", + "abbrevName": "Legouis R", + "email": null, + "isCollectiveName": false, + "name": "Renaud Legouis" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201909139", + "pmid": "33734301", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process." + } + } + ], + "secret": "read-only", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2020-11-09T16:03:07.191Z", + "_newestOpId": "cbeb6d9d-711b-4f45-b60b-7bf954293de1", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "fa615793-b1ec-410a-a426-75a4a1d34cff" + }, + { + "id": "12e5cc51-1be3-4ea7-8d24-af343658668e" + } + ], + "id": "01b1b41a-db22-4247-a2b9-4c24bee7f4c4", + "liveId": "7d919b68-5863-4b75-8556-addbacb01d60", + "lock": null, + "locked": false, + "name": "Zip1-MCU", + "position": { + "x": 127.84810126582275, + "y": 197.9746835443038 + }, + "relatedPapers": [ + { + "pmid": "27050458", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact \"coupling\" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the \"coupling\" across the double membrane for mitochondrial dynamics and quality control. ", + "authors": { + "abbreviation": "Ming Chen, Ziheng Chen, Yueying Wang, ..., Quan Chen", + "authorList": [ + { + "ForeName": "Ming", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Ming Chen" + }, + { + "ForeName": "Ziheng", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Ziheng Chen" + }, + { + "ForeName": "Yueying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yueying Wang" + }, + { + "ForeName": "Zheng", + "LastName": "Tan", + "abbrevName": "Tan Z", + "email": null, + "isCollectiveName": false, + "name": "Zheng Tan" + }, + { + "ForeName": "Chongzhuo", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Chongzhuo Zhu" + }, + { + "ForeName": "Yanjun", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanjun Li" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Linbo", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Linbo Chen" + }, + { + "ForeName": "Ruize", + "LastName": "Gao", + "abbrevName": "Gao R", + "email": null, + "isCollectiveName": false, + "name": "Ruize Gao" + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu" + }, + { + "ForeName": "Quan", + "LastName": "Chen", + "abbrevName": "Chen Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Chen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2016.1151580", + "pmid": "27050458", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 12 2016", + "title": "Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy." + } + }, + { + "pmid": "33851959", + "pubmed": { + "ISODate": "2021-06-07T00:00:00.000Z", + "abstract": "Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (\"mosaic distribution\"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.", + "authors": { + "abbreviation": "Yumiko Oshima, Etienne Cartier, Liron Boyman, ..., Mariusz Karbowski", + "authorList": [ + { + "ForeName": "Yumiko", + "LastName": "Oshima", + "abbrevName": "Oshima Y", + "email": null, + "isCollectiveName": false, + "name": "Yumiko Oshima" + }, + { + "ForeName": "Etienne", + "LastName": "Cartier", + "abbrevName": "Cartier E", + "email": null, + "isCollectiveName": false, + "name": "Etienne Cartier" + }, + { + "ForeName": "Liron", + "LastName": "Boyman", + "abbrevName": "Boyman L", + "email": null, + "isCollectiveName": false, + "name": "Liron Boyman" + }, + { + "ForeName": "Nicolas", + "LastName": "Verhoeven", + "abbrevName": "Verhoeven N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Verhoeven" + }, + { + "ForeName": "Brian", + "LastName": "Polster", + "abbrevName": "Polster BM", + "email": null, + "isCollectiveName": false, + "name": "Brian M Polster" + }, + { + "ForeName": "Weiliang", + "LastName": "Huang", + "abbrevName": "Huang W", + "email": null, + "isCollectiveName": false, + "name": "Weiliang Huang" + }, + { + "ForeName": "Maureen", + "LastName": "Kane", + "abbrevName": "Kane M", + "email": null, + "isCollectiveName": false, + "name": "Maureen Kane" + }, + { + "ForeName": "W", + "LastName": "Lederer", + "abbrevName": "Lederer WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jonathan Lederer" + }, + { + "ForeName": "Mariusz", + "LastName": "Karbowski", + "abbrevName": "Karbowski M", + "email": null, + "isCollectiveName": false, + "name": "Mariusz Karbowski" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202006043", + "pmid": "33851959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination." + } + }, + { + "pmid": "18838687", + "pubmed": { + "ISODate": "2008-10-14T00:00:00.000Z", + "abstract": "Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.", + "authors": { + "abbreviation": "G M Cereghetti, A Stangherlin, O Martins de Brito, ..., L Scorrano", + "authorList": [ + { + "ForeName": "G", + "LastName": "Cereghetti", + "abbrevName": "Cereghetti GM", + "email": null, + "isCollectiveName": false, + "name": "G M Cereghetti" + }, + { + "ForeName": "A", + "LastName": "Stangherlin", + "abbrevName": "Stangherlin A", + "email": null, + "isCollectiveName": false, + "name": "A Stangherlin" + }, + { + "ForeName": "O", + "LastName": "Martins de Brito", + "abbrevName": "Martins de Brito O", + "email": null, + "isCollectiveName": false, + "name": "O Martins de Brito" + }, + { + "ForeName": "C", + "LastName": "Chang", + "abbrevName": "Chang CR", + "email": null, + "isCollectiveName": false, + "name": "C R Chang" + }, + { + "ForeName": "C", + "LastName": "Blackstone", + "abbrevName": "Blackstone C", + "email": null, + "isCollectiveName": false, + "name": "C Blackstone" + }, + { + "ForeName": "P", + "LastName": "Bernardi", + "abbrevName": "Bernardi P", + "email": null, + "isCollectiveName": false, + "name": "P Bernardi" + }, + { + "ForeName": "L", + "LastName": "Scorrano", + "abbrevName": "Scorrano L", + "email": null, + "isCollectiveName": false, + "name": "L Scorrano" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0808249105", + "pmid": "18838687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 105 2008", + "title": "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." + } + }, + { + "pmid": "30760382", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].", + "authors": { + "abbreviation": "Hyo Min Cho, Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": null, + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "30760382", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "BMB Rep 52 2019", + "title": "The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance." + } + }, + { + "pmid": "30581142", + "pubmed": { + "ISODate": "2019-01-17T00:00:00.000Z", + "abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "authors": { + "abbreviation": "Hyo Min Cho, Jae Ryun Ryu, Youhwa Jo, ..., Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Jae", + "LastName": "Ryu", + "abbrevName": "Ryu JR", + "email": null, + "isCollectiveName": false, + "name": "Jae Ryun Ryu" + }, + { + "ForeName": "Youhwa", + "LastName": "Jo", + "abbrevName": "Jo Y", + "email": null, + "isCollectiveName": false, + "name": "Youhwa Jo" + }, + { + "ForeName": "Tae", + "LastName": "Seo", + "abbrevName": "Seo TW", + "email": null, + "isCollectiveName": false, + "name": "Tae Woong Seo" + }, + { + "ForeName": "Ye", + "LastName": "Choi", + "abbrevName": "Choi YN", + "email": null, + "isCollectiveName": false, + "name": "Ye Na Choi" + }, + { + "ForeName": "June", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": null, + "isCollectiveName": false, + "name": "June Hoan Kim" + }, + { + "ForeName": "Jee", + "LastName": "Chung", + "abbrevName": "Chung JM", + "email": null, + "isCollectiveName": false, + "name": "Jee Min Chung" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho" + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo" + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [ + { + "ForeName": "Woong", + "LastName": "Sun", + "email": [ + "woongsun@korea.ac.kr" + ], + "name": "Woong Sun" + } + ] + }, + "doi": "10.1016/j.molcel.2018.11.009", + "pmid": "30581142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 73 2019", + "title": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System." + } + }, + { + "pmid": "33734301", + "pubmed": { + "ISODate": "2021-04-05T00:00:00.000Z", + "abstract": "Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.", + "authors": { + "abbreviation": "Yanfang Chen, Romane Leboutet, Céline Largeau, ..., Renaud Legouis", + "authorList": [ + { + "ForeName": "Yanfang", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfang Chen" + }, + { + "ForeName": "Romane", + "LastName": "Leboutet", + "abbrevName": "Leboutet R", + "email": null, + "isCollectiveName": false, + "name": "Romane Leboutet" + }, + { + "ForeName": "Céline", + "LastName": "Largeau", + "abbrevName": "Largeau C", + "email": null, + "isCollectiveName": false, + "name": "Céline Largeau" + }, + { + "ForeName": "Siham", + "LastName": "Zentout", + "abbrevName": "Zentout S", + "email": null, + "isCollectiveName": false, + "name": "Siham Zentout" + }, + { + "ForeName": "Christophe", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Lefebvre" + }, + { + "ForeName": "Agnès", + "LastName": "Delahodde", + "abbrevName": "Delahodde A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Delahodde" + }, + { + "ForeName": "Emmanuel", + "LastName": "Culetto", + "abbrevName": "Culetto E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Culetto" + }, + { + "ForeName": "Renaud", + "LastName": "Legouis", + "abbrevName": "Legouis R", + "email": null, + "isCollectiveName": false, + "name": "Renaud Legouis" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201909139", + "pmid": "33734301", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process." + } + }, + { + "pmid": "23284813", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.", + "authors": { + "abbreviation": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, ..., Taiichi Katayama", + "authorList": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "abbrevName": "Takamura H", + "email": "takamura@ugscd.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Hironori Takamura" + }, + { + "ForeName": "Yoshihisa", + "LastName": "Koyama", + "abbrevName": "Koyama Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshihisa Koyama" + }, + { + "ForeName": "Shinsuke", + "LastName": "Matsuzaki", + "abbrevName": "Matsuzaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinsuke Matsuzaki" + }, + { + "ForeName": "Kohei", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kohei Yamada" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Hattori" + }, + { + "ForeName": "Shingo", + "LastName": "Miyata", + "abbrevName": "Miyata S", + "email": null, + "isCollectiveName": false, + "name": "Shingo Miyata" + }, + { + "ForeName": "Kana", + "LastName": "Takemoto", + "abbrevName": "Takemoto K", + "email": null, + "isCollectiveName": false, + "name": "Kana Takemoto" + }, + { + "ForeName": "Masaya", + "LastName": "Tohyama", + "abbrevName": "Tohyama M", + "email": null, + "isCollectiveName": false, + "name": "Masaya Tohyama" + }, + { + "ForeName": "Taiichi", + "LastName": "Katayama", + "abbrevName": "Katayama T", + "email": null, + "isCollectiveName": false, + "name": "Taiichi Katayama" + } + ], + "contacts": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "email": [ + "takamura@ugscd.osaka-u.ac.jp" + ], + "name": "Hironori Takamura" + } + ] + }, + "doi": "10.1371/journal.pone.0051912", + "pmid": "23284813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression." + } + }, + { + "pmid": "27288452", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.", + "authors": { + "abbreviation": "Teisha Y Bradshaw, Lisa E L Romano, Emma J Duncan, ..., J Paul Chapple", + "authorList": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "abbrevName": "Bradshaw TY", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "Lisa", + "LastName": "Romano", + "abbrevName": "Romano LE", + "email": null, + "isCollectiveName": false, + "name": "Lisa E L Romano" + }, + { + "ForeName": "Emma", + "LastName": "Duncan", + "abbrevName": "Duncan EJ", + "email": null, + "isCollectiveName": false, + "name": "Emma J Duncan" + }, + { + "ForeName": "Suran", + "LastName": "Nethisinghe", + "abbrevName": "Nethisinghe S", + "email": null, + "isCollectiveName": false, + "name": "Suran Nethisinghe" + }, + { + "ForeName": "Rosella", + "LastName": "Abeti", + "abbrevName": "Abeti R", + "email": null, + "isCollectiveName": false, + "name": "Rosella Abeti" + }, + { + "ForeName": "Gregory", + "LastName": "Michael", + "abbrevName": "Michael GJ", + "email": null, + "isCollectiveName": false, + "name": "Gregory J Michael" + }, + { + "ForeName": "Paola", + "LastName": "Giunti", + "abbrevName": "Giunti P", + "email": null, + "isCollectiveName": false, + "name": "Paola Giunti" + }, + { + "ForeName": "Sascha", + "LastName": "Vermeer", + "abbrevName": "Vermeer S", + "email": null, + "isCollectiveName": false, + "name": "Sascha Vermeer" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "abbrevName": "Chapple JP", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "J Paul Chapple" + } + ], + "contacts": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "J Paul Chapple" + } + ] + }, + "doi": "10.1093/hmg/ddw173", + "pmid": "27288452", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay." + } + }, + { + "pmid": "28363867", + "pubmed": { + "ISODate": "2017-05-13T00:00:00.000Z", + "abstract": "Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin-related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1.", + "authors": { + "abbreviation": "Mai-Tram Vo, Myoung Seok Ko, Unn Hwa Lee, ..., Jeong Woo Park", + "authorList": [ + { + "ForeName": "Mai-Tram", + "LastName": "Vo", + "abbrevName": "Vo MT", + "email": null, + "isCollectiveName": false, + "name": "Mai-Tram Vo" + }, + { + "ForeName": "Myoung", + "LastName": "Ko", + "abbrevName": "Ko MS", + "email": null, + "isCollectiveName": false, + "name": "Myoung Seok Ko" + }, + { + "ForeName": "Unn", + "LastName": "Lee", + "abbrevName": "Lee UH", + "email": null, + "isCollectiveName": false, + "name": "Unn Hwa Lee" + }, + { + "ForeName": "Eun", + "LastName": "Yoon", + "abbrevName": "Yoon EH", + "email": null, + "isCollectiveName": false, + "name": "Eun Hye Yoon" + }, + { + "ForeName": "Byung", + "LastName": "Lee", + "abbrevName": "Lee BJ", + "email": null, + "isCollectiveName": false, + "name": "Byung Ju Lee" + }, + { + "ForeName": "Wha", + "LastName": "Cho", + "abbrevName": "Cho WJ", + "email": null, + "isCollectiveName": false, + "name": "Wha Ja Cho" + }, + { + "ForeName": "Chang", + "LastName": "Ha", + "abbrevName": "Ha CM", + "email": null, + "isCollectiveName": false, + "name": "Chang Man Ha" + }, + { + "ForeName": "Kyungjin", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyungjin Kim" + }, + { + "ForeName": "Jeong", + "LastName": "Park", + "abbrevName": "Park JW", + "email": "jwpark@ulsan.ac.kr", + "isCollectiveName": false, + "name": "Jeong Woo Park" + } + ], + "contacts": [ + { + "ForeName": "Jeong", + "LastName": "Park", + "email": [ + "jwpark@ulsan.ac.kr" + ], + "name": "Jeong Woo Park" + } + ] + }, + "doi": "10.1016/j.bbrc.2017.03.154", + "pmid": "28363867", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochem Biophys Res Commun 486 2017", + "title": "Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1." + } + }, + { + "pmid": "32529373", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Dynamin-like protein 1 (Drp1) is the master regulator of mitochondrial fission. Drp1 translocates from the cytosol to the mitochondrial outer membrane to execute the scission process. Here we describe an immunofluorescence-based method to measure the mitochondrial translocation of Drp1 and quantify Drp1-related mitochondrial fission by labeling the mitochondrial import receptor subunit TOM20 in fixed cell culture.", + "authors": { + "abbreviation": "Di Hu, Xin Qi", + "authorList": [ + { + "ForeName": "Di", + "LastName": "Hu", + "abbrevName": "Hu D", + "email": null, + "isCollectiveName": false, + "name": "Di Hu" + }, + { + "ForeName": "Xin", + "LastName": "Qi", + "abbrevName": "Qi X", + "email": "xxq38@case.edu", + "isCollectiveName": false, + "name": "Xin Qi" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Qi", + "email": [ + "xxq38@case.edu" + ], + "name": "Xin Qi" + } + ] + }, + "doi": "10.1007/978-1-0716-0676-6_15", + "pmid": "32529373", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Methods Mol Biol 2159 2020", + "title": "Quantifying Drp1-Mediated Mitochondrial Fission by Immunostaining in Fixed Cells." + } + } + ], + "secret": "read-only", + "type": "complex" + }, + { + "_creationTimestamp": "2020-11-09T16:02:38.346Z", + "_newestOpId": "831e5195-080a-4210-984a-930ecef19ca2", + "_ops": [], + "association": { + "charge": 0, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "614197" + }, + { + "db": "HGNC", + "id": "HGNC:23526" + }, + { + "db": "Ensembl", + "id": "ENSG00000156026" + } + ], + "defaultOrganismIndex": 1, + "distance": 0, + "esScore": 11.250178, + "formulae": [ + "C21H16" + ], + "id": "90550", + "inchi": "InChI=1S/C21H16/c1-13-6-7-15-12-20-17-5-3-2-4-14(17)8-9-18(20)19-11-10-16(13)21(15)19/h2-9,12H,10-11H2,1H3", + "inchiKey": "PPQNQXQZIWHJRB-UHFFFAOYSA-N", + "mass": 268.35174, + "monoisotopicMass": 268.1252, + "name": "MCU", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "C10orf42", + "CCDC109A", + "HsMCU", + "calcium uniporter protein, mitochondrial", + "coiled-coil domain-containing protein 109A", + "mitochondrial calcium uniporter" + ], + "summary": "A pentacyclic ortho- and peri-fused polycyclic arene consisting of a dihydrocyclopenta[ij]tetraphene ring system with a methyl substituent at the 3-position.", + "synonyms": [ + "C10orf42", + "CCDC109A", + "HsMCU", + "calcium uniporter protein, mitochondrial", + "coiled-coil domain-containing protein 109A", + "mitochondrial calcium uniporter" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "fa615793-b1ec-410a-a426-75a4a1d34cff", + "liveId": "3cc4799e-67ec-4c10-aa49-eeb0881facf7", + "lock": null, + "locked": false, + "name": "MCU", + "parentId": "01b1b41a-db22-4247-a2b9-4c24bee7f4c4", + "position": { + "x": 145.31645569620247, + "y": 163.5443037974684 + }, + "relatedPapers": [ + { + "pmid": "30760382", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].", + "authors": { + "abbreviation": "Hyo Min Cho, Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": null, + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "30760382", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "BMB Rep 52 2019", + "title": "The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance." + } + }, + { + "pmid": "27050458", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact \"coupling\" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the \"coupling\" across the double membrane for mitochondrial dynamics and quality control. ", + "authors": { + "abbreviation": "Ming Chen, Ziheng Chen, Yueying Wang, ..., Quan Chen", + "authorList": [ + { + "ForeName": "Ming", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Ming Chen" + }, + { + "ForeName": "Ziheng", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Ziheng Chen" + }, + { + "ForeName": "Yueying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yueying Wang" + }, + { + "ForeName": "Zheng", + "LastName": "Tan", + "abbrevName": "Tan Z", + "email": null, + "isCollectiveName": false, + "name": "Zheng Tan" + }, + { + "ForeName": "Chongzhuo", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Chongzhuo Zhu" + }, + { + "ForeName": "Yanjun", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanjun Li" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Linbo", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Linbo Chen" + }, + { + "ForeName": "Ruize", + "LastName": "Gao", + "abbrevName": "Gao R", + "email": null, + "isCollectiveName": false, + "name": "Ruize Gao" + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu" + }, + { + "ForeName": "Quan", + "LastName": "Chen", + "abbrevName": "Chen Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Chen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2016.1151580", + "pmid": "27050458", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 12 2016", + "title": "Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy." + } + }, + { + "pmid": "23284813", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.", + "authors": { + "abbreviation": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, ..., Taiichi Katayama", + "authorList": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "abbrevName": "Takamura H", + "email": "takamura@ugscd.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Hironori Takamura" + }, + { + "ForeName": "Yoshihisa", + "LastName": "Koyama", + "abbrevName": "Koyama Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshihisa Koyama" + }, + { + "ForeName": "Shinsuke", + "LastName": "Matsuzaki", + "abbrevName": "Matsuzaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinsuke Matsuzaki" + }, + { + "ForeName": "Kohei", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kohei Yamada" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Hattori" + }, + { + "ForeName": "Shingo", + "LastName": "Miyata", + "abbrevName": "Miyata S", + "email": null, + "isCollectiveName": false, + "name": "Shingo Miyata" + }, + { + "ForeName": "Kana", + "LastName": "Takemoto", + "abbrevName": "Takemoto K", + "email": null, + "isCollectiveName": false, + "name": "Kana Takemoto" + }, + { + "ForeName": "Masaya", + "LastName": "Tohyama", + "abbrevName": "Tohyama M", + "email": null, + "isCollectiveName": false, + "name": "Masaya Tohyama" + }, + { + "ForeName": "Taiichi", + "LastName": "Katayama", + "abbrevName": "Katayama T", + "email": null, + "isCollectiveName": false, + "name": "Taiichi Katayama" + } + ], + "contacts": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "email": [ + "takamura@ugscd.osaka-u.ac.jp" + ], + "name": "Hironori Takamura" + } + ] + }, + "doi": "10.1371/journal.pone.0051912", + "pmid": "23284813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression." + } + }, + { + "pmid": "33734301", + "pubmed": { + "ISODate": "2021-04-05T00:00:00.000Z", + "abstract": "Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.", + "authors": { + "abbreviation": "Yanfang Chen, Romane Leboutet, Céline Largeau, ..., Renaud Legouis", + "authorList": [ + { + "ForeName": "Yanfang", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfang Chen" + }, + { + "ForeName": "Romane", + "LastName": "Leboutet", + "abbrevName": "Leboutet R", + "email": null, + "isCollectiveName": false, + "name": "Romane Leboutet" + }, + { + "ForeName": "Céline", + "LastName": "Largeau", + "abbrevName": "Largeau C", + "email": null, + "isCollectiveName": false, + "name": "Céline Largeau" + }, + { + "ForeName": "Siham", + "LastName": "Zentout", + "abbrevName": "Zentout S", + "email": null, + "isCollectiveName": false, + "name": "Siham Zentout" + }, + { + "ForeName": "Christophe", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Lefebvre" + }, + { + "ForeName": "Agnès", + "LastName": "Delahodde", + "abbrevName": "Delahodde A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Delahodde" + }, + { + "ForeName": "Emmanuel", + "LastName": "Culetto", + "abbrevName": "Culetto E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Culetto" + }, + { + "ForeName": "Renaud", + "LastName": "Legouis", + "abbrevName": "Legouis R", + "email": null, + "isCollectiveName": false, + "name": "Renaud Legouis" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201909139", + "pmid": "33734301", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process." + } + }, + { + "pmid": "28363867", + "pubmed": { + "ISODate": "2017-05-13T00:00:00.000Z", + "abstract": "Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin-related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1.", + "authors": { + "abbreviation": "Mai-Tram Vo, Myoung Seok Ko, Unn Hwa Lee, ..., Jeong Woo Park", + "authorList": [ + { + "ForeName": "Mai-Tram", + "LastName": "Vo", + "abbrevName": "Vo MT", + "email": null, + "isCollectiveName": false, + "name": "Mai-Tram Vo" + }, + { + "ForeName": "Myoung", + "LastName": "Ko", + "abbrevName": "Ko MS", + "email": null, + "isCollectiveName": false, + "name": "Myoung Seok Ko" + }, + { + "ForeName": "Unn", + "LastName": "Lee", + "abbrevName": "Lee UH", + "email": null, + "isCollectiveName": false, + "name": "Unn Hwa Lee" + }, + { + "ForeName": "Eun", + "LastName": "Yoon", + "abbrevName": "Yoon EH", + "email": null, + "isCollectiveName": false, + "name": "Eun Hye Yoon" + }, + { + "ForeName": "Byung", + "LastName": "Lee", + "abbrevName": "Lee BJ", + "email": null, + "isCollectiveName": false, + "name": "Byung Ju Lee" + }, + { + "ForeName": "Wha", + "LastName": "Cho", + "abbrevName": "Cho WJ", + "email": null, + "isCollectiveName": false, + "name": "Wha Ja Cho" + }, + { + "ForeName": "Chang", + "LastName": "Ha", + "abbrevName": "Ha CM", + "email": null, + "isCollectiveName": false, + "name": "Chang Man Ha" + }, + { + "ForeName": "Kyungjin", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyungjin Kim" + }, + { + "ForeName": "Jeong", + "LastName": "Park", + "abbrevName": "Park JW", + "email": "jwpark@ulsan.ac.kr", + "isCollectiveName": false, + "name": "Jeong Woo Park" + } + ], + "contacts": [ + { + "ForeName": "Jeong", + "LastName": "Park", + "email": [ + "jwpark@ulsan.ac.kr" + ], + "name": "Jeong Woo Park" + } + ] + }, + "doi": "10.1016/j.bbrc.2017.03.154", + "pmid": "28363867", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochem Biophys Res Commun 486 2017", + "title": "Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1." + } + }, + { + "pmid": "33851959", + "pubmed": { + "ISODate": "2021-06-07T00:00:00.000Z", + "abstract": "Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (\"mosaic distribution\"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.", + "authors": { + "abbreviation": "Yumiko Oshima, Etienne Cartier, Liron Boyman, ..., Mariusz Karbowski", + "authorList": [ + { + "ForeName": "Yumiko", + "LastName": "Oshima", + "abbrevName": "Oshima Y", + "email": null, + "isCollectiveName": false, + "name": "Yumiko Oshima" + }, + { + "ForeName": "Etienne", + "LastName": "Cartier", + "abbrevName": "Cartier E", + "email": null, + "isCollectiveName": false, + "name": "Etienne Cartier" + }, + { + "ForeName": "Liron", + "LastName": "Boyman", + "abbrevName": "Boyman L", + "email": null, + "isCollectiveName": false, + "name": "Liron Boyman" + }, + { + "ForeName": "Nicolas", + "LastName": "Verhoeven", + "abbrevName": "Verhoeven N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Verhoeven" + }, + { + "ForeName": "Brian", + "LastName": "Polster", + "abbrevName": "Polster BM", + "email": null, + "isCollectiveName": false, + "name": "Brian M Polster" + }, + { + "ForeName": "Weiliang", + "LastName": "Huang", + "abbrevName": "Huang W", + "email": null, + "isCollectiveName": false, + "name": "Weiliang Huang" + }, + { + "ForeName": "Maureen", + "LastName": "Kane", + "abbrevName": "Kane M", + "email": null, + "isCollectiveName": false, + "name": "Maureen Kane" + }, + { + "ForeName": "W", + "LastName": "Lederer", + "abbrevName": "Lederer WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jonathan Lederer" + }, + { + "ForeName": "Mariusz", + "LastName": "Karbowski", + "abbrevName": "Karbowski M", + "email": null, + "isCollectiveName": false, + "name": "Mariusz Karbowski" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202006043", + "pmid": "33851959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination." + } + }, + { + "pmid": "30581142", + "pubmed": { + "ISODate": "2019-01-17T00:00:00.000Z", + "abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "authors": { + "abbreviation": "Hyo Min Cho, Jae Ryun Ryu, Youhwa Jo, ..., Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Jae", + "LastName": "Ryu", + "abbrevName": "Ryu JR", + "email": null, + "isCollectiveName": false, + "name": "Jae Ryun Ryu" + }, + { + "ForeName": "Youhwa", + "LastName": "Jo", + "abbrevName": "Jo Y", + "email": null, + "isCollectiveName": false, + "name": "Youhwa Jo" + }, + { + "ForeName": "Tae", + "LastName": "Seo", + "abbrevName": "Seo TW", + "email": null, + "isCollectiveName": false, + "name": "Tae Woong Seo" + }, + { + "ForeName": "Ye", + "LastName": "Choi", + "abbrevName": "Choi YN", + "email": null, + "isCollectiveName": false, + "name": "Ye Na Choi" + }, + { + "ForeName": "June", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": null, + "isCollectiveName": false, + "name": "June Hoan Kim" + }, + { + "ForeName": "Jee", + "LastName": "Chung", + "abbrevName": "Chung JM", + "email": null, + "isCollectiveName": false, + "name": "Jee Min Chung" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho" + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo" + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [ + { + "ForeName": "Woong", + "LastName": "Sun", + "email": [ + "woongsun@korea.ac.kr" + ], + "name": "Woong Sun" + } + ] + }, + "doi": "10.1016/j.molcel.2018.11.009", + "pmid": "30581142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 73 2019", + "title": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System." + } + }, + { + "pmid": "32529373", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Dynamin-like protein 1 (Drp1) is the master regulator of mitochondrial fission. Drp1 translocates from the cytosol to the mitochondrial outer membrane to execute the scission process. Here we describe an immunofluorescence-based method to measure the mitochondrial translocation of Drp1 and quantify Drp1-related mitochondrial fission by labeling the mitochondrial import receptor subunit TOM20 in fixed cell culture.", + "authors": { + "abbreviation": "Di Hu, Xin Qi", + "authorList": [ + { + "ForeName": "Di", + "LastName": "Hu", + "abbrevName": "Hu D", + "email": null, + "isCollectiveName": false, + "name": "Di Hu" + }, + { + "ForeName": "Xin", + "LastName": "Qi", + "abbrevName": "Qi X", + "email": "xxq38@case.edu", + "isCollectiveName": false, + "name": "Xin Qi" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Qi", + "email": [ + "xxq38@case.edu" + ], + "name": "Xin Qi" + } + ] + }, + "doi": "10.1007/978-1-0716-0676-6_15", + "pmid": "32529373", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Methods Mol Biol 2159 2020", + "title": "Quantifying Drp1-Mediated Mitochondrial Fission by Immunostaining in Fixed Cells." + } + }, + { + "pmid": "27288452", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.", + "authors": { + "abbreviation": "Teisha Y Bradshaw, Lisa E L Romano, Emma J Duncan, ..., J Paul Chapple", + "authorList": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "abbrevName": "Bradshaw TY", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "Lisa", + "LastName": "Romano", + "abbrevName": "Romano LE", + "email": null, + "isCollectiveName": false, + "name": "Lisa E L Romano" + }, + { + "ForeName": "Emma", + "LastName": "Duncan", + "abbrevName": "Duncan EJ", + "email": null, + "isCollectiveName": false, + "name": "Emma J Duncan" + }, + { + "ForeName": "Suran", + "LastName": "Nethisinghe", + "abbrevName": "Nethisinghe S", + "email": null, + "isCollectiveName": false, + "name": "Suran Nethisinghe" + }, + { + "ForeName": "Rosella", + "LastName": "Abeti", + "abbrevName": "Abeti R", + "email": null, + "isCollectiveName": false, + "name": "Rosella Abeti" + }, + { + "ForeName": "Gregory", + "LastName": "Michael", + "abbrevName": "Michael GJ", + "email": null, + "isCollectiveName": false, + "name": "Gregory J Michael" + }, + { + "ForeName": "Paola", + "LastName": "Giunti", + "abbrevName": "Giunti P", + "email": null, + "isCollectiveName": false, + "name": "Paola Giunti" + }, + { + "ForeName": "Sascha", + "LastName": "Vermeer", + "abbrevName": "Vermeer S", + "email": null, + "isCollectiveName": false, + "name": "Sascha Vermeer" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "abbrevName": "Chapple JP", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "J Paul Chapple" + } + ], + "contacts": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "J Paul Chapple" + } + ] + }, + "doi": "10.1093/hmg/ddw173", + "pmid": "27288452", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay." + } + }, + { + "pmid": "18838687", + "pubmed": { + "ISODate": "2008-10-14T00:00:00.000Z", + "abstract": "Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.", + "authors": { + "abbreviation": "G M Cereghetti, A Stangherlin, O Martins de Brito, ..., L Scorrano", + "authorList": [ + { + "ForeName": "G", + "LastName": "Cereghetti", + "abbrevName": "Cereghetti GM", + "email": null, + "isCollectiveName": false, + "name": "G M Cereghetti" + }, + { + "ForeName": "A", + "LastName": "Stangherlin", + "abbrevName": "Stangherlin A", + "email": null, + "isCollectiveName": false, + "name": "A Stangherlin" + }, + { + "ForeName": "O", + "LastName": "Martins de Brito", + "abbrevName": "Martins de Brito O", + "email": null, + "isCollectiveName": false, + "name": "O Martins de Brito" + }, + { + "ForeName": "C", + "LastName": "Chang", + "abbrevName": "Chang CR", + "email": null, + "isCollectiveName": false, + "name": "C R Chang" + }, + { + "ForeName": "C", + "LastName": "Blackstone", + "abbrevName": "Blackstone C", + "email": null, + "isCollectiveName": false, + "name": "C Blackstone" + }, + { + "ForeName": "P", + "LastName": "Bernardi", + "abbrevName": "Bernardi P", + "email": null, + "isCollectiveName": false, + "name": "P Bernardi" + }, + { + "ForeName": "L", + "LastName": "Scorrano", + "abbrevName": "Scorrano L", + "email": null, + "isCollectiveName": false, + "name": "L Scorrano" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0808249105", + "pmid": "18838687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 105 2008", + "title": "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2020-11-09T16:04:36.923Z", + "_newestOpId": "cb2f85d0-48bf-42d7-b6e9-3ce0dd13b8de", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "3ed4ad3e-dab8-4b6d-b488-5c0299421da1" + }, + { + "group": "positive", + "id": "12e5cc51-1be3-4ea7-8d24-af343658668e" + } + ], + "id": "abce49de-663c-4a5b-8bc5-de1ec79a63d7", + "liveId": "425992c5-7b72-422f-bebf-2ebb24e94c91", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 58.01265822784808, + "y": 21.193037974683524 + }, + "relatedPapers": [ + { + "pmid": "18838687", + "pubmed": { + "ISODate": "2008-10-14T00:00:00.000Z", + "abstract": "Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.", + "authors": { + "abbreviation": "G M Cereghetti, A Stangherlin, O Martins de Brito, ..., L Scorrano", + "authorList": [ + { + "ForeName": "G", + "LastName": "Cereghetti", + "abbrevName": "Cereghetti GM", + "email": null, + "isCollectiveName": false, + "name": "G M Cereghetti" + }, + { + "ForeName": "A", + "LastName": "Stangherlin", + "abbrevName": "Stangherlin A", + "email": null, + "isCollectiveName": false, + "name": "A Stangherlin" + }, + { + "ForeName": "O", + "LastName": "Martins de Brito", + "abbrevName": "Martins de Brito O", + "email": null, + "isCollectiveName": false, + "name": "O Martins de Brito" + }, + { + "ForeName": "C", + "LastName": "Chang", + "abbrevName": "Chang CR", + "email": null, + "isCollectiveName": false, + "name": "C R Chang" + }, + { + "ForeName": "C", + "LastName": "Blackstone", + "abbrevName": "Blackstone C", + "email": null, + "isCollectiveName": false, + "name": "C Blackstone" + }, + { + "ForeName": "P", + "LastName": "Bernardi", + "abbrevName": "Bernardi P", + "email": null, + "isCollectiveName": false, + "name": "P Bernardi" + }, + { + "ForeName": "L", + "LastName": "Scorrano", + "abbrevName": "Scorrano L", + "email": null, + "isCollectiveName": false, + "name": "L Scorrano" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0808249105", + "pmid": "18838687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 105 2008", + "title": "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." + } + }, + { + "pmid": "33851959", + "pubmed": { + "ISODate": "2021-06-07T00:00:00.000Z", + "abstract": "Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (\"mosaic distribution\"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.", + "authors": { + "abbreviation": "Yumiko Oshima, Etienne Cartier, Liron Boyman, ..., Mariusz Karbowski", + "authorList": [ + { + "ForeName": "Yumiko", + "LastName": "Oshima", + "abbrevName": "Oshima Y", + "email": null, + "isCollectiveName": false, + "name": "Yumiko Oshima" + }, + { + "ForeName": "Etienne", + "LastName": "Cartier", + "abbrevName": "Cartier E", + "email": null, + "isCollectiveName": false, + "name": "Etienne Cartier" + }, + { + "ForeName": "Liron", + "LastName": "Boyman", + "abbrevName": "Boyman L", + "email": null, + "isCollectiveName": false, + "name": "Liron Boyman" + }, + { + "ForeName": "Nicolas", + "LastName": "Verhoeven", + "abbrevName": "Verhoeven N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Verhoeven" + }, + { + "ForeName": "Brian", + "LastName": "Polster", + "abbrevName": "Polster BM", + "email": null, + "isCollectiveName": false, + "name": "Brian M Polster" + }, + { + "ForeName": "Weiliang", + "LastName": "Huang", + "abbrevName": "Huang W", + "email": null, + "isCollectiveName": false, + "name": "Weiliang Huang" + }, + { + "ForeName": "Maureen", + "LastName": "Kane", + "abbrevName": "Kane M", + "email": null, + "isCollectiveName": false, + "name": "Maureen Kane" + }, + { + "ForeName": "W", + "LastName": "Lederer", + "abbrevName": "Lederer WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jonathan Lederer" + }, + { + "ForeName": "Mariusz", + "LastName": "Karbowski", + "abbrevName": "Karbowski M", + "email": null, + "isCollectiveName": false, + "name": "Mariusz Karbowski" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202006043", + "pmid": "33851959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination." + } + }, + { + "pmid": "33734301", + "pubmed": { + "ISODate": "2021-04-05T00:00:00.000Z", + "abstract": "Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.", + "authors": { + "abbreviation": "Yanfang Chen, Romane Leboutet, Céline Largeau, ..., Renaud Legouis", + "authorList": [ + { + "ForeName": "Yanfang", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfang Chen" + }, + { + "ForeName": "Romane", + "LastName": "Leboutet", + "abbrevName": "Leboutet R", + "email": null, + "isCollectiveName": false, + "name": "Romane Leboutet" + }, + { + "ForeName": "Céline", + "LastName": "Largeau", + "abbrevName": "Largeau C", + "email": null, + "isCollectiveName": false, + "name": "Céline Largeau" + }, + { + "ForeName": "Siham", + "LastName": "Zentout", + "abbrevName": "Zentout S", + "email": null, + "isCollectiveName": false, + "name": "Siham Zentout" + }, + { + "ForeName": "Christophe", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Lefebvre" + }, + { + "ForeName": "Agnès", + "LastName": "Delahodde", + "abbrevName": "Delahodde A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Delahodde" + }, + { + "ForeName": "Emmanuel", + "LastName": "Culetto", + "abbrevName": "Culetto E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Culetto" + }, + { + "ForeName": "Renaud", + "LastName": "Legouis", + "abbrevName": "Legouis R", + "email": null, + "isCollectiveName": false, + "name": "Renaud Legouis" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201909139", + "pmid": "33734301", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process." + } + }, + { + "pmid": "32529373", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Dynamin-like protein 1 (Drp1) is the master regulator of mitochondrial fission. Drp1 translocates from the cytosol to the mitochondrial outer membrane to execute the scission process. Here we describe an immunofluorescence-based method to measure the mitochondrial translocation of Drp1 and quantify Drp1-related mitochondrial fission by labeling the mitochondrial import receptor subunit TOM20 in fixed cell culture.", + "authors": { + "abbreviation": "Di Hu, Xin Qi", + "authorList": [ + { + "ForeName": "Di", + "LastName": "Hu", + "abbrevName": "Hu D", + "email": null, + "isCollectiveName": false, + "name": "Di Hu" + }, + { + "ForeName": "Xin", + "LastName": "Qi", + "abbrevName": "Qi X", + "email": "xxq38@case.edu", + "isCollectiveName": false, + "name": "Xin Qi" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Qi", + "email": [ + "xxq38@case.edu" + ], + "name": "Xin Qi" + } + ] + }, + "doi": "10.1007/978-1-0716-0676-6_15", + "pmid": "32529373", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Methods Mol Biol 2159 2020", + "title": "Quantifying Drp1-Mediated Mitochondrial Fission by Immunostaining in Fixed Cells." + } + }, + { + "pmid": "27288452", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.", + "authors": { + "abbreviation": "Teisha Y Bradshaw, Lisa E L Romano, Emma J Duncan, ..., J Paul Chapple", + "authorList": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "abbrevName": "Bradshaw TY", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "Lisa", + "LastName": "Romano", + "abbrevName": "Romano LE", + "email": null, + "isCollectiveName": false, + "name": "Lisa E L Romano" + }, + { + "ForeName": "Emma", + "LastName": "Duncan", + "abbrevName": "Duncan EJ", + "email": null, + "isCollectiveName": false, + "name": "Emma J Duncan" + }, + { + "ForeName": "Suran", + "LastName": "Nethisinghe", + "abbrevName": "Nethisinghe S", + "email": null, + "isCollectiveName": false, + "name": "Suran Nethisinghe" + }, + { + "ForeName": "Rosella", + "LastName": "Abeti", + "abbrevName": "Abeti R", + "email": null, + "isCollectiveName": false, + "name": "Rosella Abeti" + }, + { + "ForeName": "Gregory", + "LastName": "Michael", + "abbrevName": "Michael GJ", + "email": null, + "isCollectiveName": false, + "name": "Gregory J Michael" + }, + { + "ForeName": "Paola", + "LastName": "Giunti", + "abbrevName": "Giunti P", + "email": null, + "isCollectiveName": false, + "name": "Paola Giunti" + }, + { + "ForeName": "Sascha", + "LastName": "Vermeer", + "abbrevName": "Vermeer S", + "email": null, + "isCollectiveName": false, + "name": "Sascha Vermeer" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "abbrevName": "Chapple JP", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "J Paul Chapple" + } + ], + "contacts": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "J Paul Chapple" + } + ] + }, + "doi": "10.1093/hmg/ddw173", + "pmid": "27288452", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay." + } + }, + { + "pmid": "27050458", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact \"coupling\" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the \"coupling\" across the double membrane for mitochondrial dynamics and quality control. ", + "authors": { + "abbreviation": "Ming Chen, Ziheng Chen, Yueying Wang, ..., Quan Chen", + "authorList": [ + { + "ForeName": "Ming", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Ming Chen" + }, + { + "ForeName": "Ziheng", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Ziheng Chen" + }, + { + "ForeName": "Yueying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yueying Wang" + }, + { + "ForeName": "Zheng", + "LastName": "Tan", + "abbrevName": "Tan Z", + "email": null, + "isCollectiveName": false, + "name": "Zheng Tan" + }, + { + "ForeName": "Chongzhuo", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Chongzhuo Zhu" + }, + { + "ForeName": "Yanjun", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanjun Li" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Linbo", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Linbo Chen" + }, + { + "ForeName": "Ruize", + "LastName": "Gao", + "abbrevName": "Gao R", + "email": null, + "isCollectiveName": false, + "name": "Ruize Gao" + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu" + }, + { + "ForeName": "Quan", + "LastName": "Chen", + "abbrevName": "Chen Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Chen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2016.1151580", + "pmid": "27050458", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 12 2016", + "title": "Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy." + } + }, + { + "pmid": "30581142", + "pubmed": { + "ISODate": "2019-01-17T00:00:00.000Z", + "abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "authors": { + "abbreviation": "Hyo Min Cho, Jae Ryun Ryu, Youhwa Jo, ..., Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Jae", + "LastName": "Ryu", + "abbrevName": "Ryu JR", + "email": null, + "isCollectiveName": false, + "name": "Jae Ryun Ryu" + }, + { + "ForeName": "Youhwa", + "LastName": "Jo", + "abbrevName": "Jo Y", + "email": null, + "isCollectiveName": false, + "name": "Youhwa Jo" + }, + { + "ForeName": "Tae", + "LastName": "Seo", + "abbrevName": "Seo TW", + "email": null, + "isCollectiveName": false, + "name": "Tae Woong Seo" + }, + { + "ForeName": "Ye", + "LastName": "Choi", + "abbrevName": "Choi YN", + "email": null, + "isCollectiveName": false, + "name": "Ye Na Choi" + }, + { + "ForeName": "June", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": null, + "isCollectiveName": false, + "name": "June Hoan Kim" + }, + { + "ForeName": "Jee", + "LastName": "Chung", + "abbrevName": "Chung JM", + "email": null, + "isCollectiveName": false, + "name": "Jee Min Chung" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho" + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo" + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [ + { + "ForeName": "Woong", + "LastName": "Sun", + "email": [ + "woongsun@korea.ac.kr" + ], + "name": "Woong Sun" + } + ] + }, + "doi": "10.1016/j.molcel.2018.11.009", + "pmid": "30581142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 73 2019", + "title": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System." + } + }, + { + "pmid": "23284813", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.", + "authors": { + "abbreviation": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, ..., Taiichi Katayama", + "authorList": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "abbrevName": "Takamura H", + "email": "takamura@ugscd.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Hironori Takamura" + }, + { + "ForeName": "Yoshihisa", + "LastName": "Koyama", + "abbrevName": "Koyama Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshihisa Koyama" + }, + { + "ForeName": "Shinsuke", + "LastName": "Matsuzaki", + "abbrevName": "Matsuzaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinsuke Matsuzaki" + }, + { + "ForeName": "Kohei", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kohei Yamada" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Hattori" + }, + { + "ForeName": "Shingo", + "LastName": "Miyata", + "abbrevName": "Miyata S", + "email": null, + "isCollectiveName": false, + "name": "Shingo Miyata" + }, + { + "ForeName": "Kana", + "LastName": "Takemoto", + "abbrevName": "Takemoto K", + "email": null, + "isCollectiveName": false, + "name": "Kana Takemoto" + }, + { + "ForeName": "Masaya", + "LastName": "Tohyama", + "abbrevName": "Tohyama M", + "email": null, + "isCollectiveName": false, + "name": "Masaya Tohyama" + }, + { + "ForeName": "Taiichi", + "LastName": "Katayama", + "abbrevName": "Katayama T", + "email": null, + "isCollectiveName": false, + "name": "Taiichi Katayama" + } + ], + "contacts": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "email": [ + "takamura@ugscd.osaka-u.ac.jp" + ], + "name": "Hironori Takamura" + } + ] + }, + "doi": "10.1371/journal.pone.0051912", + "pmid": "23284813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression." + } + }, + { + "pmid": "28363867", + "pubmed": { + "ISODate": "2017-05-13T00:00:00.000Z", + "abstract": "Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin-related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1.", + "authors": { + "abbreviation": "Mai-Tram Vo, Myoung Seok Ko, Unn Hwa Lee, ..., Jeong Woo Park", + "authorList": [ + { + "ForeName": "Mai-Tram", + "LastName": "Vo", + "abbrevName": "Vo MT", + "email": null, + "isCollectiveName": false, + "name": "Mai-Tram Vo" + }, + { + "ForeName": "Myoung", + "LastName": "Ko", + "abbrevName": "Ko MS", + "email": null, + "isCollectiveName": false, + "name": "Myoung Seok Ko" + }, + { + "ForeName": "Unn", + "LastName": "Lee", + "abbrevName": "Lee UH", + "email": null, + "isCollectiveName": false, + "name": "Unn Hwa Lee" + }, + { + "ForeName": "Eun", + "LastName": "Yoon", + "abbrevName": "Yoon EH", + "email": null, + "isCollectiveName": false, + "name": "Eun Hye Yoon" + }, + { + "ForeName": "Byung", + "LastName": "Lee", + "abbrevName": "Lee BJ", + "email": null, + "isCollectiveName": false, + "name": "Byung Ju Lee" + }, + { + "ForeName": "Wha", + "LastName": "Cho", + "abbrevName": "Cho WJ", + "email": null, + "isCollectiveName": false, + "name": "Wha Ja Cho" + }, + { + "ForeName": "Chang", + "LastName": "Ha", + "abbrevName": "Ha CM", + "email": null, + "isCollectiveName": false, + "name": "Chang Man Ha" + }, + { + "ForeName": "Kyungjin", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyungjin Kim" + }, + { + "ForeName": "Jeong", + "LastName": "Park", + "abbrevName": "Park JW", + "email": "jwpark@ulsan.ac.kr", + "isCollectiveName": false, + "name": "Jeong Woo Park" + } + ], + "contacts": [ + { + "ForeName": "Jeong", + "LastName": "Park", + "email": [ + "jwpark@ulsan.ac.kr" + ], + "name": "Jeong Woo Park" + } + ] + }, + "doi": "10.1016/j.bbrc.2017.03.154", + "pmid": "28363867", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochem Biophys Res Commun 486 2017", + "title": "Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1." + } + }, + { + "pmid": "30760382", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].", + "authors": { + "abbreviation": "Hyo Min Cho, Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": null, + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "30760382", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "BMB Rep 52 2019", + "title": "The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2020-11-09T16:02:00.467Z", + "_newestOpId": "49505c60-c4b5-4336-aafb-8a3e5609ef10", + "_ops": [], + "association": { + "charge": 0, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "604740" + }, + { + "db": "HGNC", + "id": "HGNC:12876" + }, + { + "db": "Ensembl", + "id": "ENSG00000143570" + } + ], + "defaultOrganismIndex": 1, + "distance": 0, + "esScore": 11.160407, + "formulae": [ + "C6H13NO2" + ], + "id": "27173", + "inchi": "InChI=1S/C6H13NO2/c7-5-3-1-2-4-6(8)9/h1-5,7H2,(H,8,9)", + "inchiKey": "SLXKOJJOQWFEFD-UHFFFAOYSA-N", + "mass": 131.1729, + "monoisotopicMass": 131.09463, + "name": "SLC39A1", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100, + "shortSynonyms": [ + "ZIP1", + "ZIRTL", + "zinc transporter ZIP1", + "solute carrier family 39 (zinc transporter), member 1", + "solute carrier family 39 (zinc transporter), member 3", + "zrt- and Irt-like protein 1", + "solute carrier family 39 member 1" + ], + "summary": "An epsilon-amino acid comprising hexanoic acid carrying an amino substituent at position C-6. Used to control postoperative bleeding, and to treat overdose effects of the thrombolytic agents streptokinase and tissue plasminogen activator.", + "synonyms": [ + "ZIP1", + "ZIRTL", + "zinc transporter ZIP1", + "solute carrier family 39 (zinc transporter), member 1", + "solute carrier family 39 (zinc transporter), member 3", + "zrt- and Irt-like protein 1", + "solute carrier family 39 member 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "12e5cc51-1be3-4ea7-8d24-af343658668e", + "liveId": "eef076ef-9fd4-46f9-92f7-c12df330dcdd", + "lock": null, + "locked": false, + "name": "Zip1", + "parentId": "01b1b41a-db22-4247-a2b9-4c24bee7f4c4", + "position": { + "x": 109.36708860759494, + "y": 163.54430379746833 + }, + "relatedPapers": [ + { + "pmid": "30760382", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].", + "authors": { + "abbreviation": "Hyo Min Cho, Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": null, + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "30760382", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "BMB Rep 52 2019", + "title": "The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance." + } + }, + { + "pmid": "27050458", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact \"coupling\" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the \"coupling\" across the double membrane for mitochondrial dynamics and quality control. ", + "authors": { + "abbreviation": "Ming Chen, Ziheng Chen, Yueying Wang, ..., Quan Chen", + "authorList": [ + { + "ForeName": "Ming", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Ming Chen" + }, + { + "ForeName": "Ziheng", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Ziheng Chen" + }, + { + "ForeName": "Yueying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yueying Wang" + }, + { + "ForeName": "Zheng", + "LastName": "Tan", + "abbrevName": "Tan Z", + "email": null, + "isCollectiveName": false, + "name": "Zheng Tan" + }, + { + "ForeName": "Chongzhuo", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Chongzhuo Zhu" + }, + { + "ForeName": "Yanjun", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanjun Li" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Linbo", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Linbo Chen" + }, + { + "ForeName": "Ruize", + "LastName": "Gao", + "abbrevName": "Gao R", + "email": null, + "isCollectiveName": false, + "name": "Ruize Gao" + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu" + }, + { + "ForeName": "Quan", + "LastName": "Chen", + "abbrevName": "Chen Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Chen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2016.1151580", + "pmid": "27050458", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 12 2016", + "title": "Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy." + } + }, + { + "pmid": "27288452", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.", + "authors": { + "abbreviation": "Teisha Y Bradshaw, Lisa E L Romano, Emma J Duncan, ..., J Paul Chapple", + "authorList": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "abbrevName": "Bradshaw TY", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "Lisa", + "LastName": "Romano", + "abbrevName": "Romano LE", + "email": null, + "isCollectiveName": false, + "name": "Lisa E L Romano" + }, + { + "ForeName": "Emma", + "LastName": "Duncan", + "abbrevName": "Duncan EJ", + "email": null, + "isCollectiveName": false, + "name": "Emma J Duncan" + }, + { + "ForeName": "Suran", + "LastName": "Nethisinghe", + "abbrevName": "Nethisinghe S", + "email": null, + "isCollectiveName": false, + "name": "Suran Nethisinghe" + }, + { + "ForeName": "Rosella", + "LastName": "Abeti", + "abbrevName": "Abeti R", + "email": null, + "isCollectiveName": false, + "name": "Rosella Abeti" + }, + { + "ForeName": "Gregory", + "LastName": "Michael", + "abbrevName": "Michael GJ", + "email": null, + "isCollectiveName": false, + "name": "Gregory J Michael" + }, + { + "ForeName": "Paola", + "LastName": "Giunti", + "abbrevName": "Giunti P", + "email": null, + "isCollectiveName": false, + "name": "Paola Giunti" + }, + { + "ForeName": "Sascha", + "LastName": "Vermeer", + "abbrevName": "Vermeer S", + "email": null, + "isCollectiveName": false, + "name": "Sascha Vermeer" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "abbrevName": "Chapple JP", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "J Paul Chapple" + } + ], + "contacts": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "J Paul Chapple" + } + ] + }, + "doi": "10.1093/hmg/ddw173", + "pmid": "27288452", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay." + } + }, + { + "pmid": "23284813", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.", + "authors": { + "abbreviation": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, ..., Taiichi Katayama", + "authorList": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "abbrevName": "Takamura H", + "email": "takamura@ugscd.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Hironori Takamura" + }, + { + "ForeName": "Yoshihisa", + "LastName": "Koyama", + "abbrevName": "Koyama Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshihisa Koyama" + }, + { + "ForeName": "Shinsuke", + "LastName": "Matsuzaki", + "abbrevName": "Matsuzaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinsuke Matsuzaki" + }, + { + "ForeName": "Kohei", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kohei Yamada" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Hattori" + }, + { + "ForeName": "Shingo", + "LastName": "Miyata", + "abbrevName": "Miyata S", + "email": null, + "isCollectiveName": false, + "name": "Shingo Miyata" + }, + { + "ForeName": "Kana", + "LastName": "Takemoto", + "abbrevName": "Takemoto K", + "email": null, + "isCollectiveName": false, + "name": "Kana Takemoto" + }, + { + "ForeName": "Masaya", + "LastName": "Tohyama", + "abbrevName": "Tohyama M", + "email": null, + "isCollectiveName": false, + "name": "Masaya Tohyama" + }, + { + "ForeName": "Taiichi", + "LastName": "Katayama", + "abbrevName": "Katayama T", + "email": null, + "isCollectiveName": false, + "name": "Taiichi Katayama" + } + ], + "contacts": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "email": [ + "takamura@ugscd.osaka-u.ac.jp" + ], + "name": "Hironori Takamura" + } + ] + }, + "doi": "10.1371/journal.pone.0051912", + "pmid": "23284813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression." + } + }, + { + "pmid": "33851959", + "pubmed": { + "ISODate": "2021-06-07T00:00:00.000Z", + "abstract": "Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (\"mosaic distribution\"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.", + "authors": { + "abbreviation": "Yumiko Oshima, Etienne Cartier, Liron Boyman, ..., Mariusz Karbowski", + "authorList": [ + { + "ForeName": "Yumiko", + "LastName": "Oshima", + "abbrevName": "Oshima Y", + "email": null, + "isCollectiveName": false, + "name": "Yumiko Oshima" + }, + { + "ForeName": "Etienne", + "LastName": "Cartier", + "abbrevName": "Cartier E", + "email": null, + "isCollectiveName": false, + "name": "Etienne Cartier" + }, + { + "ForeName": "Liron", + "LastName": "Boyman", + "abbrevName": "Boyman L", + "email": null, + "isCollectiveName": false, + "name": "Liron Boyman" + }, + { + "ForeName": "Nicolas", + "LastName": "Verhoeven", + "abbrevName": "Verhoeven N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Verhoeven" + }, + { + "ForeName": "Brian", + "LastName": "Polster", + "abbrevName": "Polster BM", + "email": null, + "isCollectiveName": false, + "name": "Brian M Polster" + }, + { + "ForeName": "Weiliang", + "LastName": "Huang", + "abbrevName": "Huang W", + "email": null, + "isCollectiveName": false, + "name": "Weiliang Huang" + }, + { + "ForeName": "Maureen", + "LastName": "Kane", + "abbrevName": "Kane M", + "email": null, + "isCollectiveName": false, + "name": "Maureen Kane" + }, + { + "ForeName": "W", + "LastName": "Lederer", + "abbrevName": "Lederer WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jonathan Lederer" + }, + { + "ForeName": "Mariusz", + "LastName": "Karbowski", + "abbrevName": "Karbowski M", + "email": null, + "isCollectiveName": false, + "name": "Mariusz Karbowski" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202006043", + "pmid": "33851959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination." + } + }, + { + "pmid": "33734301", + "pubmed": { + "ISODate": "2021-04-05T00:00:00.000Z", + "abstract": "Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.", + "authors": { + "abbreviation": "Yanfang Chen, Romane Leboutet, Céline Largeau, ..., Renaud Legouis", + "authorList": [ + { + "ForeName": "Yanfang", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfang Chen" + }, + { + "ForeName": "Romane", + "LastName": "Leboutet", + "abbrevName": "Leboutet R", + "email": null, + "isCollectiveName": false, + "name": "Romane Leboutet" + }, + { + "ForeName": "Céline", + "LastName": "Largeau", + "abbrevName": "Largeau C", + "email": null, + "isCollectiveName": false, + "name": "Céline Largeau" + }, + { + "ForeName": "Siham", + "LastName": "Zentout", + "abbrevName": "Zentout S", + "email": null, + "isCollectiveName": false, + "name": "Siham Zentout" + }, + { + "ForeName": "Christophe", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Lefebvre" + }, + { + "ForeName": "Agnès", + "LastName": "Delahodde", + "abbrevName": "Delahodde A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Delahodde" + }, + { + "ForeName": "Emmanuel", + "LastName": "Culetto", + "abbrevName": "Culetto E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Culetto" + }, + { + "ForeName": "Renaud", + "LastName": "Legouis", + "abbrevName": "Legouis R", + "email": null, + "isCollectiveName": false, + "name": "Renaud Legouis" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201909139", + "pmid": "33734301", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process." + } + }, + { + "pmid": "28363867", + "pubmed": { + "ISODate": "2017-05-13T00:00:00.000Z", + "abstract": "Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin-related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1.", + "authors": { + "abbreviation": "Mai-Tram Vo, Myoung Seok Ko, Unn Hwa Lee, ..., Jeong Woo Park", + "authorList": [ + { + "ForeName": "Mai-Tram", + "LastName": "Vo", + "abbrevName": "Vo MT", + "email": null, + "isCollectiveName": false, + "name": "Mai-Tram Vo" + }, + { + "ForeName": "Myoung", + "LastName": "Ko", + "abbrevName": "Ko MS", + "email": null, + "isCollectiveName": false, + "name": "Myoung Seok Ko" + }, + { + "ForeName": "Unn", + "LastName": "Lee", + "abbrevName": "Lee UH", + "email": null, + "isCollectiveName": false, + "name": "Unn Hwa Lee" + }, + { + "ForeName": "Eun", + "LastName": "Yoon", + "abbrevName": "Yoon EH", + "email": null, + "isCollectiveName": false, + "name": "Eun Hye Yoon" + }, + { + "ForeName": "Byung", + "LastName": "Lee", + "abbrevName": "Lee BJ", + "email": null, + "isCollectiveName": false, + "name": "Byung Ju Lee" + }, + { + "ForeName": "Wha", + "LastName": "Cho", + "abbrevName": "Cho WJ", + "email": null, + "isCollectiveName": false, + "name": "Wha Ja Cho" + }, + { + "ForeName": "Chang", + "LastName": "Ha", + "abbrevName": "Ha CM", + "email": null, + "isCollectiveName": false, + "name": "Chang Man Ha" + }, + { + "ForeName": "Kyungjin", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyungjin Kim" + }, + { + "ForeName": "Jeong", + "LastName": "Park", + "abbrevName": "Park JW", + "email": "jwpark@ulsan.ac.kr", + "isCollectiveName": false, + "name": "Jeong Woo Park" + } + ], + "contacts": [ + { + "ForeName": "Jeong", + "LastName": "Park", + "email": [ + "jwpark@ulsan.ac.kr" + ], + "name": "Jeong Woo Park" + } + ] + }, + "doi": "10.1016/j.bbrc.2017.03.154", + "pmid": "28363867", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochem Biophys Res Commun 486 2017", + "title": "Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1." + } + }, + { + "pmid": "32529373", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Dynamin-like protein 1 (Drp1) is the master regulator of mitochondrial fission. Drp1 translocates from the cytosol to the mitochondrial outer membrane to execute the scission process. Here we describe an immunofluorescence-based method to measure the mitochondrial translocation of Drp1 and quantify Drp1-related mitochondrial fission by labeling the mitochondrial import receptor subunit TOM20 in fixed cell culture.", + "authors": { + "abbreviation": "Di Hu, Xin Qi", + "authorList": [ + { + "ForeName": "Di", + "LastName": "Hu", + "abbrevName": "Hu D", + "email": null, + "isCollectiveName": false, + "name": "Di Hu" + }, + { + "ForeName": "Xin", + "LastName": "Qi", + "abbrevName": "Qi X", + "email": "xxq38@case.edu", + "isCollectiveName": false, + "name": "Xin Qi" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Qi", + "email": [ + "xxq38@case.edu" + ], + "name": "Xin Qi" + } + ] + }, + "doi": "10.1007/978-1-0716-0676-6_15", + "pmid": "32529373", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Methods Mol Biol 2159 2020", + "title": "Quantifying Drp1-Mediated Mitochondrial Fission by Immunostaining in Fixed Cells." + } + }, + { + "pmid": "30581142", + "pubmed": { + "ISODate": "2019-01-17T00:00:00.000Z", + "abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "authors": { + "abbreviation": "Hyo Min Cho, Jae Ryun Ryu, Youhwa Jo, ..., Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Jae", + "LastName": "Ryu", + "abbrevName": "Ryu JR", + "email": null, + "isCollectiveName": false, + "name": "Jae Ryun Ryu" + }, + { + "ForeName": "Youhwa", + "LastName": "Jo", + "abbrevName": "Jo Y", + "email": null, + "isCollectiveName": false, + "name": "Youhwa Jo" + }, + { + "ForeName": "Tae", + "LastName": "Seo", + "abbrevName": "Seo TW", + "email": null, + "isCollectiveName": false, + "name": "Tae Woong Seo" + }, + { + "ForeName": "Ye", + "LastName": "Choi", + "abbrevName": "Choi YN", + "email": null, + "isCollectiveName": false, + "name": "Ye Na Choi" + }, + { + "ForeName": "June", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": null, + "isCollectiveName": false, + "name": "June Hoan Kim" + }, + { + "ForeName": "Jee", + "LastName": "Chung", + "abbrevName": "Chung JM", + "email": null, + "isCollectiveName": false, + "name": "Jee Min Chung" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho" + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo" + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [ + { + "ForeName": "Woong", + "LastName": "Sun", + "email": [ + "woongsun@korea.ac.kr" + ], + "name": "Woong Sun" + } + ] + }, + "doi": "10.1016/j.molcel.2018.11.009", + "pmid": "30581142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 73 2019", + "title": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System." + } + }, + { + "pmid": "18838687", + "pubmed": { + "ISODate": "2008-10-14T00:00:00.000Z", + "abstract": "Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.", + "authors": { + "abbreviation": "G M Cereghetti, A Stangherlin, O Martins de Brito, ..., L Scorrano", + "authorList": [ + { + "ForeName": "G", + "LastName": "Cereghetti", + "abbrevName": "Cereghetti GM", + "email": null, + "isCollectiveName": false, + "name": "G M Cereghetti" + }, + { + "ForeName": "A", + "LastName": "Stangherlin", + "abbrevName": "Stangherlin A", + "email": null, + "isCollectiveName": false, + "name": "A Stangherlin" + }, + { + "ForeName": "O", + "LastName": "Martins de Brito", + "abbrevName": "Martins de Brito O", + "email": null, + "isCollectiveName": false, + "name": "O Martins de Brito" + }, + { + "ForeName": "C", + "LastName": "Chang", + "abbrevName": "Chang CR", + "email": null, + "isCollectiveName": false, + "name": "C R Chang" + }, + { + "ForeName": "C", + "LastName": "Blackstone", + "abbrevName": "Blackstone C", + "email": null, + "isCollectiveName": false, + "name": "C Blackstone" + }, + { + "ForeName": "P", + "LastName": "Bernardi", + "abbrevName": "Bernardi P", + "email": null, + "isCollectiveName": false, + "name": "P Bernardi" + }, + { + "ForeName": "L", + "LastName": "Scorrano", + "abbrevName": "Scorrano L", + "email": null, + "isCollectiveName": false, + "name": "L Scorrano" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0808249105", + "pmid": "18838687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 105 2008", + "title": "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2020-11-09T15:59:20.969Z", + "_newestOpId": "685aaa29-3ac9-44a2-b2e9-cacefd933cf8", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 1, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "603850" + }, + { + "db": "HGNC", + "id": "HGNC:2973" + }, + { + "db": "Ensembl", + "id": "ENSG00000087470" + } + ], + "defaultOrganismIndex": 1, + "distance": 0, + "esScore": 10.055013, + "formulae": [], + "id": "10059", + "mass": null, + "monoisotopicMass": null, + "name": "DNM1L", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100100, + "shortSynonyms": [ + "DLP1", + "DRP1", + "DVLP", + "DYMPLE", + "EMPF", + "dynamin-like protein 4", + "OPA5", + "EMPF1", + "HDYNIV", + "dynamin-1-like protein" + ], + "summary": "A first-generation quark with a charge of -1/3. The up and down quarks are the fundamental constituents of the nucleons.", + "synonyms": [ + "DLP1", + "DRP1", + "DVLP", + "DYMPLE", + "EMPF", + "EMPF1", + "HDYNIV", + "OPA5", + "dynamin-1-like protein", + "Dnm1p/Vps1p-like protein", + "dynamin family member proline-rich carboxyl-terminal domain less", + "dynamin-like protein 4", + "dynamin-like protein IV", + "dynamin-related protein 1", + "dynamin 1 like" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "3ed4ad3e-dab8-4b6d-b488-5c0299421da1", + "liveId": "b06af75c-396a-4d18-9955-09ecc8496769", + "lock": null, + "locked": false, + "name": "Drp1", + "position": { + "x": 39.03337169159954, + "y": 131.79746835443035 + }, + "relatedPapers": [ + { + "pmid": "30760382", + "pubmed": { + "ISODate": "2019-02-01T00:00:00.000Z", + "abstract": "Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].", + "authors": { + "abbreviation": "Hyo Min Cho, Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": null, + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "30760382", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "BMB Rep 52 2019", + "title": "The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance." + } + }, + { + "pmid": "28363867", + "pubmed": { + "ISODate": "2017-05-13T00:00:00.000Z", + "abstract": "Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin-related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1.", + "authors": { + "abbreviation": "Mai-Tram Vo, Myoung Seok Ko, Unn Hwa Lee, ..., Jeong Woo Park", + "authorList": [ + { + "ForeName": "Mai-Tram", + "LastName": "Vo", + "abbrevName": "Vo MT", + "email": null, + "isCollectiveName": false, + "name": "Mai-Tram Vo" + }, + { + "ForeName": "Myoung", + "LastName": "Ko", + "abbrevName": "Ko MS", + "email": null, + "isCollectiveName": false, + "name": "Myoung Seok Ko" + }, + { + "ForeName": "Unn", + "LastName": "Lee", + "abbrevName": "Lee UH", + "email": null, + "isCollectiveName": false, + "name": "Unn Hwa Lee" + }, + { + "ForeName": "Eun", + "LastName": "Yoon", + "abbrevName": "Yoon EH", + "email": null, + "isCollectiveName": false, + "name": "Eun Hye Yoon" + }, + { + "ForeName": "Byung", + "LastName": "Lee", + "abbrevName": "Lee BJ", + "email": null, + "isCollectiveName": false, + "name": "Byung Ju Lee" + }, + { + "ForeName": "Wha", + "LastName": "Cho", + "abbrevName": "Cho WJ", + "email": null, + "isCollectiveName": false, + "name": "Wha Ja Cho" + }, + { + "ForeName": "Chang", + "LastName": "Ha", + "abbrevName": "Ha CM", + "email": null, + "isCollectiveName": false, + "name": "Chang Man Ha" + }, + { + "ForeName": "Kyungjin", + "LastName": "Kim", + "abbrevName": "Kim K", + "email": null, + "isCollectiveName": false, + "name": "Kyungjin Kim" + }, + { + "ForeName": "Jeong", + "LastName": "Park", + "abbrevName": "Park JW", + "email": "jwpark@ulsan.ac.kr", + "isCollectiveName": false, + "name": "Jeong Woo Park" + } + ], + "contacts": [ + { + "ForeName": "Jeong", + "LastName": "Park", + "email": [ + "jwpark@ulsan.ac.kr" + ], + "name": "Jeong Woo Park" + } + ] + }, + "doi": "10.1016/j.bbrc.2017.03.154", + "pmid": "28363867", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Biochem Biophys Res Commun 486 2017", + "title": "Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1." + } + }, + { + "pmid": "23284813", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Mitochondria are dynamic organelles that change in response to extracellular stimuli. These changes are essential for normal mitochondrial/cellular function and are controlled by a tight balance between two antagonistic pathways that promote fusion and fission. Although some molecules have been identified to mediate the mitochondrial fusion and fission process, the underlying mechanisms remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecule that regulates a variety of mitochondrial functions. Here, we examined the role of TRAP1 in the regulation of morphology. Stable TRAP1 knockdown cells showed abnormal mitochondrial morphology, and we observed significant decreases in dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff), mitochondrial fission proteins. Similar results were obtained by transient knockdown of TRAP1 in two different cell lines, SH-SY5Y neuroblastoma cells and KNS-42 glioma cells. However, TRAP1 knockdown did not affect expression levels of fusion proteins. The reduction in Drp1 and Mff protein levels was rescued following treatment with the proteasome inhibitor MG132. These results suggest that TRAP1 regulates the expression of fission proteins and controls mitochondrial fusion/fission, which affects mitochondrial/cellular function.", + "authors": { + "abbreviation": "Hironori Takamura, Yoshihisa Koyama, Shinsuke Matsuzaki, ..., Taiichi Katayama", + "authorList": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "abbrevName": "Takamura H", + "email": "takamura@ugscd.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Hironori Takamura" + }, + { + "ForeName": "Yoshihisa", + "LastName": "Koyama", + "abbrevName": "Koyama Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshihisa Koyama" + }, + { + "ForeName": "Shinsuke", + "LastName": "Matsuzaki", + "abbrevName": "Matsuzaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinsuke Matsuzaki" + }, + { + "ForeName": "Kohei", + "LastName": "Yamada", + "abbrevName": "Yamada K", + "email": null, + "isCollectiveName": false, + "name": "Kohei Yamada" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Hattori" + }, + { + "ForeName": "Shingo", + "LastName": "Miyata", + "abbrevName": "Miyata S", + "email": null, + "isCollectiveName": false, + "name": "Shingo Miyata" + }, + { + "ForeName": "Kana", + "LastName": "Takemoto", + "abbrevName": "Takemoto K", + "email": null, + "isCollectiveName": false, + "name": "Kana Takemoto" + }, + { + "ForeName": "Masaya", + "LastName": "Tohyama", + "abbrevName": "Tohyama M", + "email": null, + "isCollectiveName": false, + "name": "Masaya Tohyama" + }, + { + "ForeName": "Taiichi", + "LastName": "Katayama", + "abbrevName": "Katayama T", + "email": null, + "isCollectiveName": false, + "name": "Taiichi Katayama" + } + ], + "contacts": [ + { + "ForeName": "Hironori", + "LastName": "Takamura", + "email": [ + "takamura@ugscd.osaka-u.ac.jp" + ], + "name": "Hironori Takamura" + } + ] + }, + "doi": "10.1371/journal.pone.0051912", + "pmid": "23284813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression." + } + }, + { + "pmid": "27288452", + "pubmed": { + "ISODate": "2016-08-01T00:00:00.000Z", + "abstract": "The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation was then demonstrated by comparison of mitochondria bioenergetics through extracellular flux analyses. Moreover, staining with the mitochondrial-specific fluorescent probe MitoSox suggested increased levels of superoxide in patient cells with reduced levels of sacsin.Key to maintaining mitochondrial health is mitochondrial fission, which facilitates the dynamic exchange of mitochondrial components and separates damaged parts of the mitochondrial network for selective elimination by mitophagy. Fission is dependent on dynamin-related protein 1 (Drp1), which is recruited to prospective sites of division where it mediates scission. In sacsin knockdown cells and ARSACS fibroblasts, we observed a decreased incidence of mitochondrial associated Drp1 foci. This phenotype persists even when fission is induced by drug treatment. Mitochondrial-associated Drp1 foci are also smaller in sacsin knockdown cells and ARSACS fibroblasts. These data suggest a model for ARSACS where neurons with reduced levels of sacsin are compromised in their ability to recruit or retain Drp1 at the mitochondrial membrane leading to a decline in mitochondrial health, potentially through impaired mitochondrial quality control.", + "authors": { + "abbreviation": "Teisha Y Bradshaw, Lisa E L Romano, Emma J Duncan, ..., J Paul Chapple", + "authorList": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "abbrevName": "Bradshaw TY", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "Lisa", + "LastName": "Romano", + "abbrevName": "Romano LE", + "email": null, + "isCollectiveName": false, + "name": "Lisa E L Romano" + }, + { + "ForeName": "Emma", + "LastName": "Duncan", + "abbrevName": "Duncan EJ", + "email": null, + "isCollectiveName": false, + "name": "Emma J Duncan" + }, + { + "ForeName": "Suran", + "LastName": "Nethisinghe", + "abbrevName": "Nethisinghe S", + "email": null, + "isCollectiveName": false, + "name": "Suran Nethisinghe" + }, + { + "ForeName": "Rosella", + "LastName": "Abeti", + "abbrevName": "Abeti R", + "email": null, + "isCollectiveName": false, + "name": "Rosella Abeti" + }, + { + "ForeName": "Gregory", + "LastName": "Michael", + "abbrevName": "Michael GJ", + "email": null, + "isCollectiveName": false, + "name": "Gregory J Michael" + }, + { + "ForeName": "Paola", + "LastName": "Giunti", + "abbrevName": "Giunti P", + "email": null, + "isCollectiveName": false, + "name": "Paola Giunti" + }, + { + "ForeName": "Sascha", + "LastName": "Vermeer", + "abbrevName": "Vermeer S", + "email": null, + "isCollectiveName": false, + "name": "Sascha Vermeer" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "abbrevName": "Chapple JP", + "email": "j.p.chapple@qmul.ac.uk", + "isCollectiveName": false, + "name": "J Paul Chapple" + } + ], + "contacts": [ + { + "ForeName": "Teisha", + "LastName": "Bradshaw", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "Teisha Y Bradshaw" + }, + { + "ForeName": "J", + "LastName": "Chapple", + "email": [ + "j.p.chapple@qmul.ac.uk" + ], + "name": "J Paul Chapple" + } + ] + }, + "doi": "10.1093/hmg/ddw173", + "pmid": "27288452", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay." + } + }, + { + "pmid": "33734301", + "pubmed": { + "ISODate": "2021-04-05T00:00:00.000Z", + "abstract": "Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.", + "authors": { + "abbreviation": "Yanfang Chen, Romane Leboutet, Céline Largeau, ..., Renaud Legouis", + "authorList": [ + { + "ForeName": "Yanfang", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfang Chen" + }, + { + "ForeName": "Romane", + "LastName": "Leboutet", + "abbrevName": "Leboutet R", + "email": null, + "isCollectiveName": false, + "name": "Romane Leboutet" + }, + { + "ForeName": "Céline", + "LastName": "Largeau", + "abbrevName": "Largeau C", + "email": null, + "isCollectiveName": false, + "name": "Céline Largeau" + }, + { + "ForeName": "Siham", + "LastName": "Zentout", + "abbrevName": "Zentout S", + "email": null, + "isCollectiveName": false, + "name": "Siham Zentout" + }, + { + "ForeName": "Christophe", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Lefebvre" + }, + { + "ForeName": "Agnès", + "LastName": "Delahodde", + "abbrevName": "Delahodde A", + "email": null, + "isCollectiveName": false, + "name": "Agnès Delahodde" + }, + { + "ForeName": "Emmanuel", + "LastName": "Culetto", + "abbrevName": "Culetto E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Culetto" + }, + { + "ForeName": "Renaud", + "LastName": "Legouis", + "abbrevName": "Legouis R", + "email": null, + "isCollectiveName": false, + "name": "Renaud Legouis" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201909139", + "pmid": "33734301", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process." + } + }, + { + "pmid": "33851959", + "pubmed": { + "ISODate": "2021-06-07T00:00:00.000Z", + "abstract": "Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell (\"mosaic distribution\"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins.", + "authors": { + "abbreviation": "Yumiko Oshima, Etienne Cartier, Liron Boyman, ..., Mariusz Karbowski", + "authorList": [ + { + "ForeName": "Yumiko", + "LastName": "Oshima", + "abbrevName": "Oshima Y", + "email": null, + "isCollectiveName": false, + "name": "Yumiko Oshima" + }, + { + "ForeName": "Etienne", + "LastName": "Cartier", + "abbrevName": "Cartier E", + "email": null, + "isCollectiveName": false, + "name": "Etienne Cartier" + }, + { + "ForeName": "Liron", + "LastName": "Boyman", + "abbrevName": "Boyman L", + "email": null, + "isCollectiveName": false, + "name": "Liron Boyman" + }, + { + "ForeName": "Nicolas", + "LastName": "Verhoeven", + "abbrevName": "Verhoeven N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Verhoeven" + }, + { + "ForeName": "Brian", + "LastName": "Polster", + "abbrevName": "Polster BM", + "email": null, + "isCollectiveName": false, + "name": "Brian M Polster" + }, + { + "ForeName": "Weiliang", + "LastName": "Huang", + "abbrevName": "Huang W", + "email": null, + "isCollectiveName": false, + "name": "Weiliang Huang" + }, + { + "ForeName": "Maureen", + "LastName": "Kane", + "abbrevName": "Kane M", + "email": null, + "isCollectiveName": false, + "name": "Maureen Kane" + }, + { + "ForeName": "W", + "LastName": "Lederer", + "abbrevName": "Lederer WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jonathan Lederer" + }, + { + "ForeName": "Mariusz", + "LastName": "Karbowski", + "abbrevName": "Karbowski M", + "email": null, + "isCollectiveName": false, + "name": "Mariusz Karbowski" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202006043", + "pmid": "33851959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 220 2021", + "title": "Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination." + } + }, + { + "pmid": "30581142", + "pubmed": { + "ISODate": "2019-01-17T00:00:00.000Z", + "abstract": "Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating \"bad sectors\" in the mitochondrial network, serving as a mitochondrial quality surveillance system.", + "authors": { + "abbreviation": "Hyo Min Cho, Jae Ryun Ryu, Youhwa Jo, ..., Woong Sun", + "authorList": [ + { + "ForeName": "Hyo", + "LastName": "Cho", + "abbrevName": "Cho HM", + "email": null, + "isCollectiveName": false, + "name": "Hyo Min Cho" + }, + { + "ForeName": "Jae", + "LastName": "Ryu", + "abbrevName": "Ryu JR", + "email": null, + "isCollectiveName": false, + "name": "Jae Ryun Ryu" + }, + { + "ForeName": "Youhwa", + "LastName": "Jo", + "abbrevName": "Jo Y", + "email": null, + "isCollectiveName": false, + "name": "Youhwa Jo" + }, + { + "ForeName": "Tae", + "LastName": "Seo", + "abbrevName": "Seo TW", + "email": null, + "isCollectiveName": false, + "name": "Tae Woong Seo" + }, + { + "ForeName": "Ye", + "LastName": "Choi", + "abbrevName": "Choi YN", + "email": null, + "isCollectiveName": false, + "name": "Ye Na Choi" + }, + { + "ForeName": "June", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": null, + "isCollectiveName": false, + "name": "June Hoan Kim" + }, + { + "ForeName": "Jee", + "LastName": "Chung", + "abbrevName": "Chung JM", + "email": null, + "isCollectiveName": false, + "name": "Jee Min Chung" + }, + { + "ForeName": "Bongki", + "LastName": "Cho", + "abbrevName": "Cho B", + "email": null, + "isCollectiveName": false, + "name": "Bongki Cho" + }, + { + "ForeName": "Ho", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Ho Chul Kang" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + }, + { + "ForeName": "Soon", + "LastName": "Yoo", + "abbrevName": "Yoo SJ", + "email": null, + "isCollectiveName": false, + "name": "Soon Ji Yoo" + }, + { + "ForeName": "Hyun", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyun Kim" + }, + { + "ForeName": "Woong", + "LastName": "Sun", + "abbrevName": "Sun W", + "email": "woongsun@korea.ac.kr", + "isCollectiveName": false, + "name": "Woong Sun" + } + ], + "contacts": [ + { + "ForeName": "Woong", + "LastName": "Sun", + "email": [ + "woongsun@korea.ac.kr" + ], + "name": "Woong Sun" + } + ] + }, + "doi": "10.1016/j.molcel.2018.11.009", + "pmid": "30581142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 73 2019", + "title": "Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System." + } + }, + { + "pmid": "18838687", + "pubmed": { + "ISODate": "2008-10-14T00:00:00.000Z", + "abstract": "Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.", + "authors": { + "abbreviation": "G M Cereghetti, A Stangherlin, O Martins de Brito, ..., L Scorrano", + "authorList": [ + { + "ForeName": "G", + "LastName": "Cereghetti", + "abbrevName": "Cereghetti GM", + "email": null, + "isCollectiveName": false, + "name": "G M Cereghetti" + }, + { + "ForeName": "A", + "LastName": "Stangherlin", + "abbrevName": "Stangherlin A", + "email": null, + "isCollectiveName": false, + "name": "A Stangherlin" + }, + { + "ForeName": "O", + "LastName": "Martins de Brito", + "abbrevName": "Martins de Brito O", + "email": null, + "isCollectiveName": false, + "name": "O Martins de Brito" + }, + { + "ForeName": "C", + "LastName": "Chang", + "abbrevName": "Chang CR", + "email": null, + "isCollectiveName": false, + "name": "C R Chang" + }, + { + "ForeName": "C", + "LastName": "Blackstone", + "abbrevName": "Blackstone C", + "email": null, + "isCollectiveName": false, + "name": "C Blackstone" + }, + { + "ForeName": "P", + "LastName": "Bernardi", + "abbrevName": "Bernardi P", + "email": null, + "isCollectiveName": false, + "name": "P Bernardi" + }, + { + "ForeName": "L", + "LastName": "Scorrano", + "abbrevName": "Scorrano L", + "email": null, + "isCollectiveName": false, + "name": "L Scorrano" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0808249105", + "pmid": "18838687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 105 2008", + "title": "Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria." + } + }, + { + "pmid": "27050458", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact \"coupling\" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the \"coupling\" across the double membrane for mitochondrial dynamics and quality control. ", + "authors": { + "abbreviation": "Ming Chen, Ziheng Chen, Yueying Wang, ..., Quan Chen", + "authorList": [ + { + "ForeName": "Ming", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Ming Chen" + }, + { + "ForeName": "Ziheng", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Ziheng Chen" + }, + { + "ForeName": "Yueying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yueying Wang" + }, + { + "ForeName": "Zheng", + "LastName": "Tan", + "abbrevName": "Tan Z", + "email": null, + "isCollectiveName": false, + "name": "Zheng Tan" + }, + { + "ForeName": "Chongzhuo", + "LastName": "Zhu", + "abbrevName": "Zhu C", + "email": null, + "isCollectiveName": false, + "name": "Chongzhuo Zhu" + }, + { + "ForeName": "Yanjun", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanjun Li" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Linbo", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Linbo Chen" + }, + { + "ForeName": "Ruize", + "LastName": "Gao", + "abbrevName": "Gao R", + "email": null, + "isCollectiveName": false, + "name": "Ruize Gao" + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu" + }, + { + "ForeName": "Quan", + "LastName": "Chen", + "abbrevName": "Chen Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Chen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2016.1151580", + "pmid": "27050458", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 12 2016", + "title": "Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy." + } + }, + { + "pmid": "32529373", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Dynamin-like protein 1 (Drp1) is the master regulator of mitochondrial fission. Drp1 translocates from the cytosol to the mitochondrial outer membrane to execute the scission process. Here we describe an immunofluorescence-based method to measure the mitochondrial translocation of Drp1 and quantify Drp1-related mitochondrial fission by labeling the mitochondrial import receptor subunit TOM20 in fixed cell culture.", + "authors": { + "abbreviation": "Di Hu, Xin Qi", + "authorList": [ + { + "ForeName": "Di", + "LastName": "Hu", + "abbrevName": "Hu D", + "email": null, + "isCollectiveName": false, + "name": "Di Hu" + }, + { + "ForeName": "Xin", + "LastName": "Qi", + "abbrevName": "Qi X", + "email": "xxq38@case.edu", + "isCollectiveName": false, + "name": "Xin Qi" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Qi", + "email": [ + "xxq38@case.edu" + ], + "name": "Xin Qi" + } + ] + }, + "doi": "10.1007/978-1-0716-0676-6_15", + "pmid": "32529373", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Methods Mol Biol 2159 2020", + "title": "Quantifying Drp1-Mediated Mitochondrial Fission by Immunostaining in Fixed Cells." + } + } + ], + "secret": "read-only", + "type": "protein" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/complex_tests_4.json b/neo4j-test/document/complex_tests_4.json new file mode 100644 index 000000000..3c3058ff3 --- /dev/null +++ b/neo4j-test/document/complex_tests_4.json @@ -0,0 +1,13862 @@ +{ + "document": [ + { + "_creationTimestamp": "2021-07-23T11:50:00.820Z", + "_newestOpId": "d8631c9b-f8fe-4ca9-82e1-30f73b9b01f1", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Ubiquitin-specific protease 1 (USP1) acts together with the cofactor UAF1 during DNA repair processes to specifically remove monoubiquitin signals. One substrate of the USP1-UAF1 complex is the monoubiquitinated FANCI-FANCD2 heterodimer, which is involved in the repair of DNA interstrand crosslinks via the Fanconi anemia pathway. Here we determine structures of human USP1-UAF1 with and without ubiquitin and bound to monoubiquitinated FANCI-FANCD2. The crystal structures of USP1-UAF1 reveal plasticity in USP1 and key differences to USP12-UAF1 and USP46-UAF1, two related proteases. A cryo-EM reconstruction of USP1-UAF1 in complex with monoubiquitinated FANCI-FANCD2 highlights a highly orchestrated deubiquitination process, with USP1-UAF1 driving conformational changes in the substrate. An extensive interface between UAF1 and FANCI, confirmed by mutagenesis and biochemical assays, provides a molecular explanation for the requirement of both proteins, despite neither being directly involved in catalysis. Overall, our data provide molecular details of USP1-UAF1 regulation and substrate recognition.", + "ArticleTitle": "Structural basis of FANCD2 deubiquitination by USP1-UAF1.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Martin.Rennie@glasgow.ac.uk.", + "email": [ + "Martin.Rennie@glasgow.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Martin L", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-0799-3450" + } + ], + "Initials": "ML", + "LastName": "Rennie" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.", + "email": null + }, + { + "Affiliation": "MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Connor", + "Identifier": [], + "Initials": "C", + "LastName": "Arkinson" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.", + "email": null + }, + { + "Affiliation": "MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Viduth K", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0001-7814-5865" + } + ], + "Initials": "VK", + "LastName": "Chaugule" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rachel", + "Identifier": [], + "Initials": "R", + "LastName": "Toth" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Helen.Walden@glasgow.ac.uk.", + "email": [ + "Helen.Walden@glasgow.ac.uk" + ] + }, + { + "Affiliation": "MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK. Helen.Walden@glasgow.ac.uk.", + "email": [ + "Helen.Walden@glasgow.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Helen", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-4289-4810" + } + ], + "Initials": "H", + "LastName": "Walden" + } + ], + "Journal": { + "ISOAbbreviation": "Nat Struct Mol Biol", + "ISSN": { + "IssnType": "Electronic", + "value": "1545-9985" + }, + "JournalIssue": { + "Issue": "4", + "PubDate": { + "Day": null, + "Month": "Apr", + "Year": "2021" + }, + "Volume": "28" + }, + "Title": "Nature structural & molecular biology" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "D052236", + "value": "Fanconi Anemia Complementation Group D2 Protein" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D009687", + "value": "Nuclear Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "C526165", + "value": "USP1 associated factor 1, human" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D000072017", + "value": "Deubiquitinating Enzymes" + }, + "RegistryNumber": "EC 3.4.19.12" + }, + { + "NameOfSubstance": { + "UI": "C579228", + "value": "USP1 protein, human" + }, + "RegistryNumber": "EC 3.4.19.12" + }, + { + "NameOfSubstance": { + "UI": "D064570", + "value": "Ubiquitin-Specific Proteases" + }, + "RegistryNumber": "EC 3.4.19.12" + } + ], + "InvestigatorList": [], + "KeywordList": [], + "MeshheadingList": [ + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D004249", + "value": "DNA Damage" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D004260", + "value": "DNA Repair" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000235", + "value": "genetics" 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Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr. D Struct. Biol. 74, 531–544 (2018)." + }, + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "17681537" + }, + { + "IdType": "doi", + "id": "10.1016/j.jmb.2007.05.022" + } + ], + "Citation": "Krissinel, E. & Henrick, K. Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 372, 774–797 (2007)." + }, + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "28710774" + }, + { + "IdType": "doi", + "id": "10.1002/pro.3235" + } + ], + "Citation": "Goddard, T. D. et al. UCSF ChimeraX: Meeting modern challenges in visualization and analysis. Protein Sci. 27, 14–25 (2018)." + }, + { + "ArticleIdList": [ + { + "IdType": "doi", + "id": "10.1109/MCSE.2007.55" + } + ], + "Citation": "Hunter, J. D. Matplotlib: A 2D graphics environment. Comput. Sci. Eng. 9, 90–95 (2007)." + }, + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "16626738" + }, + { + "IdType": "doi", + "id": "10.1016/j.jmb.2006.03.036" + } + ], + "Citation": "Baba, D. et al. Crystal structure of SUMO-3-modified thymine-DNA glycosylase. J. Mol. Biol. 359, 137–147 (2006)." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Martin", + "LastName": "Rennie", + "abbrevName": "Rennie ML", + "email": "Martin.Rennie@glasgow.ac.uk", + "isCollectiveName": false, + "name": "Martin L Rennie", + "orcid": "0000-0002-0799-3450" + }, + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson", + "orcid": null + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule", + "orcid": "0000-0001-7814-5865" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth", + "orcid": null + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": "Helen.Walden@glasgow.ac.uk", + "isCollectiveName": false, + "name": "Helen Walden", + "orcid": "0000-0002-4289-4810" + } + ], + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1627041000.824, + "entries": [ + { + "id": "87ed3eb8-aff7-463b-bd2d-494aede66d78" + }, + { + "id": "53abc3ba-4d9b-431f-a100-9a6411450218" + }, + { + "id": "bafa60d9-cae7-4b27-85c7-c92e4d4fb68a" + }, + { + "id": "2af10d33-240c-4a41-94eb-78da690b2d7d" + }, + { + "id": "1297c941-b23e-461f-9cc7-46e3457d5ca4" + }, + { + "id": "54641fe7-30f1-4478-abbe-d41531f26948" + }, + { + "id": "b38116a2-5002-48b0-b156-32bcbff764a4" + }, + { + "id": "8ee9fb94-b3b8-4212-bddc-d46f1a079164" + } + ], + "id": "8d0977b5-8839-4383-ab51-5198369d3d72", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1627051936.821, + "liveId": "2eb25a6d-cc00-43e7-bfbe-e777c9bc0957", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "33582281", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Single particle cryo-EM excels in determining static structures of protein molecules, but existing 3D reconstruction methods have been ineffective in modelling flexible proteins. We introduce 3D variability analysis (3DVA), an algorithm that fits a linear subspace model of conformational change to cryo-EM data at high resolution. 3DVA enables the resolution and visualization of detailed molecular motions of both large and small proteins, revealing new biological insight from single particle cryo-EM data. Experimental results demonstrate the ability of 3DVA to resolve multiple flexible motions of α-helices in the sub-50 kDa transmembrane domain of a GPCR complex, bending modes of a sodium ion channel, five types of symmetric and symmetry-breaking flexibility in a proteasome, large motions in a spliceosome complex, and discrete conformational states of a ribosome assembly. 3DVA is implemented in the cryoSPARC software package.", + "authors": { + "abbreviation": "Ali Punjani, David J Fleet", + "authorList": [ + { + "ForeName": "Ali", + "LastName": "Punjani", + "abbrevName": "Punjani A", + "email": "alipunjani@cs.toronto.edu", + "isCollectiveName": false, + "name": "Ali Punjani" + }, + { + "ForeName": "David", + "LastName": "Fleet", + "abbrevName": "Fleet DJ", + "email": "fleet@cs.toronto.edu", + "isCollectiveName": false, + "name": "David J Fleet" + } + ], + "contacts": [ + { + "ForeName": "Ali", + "LastName": "Punjani", + "email": [ + "alipunjani@cs.toronto.edu" + ], + "name": "Ali Punjani" + }, + { + "ForeName": "David", + "LastName": "Fleet", + "email": [ + "fleet@cs.toronto.edu" + ], + "name": "David J Fleet" + } + ] + }, + "doi": "10.1016/j.jsb.2021.107702", + "pmid": "33582281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 213 2021", + "title": "3D variability analysis: Resolving continuous flexibility and discrete heterogeneity from single particle cryo-EM." + } + }, + { + "pmid": "33257830", + "pubmed": { + "ISODate": "2020-12-01T00:00:00.000Z", + "abstract": "Cryogenic electron microscopy (cryo-EM) is widely used to study biological macromolecules that comprise regions with disorder, flexibility or partial occupancy. For example, membrane proteins are often kept in solution with detergent micelles and lipid nanodiscs that are locally disordered. Such spatial variability negatively impacts computational three-dimensional (3D) reconstruction with existing iterative refinement algorithms that assume rigidity. We introduce non-uniform refinement, an algorithm based on cross-validation optimization, which automatically regularizes 3D density maps during refinement to account for spatial variability. Unlike common shift-invariant regularizers, non-uniform refinement systematically removes noise from disordered regions, while retaining signal useful for aligning particle images, yielding dramatically improved resolution and 3D map quality in many cases. We obtain high-resolution reconstructions for multiple membrane proteins as small as 100 kDa, demonstrating increased effectiveness of cryo-EM for this class of targets critical in structural biology and drug discovery. Non-uniform refinement is implemented in the cryoSPARC software package.", + "authors": { + "abbreviation": "Ali Punjani, Haowei Zhang, David J Fleet", + "authorList": [ + { + "ForeName": "Ali", + "LastName": "Punjani", + "abbrevName": "Punjani A", + "email": "alipunjani@cs.toronto.edu", + "isCollectiveName": false, + "name": "Ali Punjani" + }, + { + "ForeName": "Haowei", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Haowei Zhang" + }, + { + "ForeName": "David", + "LastName": "Fleet", + "abbrevName": "Fleet DJ", + "email": "fleet@cs.toronto.edu", + "isCollectiveName": false, + "name": "David J Fleet" + } + ], + "contacts": [ + { + "ForeName": "Ali", + "LastName": "Punjani", + "email": [ + "alipunjani@cs.toronto.edu" + ], + "name": "Ali Punjani" + }, + { + "ForeName": "David", + "LastName": "Fleet", + "email": [ + "fleet@cs.toronto.edu" + ], + "name": "David J Fleet" + } + ] + }, + "doi": "10.1038/s41592-020-00990-8", + "pmid": "33257830", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Methods 17 2020", + "title": "Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction." + } + }, + { + "pmid": "32510829", + "pubmed": { + "ISODate": "2020-07-03T00:00:00.000Z", + "abstract": "The Fanconi anaemia (FA) pathway is a dedicated pathway for the repair of DNA interstrand crosslinks and is additionally activated in response to other forms of replication stress. A key step in the FA pathway is the monoubiquitination of each of the two subunits (FANCI and FANCD2) of the ID2 complex on specific lysine residues. However, the molecular function of these modifications has been unknown for nearly two decades. Here, we find that ubiquitination of FANCD2 acts to increase ID2's affinity for double-stranded DNA via promoting a large-scale conformational change in the complex. The resulting complex encircles DNA, by forming a secondary \"Arm\" ID2 interface. Ubiquitination of FANCI, on the other hand, largely protects the ubiquitin on FANCD2 from USP1-UAF1 deubiquitination, with key hydrophobic residues of FANCI's ubiquitin being important for this protection. In effect, both of these post-translational modifications function to stabilize a conformation in which the ID2 complex encircles DNA.", + "authors": { + "abbreviation": "Martin L Rennie, Kimon Lemonidis, Connor Arkinson, ..., Helen Walden", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Rennie", + "abbrevName": "Rennie ML", + "email": null, + "isCollectiveName": false, + "name": "Martin L Rennie" + }, + { + "ForeName": "Kimon", + "LastName": "Lemonidis", + "abbrevName": "Lemonidis K", + "email": null, + "isCollectiveName": false, + "name": "Kimon Lemonidis" + }, + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Mairi", + "LastName": "Clarke", + "abbrevName": "Clarke M", + "email": null, + "isCollectiveName": false, + "name": "Mairi Clarke" + }, + { + "ForeName": "James", + "LastName": "Streetley", + "abbrevName": "Streetley J", + "email": null, + "isCollectiveName": false, + "name": "James Streetley" + }, + { + "ForeName": "Laura", + "LastName": "Spagnolo", + "abbrevName": "Spagnolo L", + "email": null, + "isCollectiveName": false, + "name": "Laura Spagnolo" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.15252/embr.202050133", + "pmid": "32510829", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO Rep 21 2020", + "title": "Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA." + } + }, + { + "pmid": "32305021", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Ubiquitination is a post-translational modification crucial for cellular signaling. A diverse range of enzymes constitute the machinery that mediates attachment of ubiquitin onto target proteins. This diversity allows the targeting of various proteins in a highly regulated fashion. Many of the enzymes have multiple domains or subunits that bind allosteric effectors and exhibit large conformational rearrangements to facilitate regulation. Here we consider recent examples of ubiquitin itself as an allosteric effector of RING and RBR E3 ligases, as well as advances in the understanding of allosteric regulatory elements within HECT E3 ligases.", + "authors": { + "abbreviation": "Martin L Rennie, Viduth K Chaugule, Helen Walden", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Rennie", + "abbrevName": "Rennie ML", + "email": null, + "isCollectiveName": false, + "name": "Martin L Rennie" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": "Helen.Walden@glasgow.ac.uk", + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [ + { + "ForeName": "Helen", + "LastName": "Walden", + "email": [ + "Helen.Walden@glasgow.ac.uk" + ], + "name": "Helen Walden" + } + ] + }, + "doi": "10.1016/j.sbi.2020.02.003", + "pmid": "32305021", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Struct Biol 62 2020", + "title": "Modes of allosteric regulation of the ubiquitination machinery." + } + }, + { + "pmid": "32269332", + "pubmed": { + "ISODate": "2020-04-01T00:00:00.000Z", + "abstract": "The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions1. These proteins are mutated in Fanconi anaemia, a disease in which patients are predisposed to cancer. The Fanconi anaemia pathway of ICL repair is activated when a replication fork stalls at an ICL2; this triggers monoubiquitination of the ID complex, in which one ubiquitin molecule is conjugated to each of FANCI and FANCD2. Monoubiquitination of ID is essential for ICL repair by excision, translesion synthesis and homologous recombination; however, its function remains unknown1,3. Here we report a cryo-electron microscopy structure of the monoubiquitinated human ID complex bound to DNA, and reveal that it forms a closed ring that encircles the DNA. By comparison with the structure of the non-ubiquitinated ID complex bound to ICL DNA-which we also report here-we show that monoubiquitination triggers a complete rearrangement of the open, trough-like ID structure through the ubiquitin of one protomer binding to the other protomer in a reciprocal fashion. These structures-together with biochemical data-indicate that the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions. Our findings also reveal how monoubiquitination in general can induce an alternative protein structure with a new function.", + "authors": { + "abbreviation": "Renjing Wang, Shengliu Wang, Ankita Dhar, ..., Nikola P Pavletich", + "authorList": [ + { + "ForeName": "Renjing", + "LastName": "Wang", + "abbrevName": "Wang R", + "email": null, + "isCollectiveName": false, + "name": "Renjing Wang" + }, + { + "ForeName": "Shengliu", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shengliu Wang" + }, + { + "ForeName": "Ankita", + "LastName": "Dhar", + "abbrevName": "Dhar A", + "email": null, + "isCollectiveName": false, + "name": "Ankita Dhar" + }, + { + "ForeName": "Christopher", + "LastName": "Peralta", + "abbrevName": "Peralta C", + "email": null, + "isCollectiveName": false, + "name": "Christopher Peralta" + }, + { + "ForeName": "Nikola", + "LastName": "Pavletich", + "abbrevName": "Pavletich NP", + "email": "pavletin@mskcc.org", + "isCollectiveName": false, + "name": "Nikola P Pavletich" + } + ], + "contacts": [ + { + "ForeName": "Nikola", + "LastName": "Pavletich", + "email": [ + "pavletin@mskcc.org" + ], + "name": "Nikola P Pavletich" + } + ] + }, + "doi": "10.1038/s41586-020-2110-6", + "pmid": "32269332", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nature 580 2020", + "title": "DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex." + } + }, + { + "pmid": "32167469", + "pubmed": { + "ISODate": "2020-03-13T00:00:00.000Z", + "abstract": "FANCI:FANCD2 monoubiquitination is a critical event for replication fork stabilization by the Fanconi anemia (FA) DNA repair pathway. It has been proposed that at stalled replication forks, monoubiquitinated-FANCD2 serves to recruit DNA repair proteins that contain ubiquitin-binding motifs. Here, we have reconstituted the FA pathway in vitro to study functional consequences of FANCI:FANCD2 monoubiquitination. We report that monoubiquitination does not promote any specific exogenous protein:protein interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA. This clamping requires monoubiquitination of only the FANCD2 subunit. We further show using electron microscopy that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA. Our results reveal how monoubiquitinated FANCI:FANCD2, defective in many cancer types and all cases of FA, is activated upon DNA binding.", + "authors": { + "abbreviation": "Winnie Tan, Sylvie van Twest, Andrew Leis, ..., Andrew J Deans", + "authorList": [ + { + "ForeName": "Winnie", + "LastName": "Tan", + "abbrevName": "Tan W", + "email": null, + "isCollectiveName": false, + "name": "Winnie Tan" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Andrew", + "LastName": "Leis", + "abbrevName": "Leis A", + "email": null, + "isCollectiveName": false, + "name": "Andrew Leis" + }, + { + "ForeName": "Rohan", + "LastName": "Bythell-Douglas", + "abbrevName": "Bythell-Douglas R", + "email": null, + "isCollectiveName": false, + "name": "Rohan Bythell-Douglas" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Michael", + "LastName": "Sharp", + "abbrevName": "Sharp M", + "email": null, + "isCollectiveName": false, + "name": "Michael Sharp" + }, + { + "ForeName": "Michael", + "LastName": "Parker", + "abbrevName": "Parker MW", + "email": null, + "isCollectiveName": false, + "name": "Michael W Parker" + }, + { + "ForeName": "Wayne", + "LastName": "Crismani", + "abbrevName": "Crismani W", + "email": null, + "isCollectiveName": false, + "name": "Wayne Crismani" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.54128", + "pmid": "32167469", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Elife 9 2020", + "title": "Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays." + } + }, + { + "pmid": "32117957", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "DNA interstrand crosslinks (ICLs) are a physical barrier to replication and therefore toxic to cell viability. An important mechanism for the removal of ICLs is the Fanconi Anemia DNA repair pathway, which is initiated by mono-ubiquitination of FANCD2 and its partner protein FANCI. Here, we show that maintenance of FANCD2 and FANCI proteins in a monoubiquitinated form is regulated by the ATR-kinase. Using recombinant proteins in biochemical reconstitution experiments we show that ATR directly phosphorylates FANCI on serine 556, 559, and 565 to stabilize its association with DNA and FANCD2. This increased association with DNA stimulates the conjugation of ubiquitin to both FANCI and FANCD2, but also inhibits ubiquitin deconjugation. Using phosphomimetic and phosphodead mutants of FANCI we show that S559 and S565 are particularly important for protecting the complex from the activity of the deubiquitinating enzyme USP1:UAF1. Our results reveal a major mechanism by which ATR kinase maintains the activation of the FA pathway, by promoting the accumulation of FANCD2 in the ubiquitinated form active in DNA repair.", + "authors": { + "abbreviation": "Winnie Tan, Sylvie van Twest, Vincent J Murphy, Andrew J Deans", + "authorList": [ + { + "ForeName": "Winnie", + "LastName": "Tan", + "abbrevName": "Tan W", + "email": null, + "isCollectiveName": false, + "name": "Winnie Tan" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + } + ], + "contacts": [] + }, + "doi": "10.3389/fcell.2020.00002", + "pmid": "32117957", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Front Cell Dev Biol 8 2020", + "title": "ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2." + } + }, + { + "pmid": "32066963", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "Vertebrate DNA crosslink repair excises toxic replication-blocking DNA crosslinks. Numerous factors involved in crosslink repair have been identified, and mutations in their corresponding genes cause Fanconi anemia (FA). A key step in crosslink repair is monoubiquitination of the FANCD2-FANCI heterodimer, which then recruits nucleases to remove the DNA lesion. Here, we use cryo-EM to determine the structures of recombinant chicken FANCD2 and FANCI complexes. FANCD2-FANCI adopts a closed conformation when the FANCD2 subunit is monoubiquitinated, creating a channel that encloses double-stranded DNA (dsDNA). Ubiquitin is positioned at the interface of FANCD2 and FANCI, where it acts as a covalent molecular pin to trap the complex on DNA. In contrast, isolated FANCD2 is a homodimer that is unable to bind DNA, suggestive of an autoinhibitory mechanism that prevents premature activation. Together, our work suggests that FANCD2-FANCI is a clamp that is locked onto DNA by ubiquitin, with distinct interfaces that may recruit other DNA repair factors.", + "authors": { + "abbreviation": "Pablo Alcón, Shabih Shakeel, Zhuo A Chen, ..., Lori A Passmore", + "authorList": [ + { + "ForeName": "Pablo", + "LastName": "Alcón", + "abbrevName": "Alcón P", + "email": null, + "isCollectiveName": false, + "name": "Pablo Alcón" + }, + { + "ForeName": "Shabih", + "LastName": "Shakeel", + "abbrevName": "Shakeel S", + "email": null, + "isCollectiveName": false, + "name": "Shabih Shakeel" + }, + { + "ForeName": "Zhuo", + "LastName": "Chen", + "abbrevName": "Chen ZA", + "email": null, + "isCollectiveName": false, + "name": "Zhuo A Chen" + }, + { + "ForeName": "Juri", + "LastName": "Rappsilber", + "abbrevName": "Rappsilber J", + "email": null, + "isCollectiveName": false, + "name": "Juri Rappsilber" + }, + { + "ForeName": "Ketan", + "LastName": "Patel", + "abbrevName": "Patel KJ", + "email": null, + "isCollectiveName": false, + "name": "Ketan J Patel" + }, + { + "ForeName": "Lori", + "LastName": "Passmore", + "abbrevName": "Passmore LA", + "email": "passmore@mrc-lmb.cam.ac.uk", + "isCollectiveName": false, + "name": "Lori A Passmore" + } + ], + "contacts": [ + { + "ForeName": "Lori", + "LastName": "Passmore", + "email": [ + "passmore@mrc-lmb.cam.ac.uk" + ], + "name": "Lori A Passmore" + } + ] + }, + "doi": "10.1038/s41594-020-0380-1", + "pmid": "32066963", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Struct Mol Biol 27 2020", + "title": "FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair." + } + }, + { + "pmid": "31873223", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "DNA-damage repair is implemented by proteins that are coordinated by specialized molecular signals. One such signal in the Fanconi anemia (FA) pathway for the repair of DNA interstrand crosslinks is the site-specific monoubiquitination of FANCD2 and FANCI. The signal is mediated by a multiprotein FA core complex (FA-CC) however, the mechanics for precise ubiquitination remain elusive. We show that FANCL, the RING-bearing module in FA-CC, allosterically activates its cognate ubiqutin-conjugating enzyme E2 UBE2T to drive site-specific FANCD2 ubiquitination. Unlike typical RING E3 ligases, FANCL catalyzes ubiquitination by rewiring the intraresidue network of UBE2T to influence the active site. Consequently, a basic triad unique to UBE2T engages a structured acidic patch near the target lysine on FANCD2. This three-dimensional complementarity, between the E2 active site and substrate surface, induced by FANCL is central to site-specific monoubiquitination in the FA pathway. Furthermore, the allosteric network of UBE2T can be engineered to enhance FANCL-catalyzed FANCD2-FANCI di-monoubiquitination without compromising site specificity.", + "authors": { + "abbreviation": "Viduth K Chaugule, Connor Arkinson, Martin L Rennie, ..., Helen Walden", + "authorList": [ + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": "Chaugule.Viduth@gmail.com", + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Martin", + "LastName": "Rennie", + "abbrevName": "Rennie ML", + "email": null, + "isCollectiveName": false, + "name": "Martin L Rennie" + }, + { + "ForeName": "Outi", + "LastName": "Kämäräinen", + "abbrevName": "Kämäräinen O", + "email": null, + "isCollectiveName": false, + "name": "Outi Kämäräinen" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": "helen.walden@glasgow.ac.uk", + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [ + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "email": [ + "Chaugule.Viduth@gmail.com" + ], + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "email": [ + "helen.walden@glasgow.ac.uk" + ], + "name": "Helen Walden" + } + ] + }, + "doi": "10.1038/s41589-019-0426-z", + "pmid": "31873223", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Chem Biol 16 2020", + "title": "Allosteric mechanism for site-specific ubiquitination of FANCD2." + } + }, + { + "pmid": "31632687", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Hanwen Zhu, Tianlong Zhang, Fang Wang, ..., Jianping Ding", + "authorList": [ + { + "ForeName": "Hanwen", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hanwen Zhu" + }, + { + "ForeName": "Tianlong", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tianlong Zhang" + }, + { + "ForeName": "Fang", + "LastName": "Wang", + "abbrevName": "Wang F", + "email": null, + "isCollectiveName": false, + "name": "Fang Wang" + }, + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Jianping", + "LastName": "Ding", + "abbrevName": "Ding J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Ding" + } + ], + "contacts": [] + }, + "doi": "10.1038/s41421-019-0102-1", + "pmid": "31632687", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Discov 5 2019", + "title": "Structural insights into the activation of USP46 by WDR48 and WDR20." + } + }, + { + "pmid": "31588918", + "pubmed": { + "ISODate": "2019-10-01T00:00:00.000Z", + "abstract": "Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.", + "authors": { + "abbreviation": "Dorothee Liebschner, Pavel V Afonine, Matthew L Baker, ..., Paul D Adams", + "authorList": [ + { + "ForeName": "Dorothee", + "LastName": "Liebschner", + "abbrevName": "Liebschner D", + "email": null, + "isCollectiveName": false, + "name": "Dorothee Liebschner" + }, + { + "ForeName": "Pavel", + "LastName": "Afonine", + "abbrevName": "Afonine PV", + "email": null, + "isCollectiveName": false, + "name": "Pavel V Afonine" + }, + { + "ForeName": "Matthew", + "LastName": "Baker", + "abbrevName": "Baker ML", + "email": null, + "isCollectiveName": false, + "name": "Matthew L Baker" + }, + { + "ForeName": "Gábor", + "LastName": "Bunkóczi", + "abbrevName": "Bunkóczi G", + "email": null, + "isCollectiveName": false, + "name": "Gábor Bunkóczi" + }, + { + "ForeName": "Vincent", + "LastName": "Chen", + "abbrevName": "Chen VB", + "email": null, + "isCollectiveName": false, + "name": "Vincent B Chen" + }, + { + "ForeName": "Tristan", + "LastName": "Croll", + "abbrevName": "Croll TI", + "email": null, + "isCollectiveName": false, + "name": "Tristan I Croll" + }, + { + "ForeName": "Bradley", + "LastName": "Hintze", + "abbrevName": "Hintze B", + "email": null, + "isCollectiveName": false, + "name": "Bradley Hintze" + }, + { + "ForeName": "Li", + "LastName": "Hung", + "abbrevName": "Hung LW", + "email": null, + "isCollectiveName": false, + "name": "Li Wei Hung" + }, + { + "ForeName": "Swati", + "LastName": "Jain", + "abbrevName": "Jain S", + "email": null, + "isCollectiveName": false, + "name": "Swati Jain" + }, + { + "ForeName": "Airlie", + "LastName": "McCoy", + "abbrevName": "McCoy AJ", + "email": null, + "isCollectiveName": false, + "name": "Airlie J McCoy" + }, + { + "ForeName": "Nigel", + "LastName": "Moriarty", + "abbrevName": "Moriarty NW", + "email": null, + "isCollectiveName": false, + "name": "Nigel W Moriarty" + }, + { + "ForeName": "Robert", + "LastName": "Oeffner", + "abbrevName": "Oeffner RD", + "email": null, + "isCollectiveName": false, + "name": "Robert D Oeffner" + }, + { + "ForeName": "Billy", + "LastName": "Poon", + "abbrevName": "Poon BK", + "email": null, + "isCollectiveName": false, + "name": "Billy K Poon" + }, + { + "ForeName": "Michael", + "LastName": "Prisant", + "abbrevName": "Prisant MG", + "email": null, + "isCollectiveName": false, + "name": "Michael G Prisant" + }, + { + "ForeName": "Randy", + "LastName": "Read", + "abbrevName": "Read RJ", + "email": null, + "isCollectiveName": false, + "name": "Randy J Read" + }, + { + "ForeName": "Jane", + "LastName": "Richardson", + "abbrevName": "Richardson JS", + "email": null, + "isCollectiveName": false, + "name": "Jane S Richardson" + }, + { + "ForeName": "David", + "LastName": "Richardson", + "abbrevName": "Richardson DC", + "email": null, + "isCollectiveName": false, + "name": "David C Richardson" + }, + { + "ForeName": "Massimo", + "LastName": "Sammito", + "abbrevName": "Sammito MD", + "email": null, + "isCollectiveName": false, + "name": "Massimo D Sammito" + }, + { + "ForeName": "Oleg", + "LastName": "Sobolev", + "abbrevName": "Sobolev OV", + "email": null, + "isCollectiveName": false, + "name": "Oleg V Sobolev" + }, + { + "ForeName": "Duncan", + "LastName": "Stockwell", + "abbrevName": "Stockwell DH", + "email": null, + "isCollectiveName": false, + "name": "Duncan H Stockwell" + }, + { + "ForeName": "Thomas", + "LastName": "Terwilliger", + "abbrevName": "Terwilliger TC", + "email": null, + "isCollectiveName": false, + "name": "Thomas C Terwilliger" + }, + { + "ForeName": "Alexandre", + "LastName": "Urzhumtsev", + "abbrevName": "Urzhumtsev AG", + "email": null, + "isCollectiveName": false, + "name": "Alexandre G Urzhumtsev" + }, + { + "ForeName": "Lizbeth", + "LastName": "Videau", + "abbrevName": "Videau LL", + "email": null, + "isCollectiveName": false, + "name": "Lizbeth L Videau" + }, + { + "ForeName": "Christopher", + "LastName": "Williams", + "abbrevName": "Williams CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J Williams" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + } + ], + "contacts": [] + }, + "doi": "10.1107/S2059798319011471", + "pmid": "31588918", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Acta Crystallogr D Struct Biol 75 2019", + "title": "Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "30850063", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "In higher eukaryotes, DNA damage repair response pathways are orchestrated by several molecular signals including ubiquitination. In particular the repair of DNA interstrand crosslinks, toxic to transcription and replication processes, involve the activation of the Fanconi anemia repair pathway. At the heart of this pathway lies the monoubiquitination of FANCD2 and FANCI proteins, which triggers the recruitment of DNA repair factors. A major road block in our understanding of this fundamental repair pathway arises from the challenge with generating sufficient quantities of site-specifically monoubiquitinated FANCD2 and FANCI proteins to enable mechanistic and molecular studies. Current in vitro methods rely on the purification of a large (~0.8MDa), multiprotein E3 complex that can only partially monoubiquitinate a FANCD2-FANCI-DNA complex. In this chapter, we describe detailed protocols for the preparation of homogeneously and natively monoubiquitinated FANCD2 and FANCI proteins in isolation. The method relies on the use of a minimal E3 module and an engineered E2 variant that together drive site-specific ubiquitination of the isolated substrates, without the requirement of DNA cofactors. Using the enzymatic approach, we also demonstrate how added functionalities such as a fluorescently labeled ubiquitin can be conjugated on the FANCD2 and FANCI substrates, thus enabling multiple downstream applications.", + "authors": { + "abbreviation": "Viduth K Chaugule, Connor Arkinson, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": "viduth.chaugule@glasgow.ac.uk", + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": "helen.walden@glasgow.ac.uk", + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [ + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "email": [ + "viduth.chaugule@glasgow.ac.uk" + ], + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "email": [ + "helen.walden@glasgow.ac.uk" + ], + "name": "Helen Walden" + } + ] + }, + "doi": "10.1016/bs.mie.2018.12.021", + "pmid": "30850063", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Methods Enzymol 618 2019", + "title": "Enzymatic preparation of monoubiquitinated FANCD2 and FANCI proteins." + } + }, + { + "pmid": "30576655", + "pubmed": { + "ISODate": "2018-12-20T00:00:00.000Z", + "abstract": "BRCA1-deficient tumor cells have defects in homologous-recombination repair and replication fork stability, resulting in PARP inhibitor sensitivity. Here, we demonstrate that a deubiquitinase, USP1, is upregulated in tumors with mutations in BRCA1. Knockdown or inhibition of USP1 resulted in replication fork destabilization and decreased viability of BRCA1-deficient cells, revealing a synthetic lethal relationship. USP1 binds to and is stimulated by fork DNA. A truncated form of USP1, lacking its DNA-binding region, was not stimulated by DNA and failed to localize and protect replication forks. Persistence of monoubiquitinated PCNA at the replication fork was the mechanism of cell death in the absence of USP1. Taken together, USP1 exhibits DNA-mediated activation at the replication fork, protects the fork, and promotes survival in BRCA1-deficient cells. Inhibition of USP1 may be a useful treatment for a subset of PARP-inhibitor-resistant BRCA1-deficient tumors with acquired replication fork stabilization.", + "authors": { + "abbreviation": "Kah Suan Lim, Heng Li, Emma A Roberts, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Emma", + "LastName": "Roberts", + "abbrevName": "Roberts EA", + "email": null, + "isCollectiveName": false, + "name": "Emma A Roberts" + }, + { + "ForeName": "Emily", + "LastName": "Gaudiano", + "abbrevName": "Gaudiano EF", + "email": null, + "isCollectiveName": false, + "name": "Emily F Gaudiano" + }, + { + "ForeName": "Connor", + "LastName": "Clairmont", + "abbrevName": "Clairmont C", + "email": null, + "isCollectiveName": false, + "name": "Connor Clairmont" + }, + { + "ForeName": "Larissa", + "LastName": "Sambel", + "abbrevName": "Sambel LA", + "email": null, + "isCollectiveName": false, + "name": "Larissa Alina Sambel" + }, + { + "ForeName": "Karthikeyan", + "LastName": "Ponnienselvan", + "abbrevName": "Ponnienselvan K", + "email": null, + "isCollectiveName": false, + "name": "Karthikeyan Ponnienselvan" + }, + { + "ForeName": "Jessica", + "LastName": "Liu", + "abbrevName": "Liu JC", + "email": null, + "isCollectiveName": false, + "name": "Jessica C Liu" + }, + { + "ForeName": "Chunyu", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Chunyu Yang" + }, + { + "ForeName": "David", + "LastName": "Kozono", + "abbrevName": "Kozono D", + "email": null, + "isCollectiveName": false, + "name": "David Kozono" + }, + { + "ForeName": "Kalindi", + "LastName": "Parmar", + "abbrevName": "Parmar K", + "email": null, + "isCollectiveName": false, + "name": "Kalindi Parmar" + }, + { + "ForeName": "Timur", + "LastName": "Yusufzai", + "abbrevName": "Yusufzai T", + "email": null, + "isCollectiveName": false, + "name": "Timur Yusufzai" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": null, + "isCollectiveName": false, + "name": "Ning Zheng" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": "alan_dandrea@dfci.harvard.edu", + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [ + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "email": [ + "alan_dandrea@dfci.harvard.edu" + ], + "name": "Alan D D'Andrea" + } + ] + }, + "doi": "10.1016/j.molcel.2018.10.045", + "pmid": "30576655", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 72 2018", + "title": "USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "30412051", + "pubmed": { + "ISODate": "2018-11-09T00:00:00.000Z", + "abstract": "Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal. Ewald sphere curvature correction improves resolution for large particles. We illustrate these developments with publicly available data sets: together with a Bayesian approach to beam-induced motion correction it leads to resolution improvements of 0.2-0.7 Å compared to previous RELION versions.", + "authors": { + "abbreviation": "Jasenko Zivanov, Takanori Nakane, Björn O Forsberg, ..., Sjors Hw Scheres", + "authorList": [ + { + "ForeName": "Jasenko", + "LastName": "Zivanov", + "abbrevName": "Zivanov J", + "email": null, + "isCollectiveName": false, + "name": "Jasenko Zivanov" + }, + { + "ForeName": "Takanori", + "LastName": "Nakane", + "abbrevName": "Nakane T", + "email": null, + "isCollectiveName": false, + "name": "Takanori Nakane" + }, + { + "ForeName": "Björn", + "LastName": "Forsberg", + "abbrevName": "Forsberg BO", + "email": null, + "isCollectiveName": false, + "name": "Björn O Forsberg" + }, + { + "ForeName": "Dari", + "LastName": "Kimanius", + "abbrevName": "Kimanius D", + "email": null, + "isCollectiveName": false, + "name": "Dari Kimanius" + }, + { + "ForeName": "Wim", + "LastName": "Hagen", + "abbrevName": "Hagen WJ", + "email": null, + "isCollectiveName": false, + "name": "Wim Jh Hagen" + }, + { + "ForeName": "Erik", + "LastName": "Lindahl", + "abbrevName": "Lindahl E", + "email": null, + "isCollectiveName": false, + "name": "Erik Lindahl" + }, + { + "ForeName": "Sjors", + "LastName": "Scheres", + "abbrevName": "Scheres SH", + "email": null, + "isCollectiveName": false, + "name": "Sjors Hw Scheres" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.42166", + "pmid": "30412051", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Elife 7 2018", + "title": "New tools for automated high-resolution cryo-EM structure determination in RELION-3." + } + }, + { + "pmid": "29872004", + "pubmed": { + "ISODate": "2018-06-01T00:00:00.000Z", + "abstract": "This article describes the implementation of real-space refinement in the phenix.real_space_refine program from the PHENIX suite. The use of a simplified refinement target function enables very fast calculation, which in turn makes it possible to identify optimal data-restraint weights as part of routine refinements with little runtime cost. Refinement of atomic models against low-resolution data benefits from the inclusion of as much additional information as is available. In addition to standard restraints on covalent geometry, phenix.real_space_refine makes use of extra information such as secondary-structure and rotamer-specific restraints, as well as restraints or constraints on internal molecular symmetry. The re-refinement of 385 cryo-EM-derived models available in the Protein Data Bank at resolutions of 6 Å or better shows significant improvement of the models and of the fit of these models to the target maps.", + "authors": { + "abbreviation": "Pavel V Afonine, Billy K Poon, Randy J Read, ..., Paul D Adams", + "authorList": [ + { + "ForeName": "Pavel", + "LastName": "Afonine", + "abbrevName": "Afonine PV", + "email": null, + "isCollectiveName": false, + "name": "Pavel V Afonine" + }, + { + "ForeName": "Billy", + "LastName": "Poon", + "abbrevName": "Poon BK", + "email": null, + "isCollectiveName": false, + "name": "Billy K Poon" + }, + { + "ForeName": "Randy", + "LastName": "Read", + "abbrevName": "Read RJ", + "email": null, + "isCollectiveName": false, + "name": "Randy J Read" + }, + { + "ForeName": "Oleg", + "LastName": "Sobolev", + "abbrevName": "Sobolev OV", + "email": null, + "isCollectiveName": false, + "name": "Oleg V Sobolev" + }, + { + "ForeName": "Thomas", + "LastName": "Terwilliger", + "abbrevName": "Terwilliger TC", + "email": null, + "isCollectiveName": false, + "name": "Thomas C Terwilliger" + }, + { + "ForeName": "Alexandre", + "LastName": "Urzhumtsev", + "abbrevName": "Urzhumtsev A", + "email": null, + "isCollectiveName": false, + "name": "Alexandre Urzhumtsev" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + } + ], + "contacts": [] + }, + "doi": "10.1107/S2059798318006551", + "pmid": "29872004", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Acta Crystallogr D Struct Biol 74 2018", + "title": "Real-space refinement in PHENIX for cryo-EM and crystallography." + } + }, + { + "pmid": "29021737", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "BioXTAS RAW is a graphical-user-interface-based free open-source Python program for reduction and analysis of small-angle X-ray solution scattering (SAXS) data. The software is designed for biological SAXS data and enables creation and plotting of one-dimensional scattering profiles from two-dimensional detector images, standard data operations such as averaging and subtraction and analysis of radius of gyration and molecular weight, and advanced analysis such as calculation of inverse Fourier transforms and envelopes. It also allows easy processing of inline size-exclusion chromatography coupled SAXS data and data deconvolution using the evolving factor analysis method. It provides an alternative to closed-source programs such as Primus and ScÅtter for primary data analysis. Because it can calibrate, mask and integrate images it also provides an alternative to synchrotron beamline pipelines that scientists can install on their own computers and use both at home and at the beamline.", + "authors": { + "abbreviation": "Jesse Bennett Hopkins, Richard E Gillilan, Soren Skou", + "authorList": [ + { + "ForeName": "Jesse", + "LastName": "Hopkins", + "abbrevName": "Hopkins JB", + "email": null, + "isCollectiveName": false, + "name": "Jesse Bennett Hopkins" + }, + { + "ForeName": "Richard", + "LastName": "Gillilan", + "abbrevName": "Gillilan RE", + "email": null, + "isCollectiveName": false, + "name": "Richard E Gillilan" + }, + { + "ForeName": "Soren", + "LastName": "Skou", + "abbrevName": "Skou S", + "email": null, + "isCollectiveName": false, + "name": "Soren Skou" + } + ], + "contacts": [] + }, + "doi": "10.1107/S1600576717011438", + "pmid": "29021737", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Appl Crystallogr 50 2017", + "title": "BioXTAS RAW: improvements to a free open-source program for small-angle X-ray scattering data reduction and analysis." + } + }, + { + "pmid": "28808438", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "ATSAS is a comprehensive software suite for the analysis of small-angle scattering data from dilute solutions of biological macromolecules or nanoparticles. It contains applications for primary data processing and assessment, ab initio bead modelling, and model validation, as well as methods for the analysis of flexibility and mixtures. In addition, approaches are supported that utilize information from X-ray crystallography, nuclear magnetic resonance spectroscopy or atomistic homology modelling to construct hybrid models based on the scattering data. This article summarizes the progress made during the 2.5-2.8 ATSAS release series and highlights the latest developments. These include AMBIMETER, an assessment of the reconstruction ambiguity of experimental data; DATCLASS, a multiclass shape classification based on experimental data; SASRES, for estimating the resolution of ab initio model reconstructions; CHROMIXS, a convenient interface to analyse in-line size exclusion chromatography data; SHANUM, to evaluate the useful angular range in measured data; SREFLEX, to refine available high-resolution models using normal mode analysis; SUPALM for a rapid superposition of low- and high-resolution models; and SASPy, the ATSAS plugin for interactive modelling in PyMOL. All these features and other improvements are included in the ATSAS release 2.8, freely available for academic users from https://www.embl-hamburg.de/biosaxs/software.html.", + "authors": { + "abbreviation": "D Franke, M V Petoukhov, P V Konarev, ..., D I Svergun", + "authorList": [ + { + "ForeName": "D", + "LastName": "Franke", + "abbrevName": "Franke D", + "email": null, + "isCollectiveName": false, + "name": "D Franke" + }, + { + "ForeName": "M", + "LastName": "Petoukhov", + "abbrevName": "Petoukhov MV", + "email": null, + "isCollectiveName": false, + "name": "M V Petoukhov" + }, + { + "ForeName": "P", + "LastName": "Konarev", + "abbrevName": "Konarev PV", + "email": null, + "isCollectiveName": false, + "name": "P V Konarev" + }, + { + "ForeName": "A", + "LastName": "Panjkovich", + "abbrevName": "Panjkovich A", + "email": null, + "isCollectiveName": false, + "name": "A Panjkovich" + }, + { + "ForeName": "A", + "LastName": "Tuukkanen", + "abbrevName": "Tuukkanen A", + "email": null, + "isCollectiveName": false, + "name": "A Tuukkanen" + }, + { + "ForeName": "H", + "LastName": "Mertens", + "abbrevName": "Mertens HDT", + "email": null, + "isCollectiveName": false, + "name": "H D T Mertens" + }, + { + "ForeName": "A", + "LastName": "Kikhney", + "abbrevName": "Kikhney AG", + "email": null, + "isCollectiveName": false, + "name": "A G Kikhney" + }, + { + "ForeName": "N", + "LastName": "Hajizadeh", + "abbrevName": "Hajizadeh NR", + "email": null, + "isCollectiveName": false, + "name": "N R Hajizadeh" + }, + { + "ForeName": "J", + "LastName": "Franklin", + "abbrevName": "Franklin JM", + "email": null, + "isCollectiveName": false, + "name": "J M Franklin" + }, + { + "ForeName": "C", + "LastName": "Jeffries", + "abbrevName": "Jeffries CM", + "email": null, + "isCollectiveName": false, + "name": "C M Jeffries" + }, + { + "ForeName": "D", + "LastName": "Svergun", + "abbrevName": "Svergun DI", + "email": null, + "isCollectiveName": false, + "name": "D I Svergun" + } + ], + "contacts": [] + }, + "doi": "10.1107/S1600576717007786", + "pmid": "28808438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Appl Crystallogr 50 2017", + "title": "ATSAS 2.8: a comprehensive data analysis suite for small-angle scattering from macromolecular solutions." + } + }, + { + "pmid": "28710774", + "pubmed": { + "ISODate": "2018-01-01T00:00:00.000Z", + "abstract": "UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and disparate types of data attendant with cutting-edge experimental methods, while providing advanced options for high-quality rendering (interactive ambient occlusion, reliable molecular surface calculations, etc.) and professional approaches to software design and distribution. This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility. ChimeraX is free for noncommercial use and is available from http://www.rbvi.ucsf.edu/chimerax/ for Windows, Mac, and Linux.", + "authors": { + "abbreviation": "Thomas D Goddard, Conrad C Huang, Elaine C Meng, ..., Thomas E Ferrin", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Goddard", + "abbrevName": "Goddard TD", + "email": null, + "isCollectiveName": false, + "name": "Thomas D Goddard" + }, + { + "ForeName": "Conrad", + "LastName": "Huang", + "abbrevName": "Huang CC", + "email": null, + "isCollectiveName": false, + "name": "Conrad C Huang" + }, + { + "ForeName": "Elaine", + "LastName": "Meng", + "abbrevName": "Meng EC", + "email": null, + "isCollectiveName": false, + "name": "Elaine C Meng" + }, + { + "ForeName": "Eric", + "LastName": "Pettersen", + "abbrevName": "Pettersen EF", + "email": null, + "isCollectiveName": false, + "name": "Eric F Pettersen" + }, + { + "ForeName": "Gregory", + "LastName": "Couch", + "abbrevName": "Couch GS", + "email": null, + "isCollectiveName": false, + "name": "Gregory S Couch" + }, + { + "ForeName": "John", + "LastName": "Morris", + "abbrevName": "Morris JH", + "email": null, + "isCollectiveName": false, + "name": "John H Morris" + }, + { + "ForeName": "Thomas", + "LastName": "Ferrin", + "abbrevName": "Ferrin TE", + "email": null, + "isCollectiveName": false, + "name": "Thomas E Ferrin" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.3235", + "pmid": "28710774", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Protein Sci 27 2018", + "title": "UCSF ChimeraX: Meeting modern challenges in visualization and analysis." + } + }, + { + "pmid": "28636932", + "pubmed": { + "ISODate": "2017-06-20T00:00:00.000Z", + "abstract": "Repair of interstrand crosslinks by the Fanconi anemia (FA) pathway requires both monoubiquitination and de-ubiquitination of the FANCI/FANCD2 (FANCI/D2) complex. In the standing model, the phosphorylation of six sites in the FANCI S/TQ cluster domain occurs upstream of, and promotes, FANCI/D2 monoubiquitination. We generated phospho-specific antibodies against three different S/TQ cluster sites (serines 556, 559, and 565) on human FANCI and found that, in contrast to the standing model, distinct FANCI sites were phosphorylated either predominantly upstream (ubiquitination independent; serine 556) or downstream (ubiquitination-linked; serines 559 and 565) of FANCI/D2 monoubiquitination. Ubiquitination-linked FANCI phosphorylation inhibited FANCD2 de-ubiquitination and bypassed the need to de-ubiquitinate FANCD2 to achieve effective interstrand crosslink repair. USP1 depletion suppressed ubiquitination-linked FANCI phosphorylation despite increasing FANCI/D2 monoubiquitination, providing an explanation of why FANCD2 de-ubiquitination is important for function of the FA pathway. Our work results in a refined model of how FANCI phosphorylation activates the FANCI/D2 complex.", + "authors": { + "abbreviation": "Ronald S Cheung, Maria Castella, Antonio Abeyta, ..., Toshiyasu Taniguchi", + "authorList": [ + { + "ForeName": "Ronald", + "LastName": "Cheung", + "abbrevName": "Cheung RS", + "email": null, + "isCollectiveName": false, + "name": "Ronald S Cheung" + }, + { + "ForeName": "Maria", + "LastName": "Castella", + "abbrevName": "Castella M", + "email": null, + "isCollectiveName": false, + "name": "Maria Castella" + }, + { + "ForeName": "Antonio", + "LastName": "Abeyta", + "abbrevName": "Abeyta A", + "email": null, + "isCollectiveName": false, + "name": "Antonio Abeyta" + }, + { + "ForeName": "Philip", + "LastName": "Gafken", + "abbrevName": "Gafken PR", + "email": null, + "isCollectiveName": false, + "name": "Philip R Gafken" + }, + { + "ForeName": "Nyka", + "LastName": "Tucker", + "abbrevName": "Tucker N", + "email": null, + "isCollectiveName": false, + "name": "Nyka Tucker" + }, + { + "ForeName": "Toshiyasu", + "LastName": "Taniguchi", + "abbrevName": "Taniguchi T", + "email": "ttaniguc@fhcrc.org", + "isCollectiveName": false, + "name": "Toshiyasu Taniguchi" + } + ], + "contacts": [ + { + "ForeName": "Toshiyasu", + "LastName": "Taniguchi", + "email": [ + "ttaniguc@fhcrc.org" + ], + "name": "Toshiyasu Taniguchi" + } + ] + }, + "doi": "10.1016/j.celrep.2017.05.081", + "pmid": "28636932", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Cell Rep 19 2017", + "title": "Ubiquitination-Linked Phosphorylation of the FANCI S/TQ Cluster Contributes to Activation of the Fanconi Anemia I/D2 Complex." + } + }, + { + "pmid": "28498721", + "pubmed": { + "ISODate": "2017-06-20T00:00:00.000Z", + "abstract": "Protein ubiquitination is one of the most powerful posttranslational modifications of proteins, as it regulates a plethora of cellular processes in distinct manners. Simple monoubiquitination events coexist with more complex forms of polyubiquitination, the latter featuring many different chain architectures. Ubiquitin can be subjected to further posttranslational modifications (e.g., phosphorylation and acetylation) and can also be part of mixed polymers with ubiquitin-like modifiers such as SUMO (small ubiquitin-related modifier) or NEDD8 (neural precursor cell expressed, developmentally downregulated 8). Together, cellular ubiquitination events form a sophisticated and versatile ubiquitin code. Deubiquitinases (DUBs) reverse ubiquitin signals with equally high sophistication. In this review, we conceptualize the many layers of specificity that DUBs encompass to control the ubiquitin code and discuss examples in which DUB specificity has been understood at the molecular level. We further discuss the many mechanisms of DUB regulation with a focus on those that modulate catalytic activity. Our review provides a framework to tackle lingering questions in DUB biology.", + "authors": { + "abbreviation": "Tycho E T Mevissen, David Komander", + "authorList": [ + { + "ForeName": "Tycho", + "LastName": "Mevissen", + "abbrevName": "Mevissen TET", + "email": "dk@mrc-lmb.cam.ac.uk", + "isCollectiveName": false, + "name": "Tycho E T Mevissen" + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": "dk@mrc-lmb.cam.ac.uk", + "isCollectiveName": false, + "name": "David Komander" + } + ], + "contacts": [ + { + "ForeName": "Tycho", + "LastName": "Mevissen", + "email": [ + "dk@mrc-lmb.cam.ac.uk" + ], + "name": "Tycho E T Mevissen" + }, + { + "ForeName": "David", + "LastName": "Komander", + "email": [ + "dk@mrc-lmb.cam.ac.uk" + ], + "name": "David Komander" + } + ] + }, + "doi": "10.1146/annurev-biochem-061516-044916", + "pmid": "28498721", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Biochem 86 2017", + "title": "Mechanisms of Deubiquitinase Specificity and Regulation." + } + }, + { + "pmid": "28165473", + "pubmed": { + "ISODate": "2017-03-01T00:00:00.000Z", + "abstract": "Single-particle electron cryomicroscopy (cryo-EM) is a powerful method for determining the structures of biological macromolecules. With automated microscopes, cryo-EM data can often be obtained in a few days. However, processing cryo-EM image data to reveal heterogeneity in the protein structure and to refine 3D maps to high resolution frequently becomes a severe bottleneck, requiring expert intervention, prior structural knowledge, and weeks of calculations on expensive computer clusters. Here we show that stochastic gradient descent (SGD) and branch-and-bound maximum likelihood optimization algorithms permit the major steps in cryo-EM structure determination to be performed in hours or minutes on an inexpensive desktop computer. Furthermore, SGD with Bayesian marginalization allows ab initio 3D classification, enabling automated analysis and discovery of unexpected structures without bias from a reference map. These algorithms are combined in a user-friendly computer program named cryoSPARC (http://www.cryosparc.com).", + "authors": { + "abbreviation": "Ali Punjani, John L Rubinstein, David J Fleet, Marcus A Brubaker", + "authorList": [ + { + "ForeName": "Ali", + "LastName": "Punjani", + "abbrevName": "Punjani A", + "email": null, + "isCollectiveName": false, + "name": "Ali Punjani" + }, + { + "ForeName": "John", + "LastName": "Rubinstein", + "abbrevName": "Rubinstein JL", + "email": null, + "isCollectiveName": false, + "name": "John L Rubinstein" + }, + { + "ForeName": "David", + "LastName": "Fleet", + "abbrevName": "Fleet DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Fleet" + }, + { + "ForeName": "Marcus", + "LastName": "Brubaker", + "abbrevName": "Brubaker MA", + "email": null, + "isCollectiveName": false, + "name": "Marcus A Brubaker" + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth.4169", + "pmid": "28165473", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Methods 14 2017", + "title": "cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination." + } + }, + { + "pmid": "27986371", + "pubmed": { + "ISODate": "2017-01-19T00:00:00.000Z", + "abstract": "Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The \"FA core complex\" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. FANCA and FANCG are dispensable for maximal in vitro ubiquitination. Finally, we show that the reversal of this reaction by the USP1:UAF1 deubiquitinase only occurs when DNA is disengaged. Our work reveals the mechanistic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for chemotherapy responses and prevention of Fanconi anemia.", + "authors": { + "abbreviation": "Sylvie van Twest, Vincent J Murphy, Charlotte Hodson, ..., Andrew J Deans", + "authorList": [ + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Charlotte", + "LastName": "Hodson", + "abbrevName": "Hodson C", + "email": null, + "isCollectiveName": false, + "name": "Charlotte Hodson" + }, + { + "ForeName": "Winnie", + "LastName": "Tan", + "abbrevName": "Tan W", + "email": null, + "isCollectiveName": false, + "name": "Winnie Tan" + }, + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Julienne", + "LastName": "O'Rourke", + "abbrevName": "O'Rourke JJ", + "email": null, + "isCollectiveName": false, + "name": "Julienne J O'Rourke" + }, + { + "ForeName": "Jörg", + "LastName": "Heierhorst", + "abbrevName": "Heierhorst J", + "email": null, + "isCollectiveName": false, + "name": "Jörg Heierhorst" + }, + { + "ForeName": "Wayne", + "LastName": "Crismani", + "abbrevName": "Crismani W", + "email": null, + "isCollectiveName": false, + "name": "Wayne Crismani" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": "adeans@svi.edu.au", + "isCollectiveName": false, + "name": "Andrew J Deans" + } + ], + "contacts": [ + { + "ForeName": "Andrew", + "LastName": "Deans", + "email": [ + "adeans@svi.edu.au" + ], + "name": "Andrew J Deans" + } + ] + }, + "doi": "10.1016/j.molcel.2016.11.005", + "pmid": "27986371", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 65 2017", + "title": "Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "27230526", + "pubmed": { + "ISODate": "2016-05-27T00:00:00.000Z", + "abstract": "Ubiquitylation is essential for signal transduction as well as cell division and differentiation in all eukaryotes. Substrate modifications range from a single ubiquitin molecule to complex polymeric chains, with different types of ubiquitylation often eliciting distinct outcomes. The recent identification of novel chain topologies has improved our understanding of how ubiquitylation establishes precise communication within cells. Here, we discuss how the increasing complexity of ubiquitylation is employed to ensure robust and faithful signal transduction in eukaryotic cells.", + "authors": { + "abbreviation": "Richard Yau, Michael Rape", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Yau", + "abbrevName": "Yau R", + "email": null, + "isCollectiveName": false, + "name": "Richard Yau" + }, + { + "ForeName": "Michael", + "LastName": "Rape", + "abbrevName": "Rape M", + "email": null, + "isCollectiveName": false, + "name": "Michael Rape" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3358", + "pmid": "27230526", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "The increasing complexity of the ubiquitin code." + } + }, + { + "pmid": "26388029", + "pubmed": { + "ISODate": "2015-11-03T00:00:00.000Z", + "abstract": "Protein ubiquitination patterns are an important component of cellular signaling. The WD-repeat protein WDR48 (USP1-associated factor UAF-1) stimulates activity of ubiquitin-specific proteases USP1, USP12, and USP46. To understand how WDR48 exerts its effect on the USP scaffold, we determined structures of the ternary WDR48:USP46:ubiquitin complex. WDR48 interacts with the USP46 fingers subdomain via a relatively small, highly polar surface on the top center of the WDR48 β propeller. In addition, WDR48 has a novel ancillary domain and a C-terminal SUMO-like domain encircling the USP46-bound ubiquitin. Mutation of residues involved in the WDR48:USP46 interaction abrogated both binding and deubiquitinase activity of the complex. An analogous mutation in USP1 similarly blocked WDR48-dependent activation. Our data suggest a possible mechanism of deubiquitinase stimulation via stabilization and prolonged residence time of substrate. The unprecedented mode of interaction between the USP fingers domain and the WD-repeat β propeller serves as a prototypical example for this family of deubiquitinases.", + "authors": { + "abbreviation": "Jianping Yin, Allyn J Schoeffler, Katherine Wickliffe, ..., Seth F Harris", + "authorList": [ + { + "ForeName": "Jianping", + "LastName": "Yin", + "abbrevName": "Yin J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Yin" + }, + { + "ForeName": "Allyn", + "LastName": "Schoeffler", + "abbrevName": "Schoeffler AJ", + "email": null, + "isCollectiveName": false, + "name": "Allyn J Schoeffler" + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe K", + "email": null, + "isCollectiveName": false, + "name": "Katherine Wickliffe" + }, + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton" + }, + { + "ForeName": "Melissa", + "LastName": "Starovasnik", + "abbrevName": "Starovasnik MA", + "email": null, + "isCollectiveName": false, + "name": "Melissa A Starovasnik" + }, + { + "ForeName": "Erin", + "LastName": "Dueber", + "abbrevName": "Dueber EC", + "email": "dueber.erin@gene.com", + "isCollectiveName": false, + "name": "Erin C Dueber" + }, + { + "ForeName": "Seth", + "LastName": "Harris", + "abbrevName": "Harris SF", + "email": "harris.seth@gene.com", + "isCollectiveName": false, + "name": "Seth F Harris" + } + ], + "contacts": [ + { + "ForeName": "Erin", + "LastName": "Dueber", + "email": [ + "dueber.erin@gene.com" + ], + "name": "Erin C Dueber" + }, + { + "ForeName": "Seth", + "LastName": "Harris", + "email": [ + "harris.seth@gene.com" + ], + "name": "Seth F Harris" + } + ] + }, + "doi": "10.1016/j.str.2015.08.010", + "pmid": "26388029", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Structure 23 2015", + "title": "Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46." + } + }, + { + "pmid": "25404403", + "pubmed": { + "ISODate": "2014-11-18T00:00:00.000Z", + "abstract": "Ubiquitin-specific protease USP4 is emerging as an important regulator of cellular pathways, including the TGF-β response, NF-κB signalling and splicing, with possible roles in cancer. Here we show that USP4 has its catalytic triad arranged in a productive conformation. Nevertheless, it requires its N-terminal DUSP-Ubl domain to achieve full catalytic turnover. Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis. The DUSP-Ubl domain is able to enhance ubiquitin dissociation, hence promoting efficient turnover. In a mechanism that requires all USP4 domains, binding of the DUSP-Ubl domain promotes a change of a switching loop near the active site. This 'allosteric regulation of product discharge' provides a novel way of regulating deubiquitinating enzymes that may have relevance for other enzyme classes. ", + "authors": { + "abbreviation": "Marcello Clerici, Mark P A Luna-Vargas, Alex C Faesen, Titia K Sixma", + "authorList": [ + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Mark", + "LastName": "Luna-Vargas", + "abbrevName": "Luna-Vargas MP", + "email": null, + "isCollectiveName": false, + "name": "Mark P A Luna-Vargas" + }, + { + "ForeName": "Alex", + "LastName": "Faesen", + "abbrevName": "Faesen AC", + "email": null, + "isCollectiveName": false, + "name": "Alex C Faesen" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": null, + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6399", + "pmid": "25404403", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 5 2014", + "title": "The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange." + } + }, + { + "pmid": "24531842", + "pubmed": { + "ISODate": "2014-04-01T00:00:00.000Z", + "abstract": "Protein ubiquitination and deubiquitination are central to the control of a large number of cellular pathways and signaling networks in eukaryotes. Although the essential roles of ubiquitination have been established in the eukaryotic DNA damage response, the deubiquitination process remains poorly defined. Chemical probes that perturb the activity of deubiquitinases (DUBs) are needed to characterize the cellular function of deubiquitination. Here we report ML323 (2), a highly potent inhibitor of the USP1-UAF1 deubiquitinase complex with excellent selectivity against human DUBs, deSUMOylase, deneddylase and unrelated proteases. Using ML323, we interrogated deubiquitination in the cellular response to UV- and cisplatin-induced DNA damage and revealed new insights into the requirement of deubiquitination in the DNA translesion synthesis and Fanconi anemia pathways. Moreover, ML323 potentiates cisplatin cytotoxicity in non-small cell lung cancer and osteosarcoma cells. Our findings point to USP1-UAF1 as a key regulator of the DNA damage response and a target for overcoming resistance to the platinum-based anticancer drugs. ", + "authors": { + "abbreviation": "Qin Liang, Thomas S Dexheimer, Ping Zhang, ..., Zhihao Zhuang", + "authorList": [ + { + "ForeName": "Qin", + "LastName": "Liang", + "abbrevName": "Liang Q", + "email": null, + "isCollectiveName": false, + "name": "Qin Liang" + }, + { + "ForeName": "Thomas", + "LastName": "Dexheimer", + "abbrevName": "Dexheimer TS", + "email": null, + "isCollectiveName": false, + "name": "Thomas S Dexheimer" + }, + { + "ForeName": "Ping", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Ping Zhang" + }, + { + "ForeName": "Andrew", + "LastName": "Rosenthal", + "abbrevName": "Rosenthal AS", + "email": null, + "isCollectiveName": false, + "name": "Andrew S Rosenthal" + }, + { + "ForeName": "Mark", + "LastName": "Villamil", + "abbrevName": "Villamil MA", + "email": null, + "isCollectiveName": false, + "name": "Mark A Villamil" + }, + { + "ForeName": "Changjun", + "LastName": "You", + "abbrevName": "You C", + "email": null, + "isCollectiveName": false, + "name": "Changjun You" + }, + { + "ForeName": "Qiuting", + "LastName": "Zhang", + "abbrevName": "Zhang Q", + "email": null, + "isCollectiveName": false, + "name": "Qiuting Zhang" + }, + { + "ForeName": "Junjun", + "LastName": "Chen", + "abbrevName": "Chen J", + "email": null, + "isCollectiveName": false, + "name": "Junjun Chen" + }, + { + "ForeName": "Christine", + "LastName": "Ott", + "abbrevName": "Ott CA", + "email": null, + "isCollectiveName": false, + "name": "Christine A Ott" + }, + { + "ForeName": "Hongmao", + "LastName": "Sun", + "abbrevName": "Sun H", + "email": null, + "isCollectiveName": false, + "name": "Hongmao Sun" + }, + { + "ForeName": "Diane", + "LastName": "Luci", + "abbrevName": "Luci DK", + "email": null, + "isCollectiveName": false, + "name": "Diane K Luci" + }, + { + "ForeName": "Bifeng", + "LastName": "Yuan", + "abbrevName": "Yuan B", + "email": null, + "isCollectiveName": false, + "name": "Bifeng Yuan" + }, + { + "ForeName": "Anton", + "LastName": "Simeonov", + "abbrevName": "Simeonov A", + "email": null, + "isCollectiveName": false, + "name": "Anton Simeonov" + }, + { + "ForeName": "Ajit", + "LastName": "Jadhav", + "abbrevName": "Jadhav A", + "email": null, + "isCollectiveName": false, + "name": "Ajit Jadhav" + }, + { + "ForeName": "Hui", + "LastName": "Xiao", + "abbrevName": "Xiao H", + "email": null, + "isCollectiveName": false, + "name": "Hui Xiao" + }, + { + "ForeName": "Yinsheng", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinsheng Wang" + }, + { + "ForeName": "David", + "LastName": "Maloney", + "abbrevName": "Maloney DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Maloney" + }, + { + "ForeName": "Zhihao", + "LastName": "Zhuang", + "abbrevName": "Zhuang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhihao Zhuang" + } + ], + "contacts": [] + }, + "doi": "10.1038/nchembio.1455", + "pmid": "24531842", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Nat Chem Biol 10 2014", + "title": "A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses." + } + }, + { + "pmid": "24356955", + "pubmed": { + "ISODate": "2014-02-07T00:00:00.000Z", + "abstract": "Ubiquitin-mediated endocytosis and degradation of glutamate receptors controls their synaptic abundance and is implicated in modulating synaptic strength. The deubiquitinating enzymes (DUBs) that function in the nervous system are beginning to be defined, but the mechanisms that control DUB activity in vivo are understood poorly. We found previously that the DUB USP-46 deubiquitinates the Caenorhabditis elegans glutamate receptor GLR-1 and prevents its degradation in the lysosome. The WD40-repeat (WDR) proteins WDR20 and WDR48/UAF1 have been shown to bind to USP46 and stimulate its catalytic activity in other systems. Here we identify the C. elegans homologs of these WDR proteins and show that C. elegans WDR-20 and WDR-48 can bind and stimulate USP-46 catalytic activity in vitro. Overexpression of these activator proteins in vivo increases the abundance of GLR-1 in the ventral nerve cord, and this effect is further enhanced by coexpression of USP-46. Biochemical characterization indicates that this increase in GLR-1 abundance correlates with decreased levels of ubiquitin-GLR-1 conjugates, suggesting that WDR-20, WDR-48, and USP-46 function together to deubiquitinate and stabilize GLR-1 in neurons. Overexpression of WDR-20 and WDR-48 results in alterations in locomotion behavior consistent with increased glutamatergic signaling, and this effect is blocked in usp-46 loss-of-function mutants. Conversely, wdr-20 and wdr-48 loss-of-function mutants exhibit changes in locomotion behavior that are consistent with decreased glutamatergic signaling. We propose that WDR-20 and WDR-48 form a complex with USP-46 and stimulate the DUB to deubiquitinate and stabilize GLR-1 in vivo. ", + "authors": { + "abbreviation": "Caroline L Dahlberg, Peter Juo", + "authorList": [ + { + "ForeName": "Caroline", + "LastName": "Dahlberg", + "abbrevName": "Dahlberg CL", + "email": null, + "isCollectiveName": false, + "name": "Caroline L Dahlberg" + }, + { + "ForeName": "Peter", + "LastName": "Juo", + "abbrevName": "Juo P", + "email": null, + "isCollectiveName": false, + "name": "Peter Juo" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M113.507541", + "pmid": "24356955", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "The WD40-repeat proteins WDR-20 and WDR-48 bind and activate the deubiquitinating enzyme USP-46 to promote the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans." + } + }, + { + "pmid": "23937906", + "pubmed": { + "ISODate": "2013-08-10T00:00:00.000Z", + "abstract": "Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells. ", + "authors": { + "abbreviation": "Iraia García-Santisteban, Godefridus J Peters, Elisa Giovannetti, Jose Antonio Rodríguez", + "authorList": [ + { + "ForeName": "Iraia", + "LastName": "García-Santisteban", + "abbrevName": "García-Santisteban I", + "email": null, + "isCollectiveName": false, + "name": "Iraia García-Santisteban" + }, + { + "ForeName": "Godefridus", + "LastName": "Peters", + "abbrevName": "Peters GJ", + "email": null, + "isCollectiveName": false, + "name": "Godefridus J Peters" + }, + { + "ForeName": "Elisa", + "LastName": "Giovannetti", + "abbrevName": "Giovannetti E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Giovannetti" + }, + { + "ForeName": "Jose", + "LastName": "Rodríguez", + "abbrevName": "Rodríguez JA", + "email": null, + "isCollectiveName": false, + "name": "Jose Antonio Rodríguez" + } + ], + "contacts": [] + }, + "doi": "10.1186/1476-4598-12-91", + "pmid": "23937906", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Mol Cancer 12 2013", + "title": "USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy." + } + }, + { + "pmid": "23387960", + "pubmed": { + "ISODate": "2013-02-27T00:00:00.000Z", + "abstract": "Active-site directed probes are powerful in studies of enzymatic function. We report an active-site directed probe based on a warhead so far considered unreactive. By replacing the C-terminal carboxylate of ubiquitin (Ub) with an alkyne functionality, a selective reaction with the active-site cysteine residue of de-ubiquitinating enzymes was observed. The resulting product was shown to be a quaternary vinyl thioether, as determined by X-ray crystallography. Proteomic analysis of proteins bound to an immobilized Ub alkyne probe confirmed the selectivity toward de-ubiquitinating enzymes. The observed reactivity is not just restricted to propargylated Ub, as highlighted by the selective reaction between caspase-1 (interleukin converting enzyme) and a propargylated peptide derived from IL-1β, a caspase-1 substrate.", + "authors": { + "abbreviation": "Reggy Ekkebus, Sander I van Kasteren, Yogesh Kulathu, ..., Huib Ovaa", + "authorList": [ + { + "ForeName": "Reggy", + "LastName": "Ekkebus", + "abbrevName": "Ekkebus R", + "email": null, + "isCollectiveName": false, + "name": "Reggy Ekkebus" + }, + { + "ForeName": "Sander", + "LastName": "van Kasteren", + "abbrevName": "van Kasteren SI", + "email": null, + "isCollectiveName": false, + "name": "Sander I van Kasteren" + }, + { + "ForeName": "Yogesh", + "LastName": "Kulathu", + "abbrevName": "Kulathu Y", + "email": null, + "isCollectiveName": false, + "name": "Yogesh Kulathu" + }, + { + "ForeName": "Arjen", + "LastName": "Scholten", + "abbrevName": "Scholten A", + "email": null, + "isCollectiveName": false, + "name": "Arjen Scholten" + }, + { + "ForeName": "Ilana", + "LastName": "Berlin", + "abbrevName": "Berlin I", + "email": null, + "isCollectiveName": false, + "name": "Ilana Berlin" + }, + { + "ForeName": "Paul", + "LastName": "Geurink", + "abbrevName": "Geurink PP", + "email": null, + "isCollectiveName": false, + "name": "Paul P Geurink" + }, + { + "ForeName": "Annemieke", + "LastName": "de Jong", + "abbrevName": "de Jong A", + "email": null, + "isCollectiveName": false, + "name": "Annemieke de Jong" + }, + { + "ForeName": "Soenita", + "LastName": "Goerdayal", + "abbrevName": "Goerdayal S", + "email": null, + "isCollectiveName": false, + "name": "Soenita Goerdayal" + }, + { + "ForeName": "Jacques", + "LastName": "Neefjes", + "abbrevName": "Neefjes J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Neefjes" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert J R Heck" + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander" + }, + { + "ForeName": "Huib", + "LastName": "Ovaa", + "abbrevName": "Ovaa H", + "email": null, + "isCollectiveName": false, + "name": "Huib Ovaa" + } + ], + "contacts": [] + }, + "doi": "10.1021/ja309802n", + "pmid": "23387960", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Am Chem Soc 135 2013", + "title": "On terminal alkynes that can react with active-site cysteine nucleophiles in proteases." + } + }, + { + "pmid": "22118673", + "pubmed": { + "ISODate": "2011-11-23T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) have in recent years emerged as a promising therapeutic target class. We identified selective small-molecule inhibitors against a deubiquitinase complex, the human USP1/UAF1, through quantitative high throughput screening (qHTS) of a collection of bioactive molecules. The top inhibitors, pimozide and GW7647, inhibited USP1/UAF1 noncompetitively with a K(i) of 0.5 and 0.7 μM, respectively, and displayed selectivity against a number of deubiquitinases, deSUMOylase, and cysteine proteases. The USP1/UAF1 inhibitors act synergistically with cisplatin in inhibiting cisplatin-resistant non-small cell lung cancer (NSCLC) cell proliferation. USP1/UAF1 represents a promising target for drug intervention because of its involvement in translesion synthesis and Fanconi anemia pathway important for normal DNA damage response. Our results support USP1/UAF1 as a potential therapeutic target and provide an example of targeting the USP/WD40 repeat protein complex for inhibitor discovery.", + "authors": { + "abbreviation": "Junjun Chen, Thomas S Dexheimer, Yongxing Ai, ..., Zhihao Zhuang", + "authorList": [ + { + "ForeName": "Junjun", + "LastName": "Chen", + "abbrevName": "Chen J", + "email": null, + "isCollectiveName": false, + "name": "Junjun Chen" + }, + { + "ForeName": "Thomas", + "LastName": "Dexheimer", + "abbrevName": "Dexheimer TS", + "email": null, + "isCollectiveName": false, + "name": "Thomas S Dexheimer" + }, + { + "ForeName": "Yongxing", + "LastName": "Ai", + "abbrevName": "Ai Y", + "email": null, + "isCollectiveName": false, + "name": "Yongxing Ai" + }, + { + "ForeName": "Qin", + "LastName": "Liang", + "abbrevName": "Liang Q", + "email": null, + "isCollectiveName": false, + "name": "Qin Liang" + }, + { + "ForeName": "Mark", + "LastName": "Villamil", + "abbrevName": "Villamil MA", + "email": null, + "isCollectiveName": false, + "name": "Mark A Villamil" + }, + { + "ForeName": "James", + "LastName": "Inglese", + "abbrevName": "Inglese J", + "email": null, + "isCollectiveName": false, + "name": "James Inglese" + }, + { + "ForeName": "David", + "LastName": "Maloney", + "abbrevName": "Maloney DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Maloney" + }, + { + "ForeName": "Ajit", + "LastName": "Jadhav", + "abbrevName": "Jadhav A", + "email": null, + "isCollectiveName": false, + "name": "Ajit Jadhav" + }, + { + "ForeName": "Anton", + "LastName": "Simeonov", + "abbrevName": "Simeonov A", + "email": null, + "isCollectiveName": false, + "name": "Anton Simeonov" + }, + { + "ForeName": "Zhihao", + "LastName": "Zhuang", + "abbrevName": "Zhuang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhihao Zhuang" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.chembiol.2011.08.014", + "pmid": "22118673", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Chem Biol 18 2011", + "title": "Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "21764741", + "pubmed": { + "ISODate": "2011-07-15T00:00:00.000Z", + "abstract": "Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the ~300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.", + "authors": { + "abbreviation": "Woo Joo, Guozhou Xu, Nicole S Persky, ..., Nikola P Pavletich", + "authorList": [ + { + "ForeName": "Woo", + "LastName": "Joo", + "abbrevName": "Joo W", + "email": null, + "isCollectiveName": false, + "name": "Woo Joo" + }, + { + "ForeName": "Guozhou", + "LastName": "Xu", + "abbrevName": "Xu G", + "email": null, + "isCollectiveName": false, + "name": "Guozhou Xu" + }, + { + "ForeName": "Nicole", + "LastName": "Persky", + "abbrevName": "Persky NS", + "email": null, + "isCollectiveName": false, + "name": "Nicole S Persky" + }, + { + "ForeName": "Agata", + "LastName": "Smogorzewska", + "abbrevName": "Smogorzewska A", + "email": null, + "isCollectiveName": false, + "name": "Agata Smogorzewska" + }, + { + "ForeName": "Derek", + "LastName": "Rudge", + "abbrevName": "Rudge DG", + "email": null, + "isCollectiveName": false, + "name": "Derek G Rudge" + }, + { + "ForeName": "Olga", + "LastName": "Buzovetsky", + "abbrevName": "Buzovetsky O", + "email": null, + "isCollectiveName": false, + "name": "Olga Buzovetsky" + }, + { + "ForeName": "Stephen", + "LastName": "Elledge", + "abbrevName": "Elledge SJ", + "email": null, + "isCollectiveName": false, + "name": "Stephen J Elledge" + }, + { + "ForeName": "Nikola", + "LastName": "Pavletich", + "abbrevName": "Pavletich NP", + "email": null, + "isCollectiveName": false, + "name": "Nikola P Pavletich" + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1205805", + "pmid": "21764741", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 333 2011", + "title": "Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway." + } + }, + { + "pmid": "21482670", + "pubmed": { + "ISODate": "2011-06-01T00:00:00.000Z", + "abstract": "Protein ubiquitination plays a key role in the regulation of a variety of DNA repair mechanisms. Protein ubiquitination is controlled by the coordinate activity of ubiquitin ligases and deubiquitinating enzymes (DUBs). The deubiquitinating enzyme USP1 regulates DNA repair and the Fanconi anemia pathway through its association with its WD40 binding partner, UAF1, and through its deubiquitination of two critical DNA repair proteins, FANCD2-Ub and PCNA-Ub. To investigate the function of USP1 and UAF1, we generated USP1⁻/⁻, UAF1⁻/⁻/⁻, and USP1⁻/⁻ UAF1⁻/⁻/⁻ chicken DT40 cell clones. These three clones showed similar sensitivities to chemical cross-linking agents, to a topoisomerase poison, camptothecin, and to an inhibitor of poly(ADP-ribose) polymerase (PARP), indicating that the USP1/UAF1 complex is a regulator of the cellular response to DNA damage. The hypersensitivity to both camptothecin and a PARP inhibitor suggests that the USP1/UAF1 complex promotes homologous recombination (HR)-mediated double-strand break (DSB) repair. To gain insight into the mechanism of the USP1/UAF1 complex in HR, we inactivated the nonhomologous end-joining (NHEJ) pathway in UAF1-deficient cells. Disruption of NHEJ in UAF1-deficient cells restored cellular resistance to camptothecin and the PARP inhibitor. Our results indicate that the USP1/UAF1 complex promotes HR, at least in part by suppressing NHEJ.", + "authors": { + "abbreviation": "Junko Murai, Kailin Yang, Donniphat Dejsuphong, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Donniphat", + "LastName": "Dejsuphong", + "abbrevName": "Dejsuphong D", + "email": null, + "isCollectiveName": false, + "name": "Donniphat Dejsuphong" + }, + { + "ForeName": "Kouji", + "LastName": "Hirota", + "abbrevName": "Hirota K", + "email": null, + "isCollectiveName": false, + "name": "Kouji Hirota" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1128/MCB.05058-11", + "pmid": "21482670", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell Biol 31 2011", + "title": "The USP1/UAF1 complex promotes double-strand break repair through homologous recombination." + } + }, + { + "pmid": "21448225", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "In the past decade, the diversity of signals generated by the ubiquitin system has emerged as a dominant regulator of biological processes and propagation of information in the eukaryotic cell. A wealth of information has been gained about the crucial role of spatial and temporal regulation of ubiquitin species of different lengths and linkages in the nuclear factor-κB (NF-κB) pathway, endocytic trafficking, protein degradation and DNA repair. This spatiotemporal regulation is achieved through sophisticated mechanisms of compartmentalization and sequential series of ubiquitylation events and signal decoding, which control diverse biological processes not only in the cell but also during the development of tissues and entire organisms.", + "authors": { + "abbreviation": "Caroline Grabbe, Koraljka Husnjak, Ivan Dikic", + "authorList": [ + { + "ForeName": "Caroline", + "LastName": "Grabbe", + "abbrevName": "Grabbe C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Grabbe" + }, + { + "ForeName": "Koraljka", + "LastName": "Husnjak", + "abbrevName": "Husnjak K", + "email": null, + "isCollectiveName": false, + "name": "Koraljka Husnjak" + }, + { + "ForeName": "Ivan", + "LastName": "Dikic", + "abbrevName": "Dikic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Dikic" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm3099", + "pmid": "21448225", + "pubTypes": [ + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 12 2011", + "title": "The spatial and temporal organization of ubiquitin networks." + } + }, + { + "pmid": "20147737", + "pubmed": { + "ISODate": "2010-04-09T00:00:00.000Z", + "abstract": "The UAF1 (Usp1-associated factor 1) protein binds and stimulates three deubiquitinating enzymes: USP1, USP12, and USP46. Although the USP1 x UAF1 complex is required for regulation of the Fanconi anemia (FA) DNA repair pathway, less is known about the USP12 x UAF1 and the USP46 x UAF1 complexes. To understand further the nature of the USP12 and USP46 complexes, we attempted to identify proteins that interact with the USP12 and USP46 deubiquitinating enzyme complexes. We identified WDR20, a WD40-repeat containing protein, as a common binding partner of UAF1, USP12, and USP46. Further analysis showed that WDR20 associates exclusively with USP12 and USP46, not with USP1. Furthermore, we demonstrate the purification of a ternary USP12 x UAF1 x WDR20 complex. Interestingly, and consistent with the binding assays, WDR20 stimulated the enzymatic activity of USP12 x UAF1, but not of USP1 x UAF1. Consistent with our previous report that USP12 and USP46 do not regulate the FA pathway, small interference RNA-mediated depletion of WDR20 protein did not affect the FA pathway or DNA damage responses. We provide a model in which WDR20 serves as a stimulatory subunit for preserving and regulating the activity of the subset of the UAF1 x USP complexes.", + "authors": { + "abbreviation": "Younghoon Kee, Kailin Yang, Martin A Cohn, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095141", + "pmid": "20147737", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "WDR20 regulates activity of the USP12 x UAF1 deubiquitinating enzyme complex." + } + }, + { + "pmid": "19626045", + "pubmed": { + "ISODate": "2009-08-01T00:00:00.000Z", + "abstract": "Ubiquitylation is a reversible protein modification that is implicated in many cellular functions. Recently, much progress has been made in the characterization of a superfamily of isopeptidases that remove ubiquitin: the deubiquitinases (DUBs; also known as deubiquitylating or deubiquitinating enzymes). Far from being uniform in structure and function, these enzymes display a myriad of distinct mechanistic features. The small number (<100) of DUBs might at first suggest a low degree of selectivity; however, DUBs are subject to multiple layers of regulation that modulate both their activity and their specificity. Due to their wide-ranging involvement in key regulatory processes, these enzymes might provide new therapeutic targets.", + "authors": { + "abbreviation": "David Komander, Michael J Clague, Sylvie Urbé", + "authorList": [ + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": "dk@mrc-lmb.cam.ac.uk", + "isCollectiveName": false, + "name": "David Komander" + }, + { + "ForeName": "Michael", + "LastName": "Clague", + "abbrevName": "Clague MJ", + "email": null, + "isCollectiveName": false, + "name": "Michael J Clague" + }, + { + "ForeName": "Sylvie", + "LastName": "Urbé", + "abbrevName": "Urbé S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Urbé" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Komander", + "email": [ + "dk@mrc-lmb.cam.ac.uk" + ], + "name": "David Komander" + } + ] + }, + "doi": "10.1038/nrm2731", + "pmid": "19626045", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 10 2009", + "title": "Breaking the chains: structure and function of the deubiquitinases." + } + }, + { + "pmid": "19461840", + "pubmed": { + "ISODate": "2007-08-01T00:00:00.000Z", + "abstract": "Phaser is a program for phasing macromolecular crystal structures by both molecular replacement and experimental phasing methods. The novel phasing algorithms implemented in Phaser have been developed using maximum likelihood and multivariate statistics. For molecular replacement, the new algorithms have proved to be significantly better than traditional methods in discriminating correct solutions from noise, and for single-wavelength anomalous dispersion experimental phasing, the new algorithms, which account for correlations between F(+) and F(-), give better phases (lower mean phase error with respect to the phases given by the refined structure) than those that use mean F and anomalous differences DeltaF. One of the design concepts of Phaser was that it be capable of a high degree of automation. To this end, Phaser (written in C++) can be called directly from Python, although it can also be called using traditional CCP4 keyword-style input. Phaser is a platform for future development of improved phasing methods and their release, including source code, to the crystallographic community.", + "authors": { + "abbreviation": "Airlie J McCoy, Ralf W Grosse-Kunstleve, Paul D Adams, ..., Randy J Read", + "authorList": [ + { + "ForeName": "Airlie", + "LastName": "McCoy", + "abbrevName": "McCoy AJ", + "email": null, + "isCollectiveName": false, + "name": "Airlie J McCoy" + }, + { + "ForeName": "Ralf", + "LastName": "Grosse-Kunstleve", + "abbrevName": "Grosse-Kunstleve RW", + "email": null, + "isCollectiveName": false, + "name": "Ralf W Grosse-Kunstleve" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + }, + { + "ForeName": "Martyn", + "LastName": "Winn", + "abbrevName": "Winn MD", + "email": null, + "isCollectiveName": false, + "name": "Martyn D Winn" + }, + { + "ForeName": "Laurent", + "LastName": "Storoni", + "abbrevName": "Storoni LC", + "email": null, + "isCollectiveName": false, + "name": "Laurent C Storoni" + }, + { + "ForeName": "Randy", + "LastName": "Read", + "abbrevName": "Read RJ", + "email": null, + "isCollectiveName": false, + "name": "Randy J Read" + } + ], + "contacts": [] + }, + "doi": "10.1107/S0021889807021206", + "pmid": "19461840", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Appl Crystallogr 40 2007", + "title": "Phaser crystallographic software." + } + }, + { + "pmid": "19075014", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "A balance between ubiquitination and deubiquitination regulates numerous cellular processes and pathways, and specific deubiquitinating enzymes often play the decisive role of controlling this balance. We recently reported that the USP1 deubiquitinating enzyme, which regulates the Fanconi anemia pathway by deubiquitinating the central player of the pathway, FANCD2, is activated by the WD40-repeat containing UAF1 protein through formation of a stable USP1/UAF1 protein complex. Here we present the isolation of two novel multisubunit deubiquitinating enzyme complexes containing USP12 and USP46, respectively. Both complexes contain the UAF1 protein as a bona fide subunit. Interestingly, UAF1 regulates the enzymatic activity of both enzyme complexes, suggesting that this activator protein may regulate a subclass of human deubiquitinating enzymes. We postulate that additional WD40-containing proteins may also form complexes with other human deubiquitinating enzymes and thereby regulate their activity and substrate specificity.", + "authors": { + "abbreviation": "Martin A Cohn, Younghoon Kee, Wilhelm Haas, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M808430200", + "pmid": "19075014", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "UAF1 is a subunit of multiple deubiquitinating enzyme complexes." + } + }, + { + "pmid": "18082605", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "Monoubiquitination of FANCD2 and PCNA promotes DNA repair. It causes chromatin accumulation of FANCD2 and facilitates PCNA's recruitment of translesion polymerases to stalled replication. USP1, a protease that removes monoubiquitin from FANCD2 and PCNA, was thought to reverse the DNA damage response of these substrates. We disrupted USP1 in chicken cells to dissect its role in a stable genetic system. USP1 ablation increases FANCD2 and PCNA monoubiquitination but unexpectedly results in DNA crosslinker sensitivity. This defective DNA repair is associated with constitutively chromatin-bound, monoubiquitinated FANCD2. In contrast, persistent PCNA monoubiquitination has negligible impact on DNA repair or mutagenesis. USP1 was previously shown to autocleave after DNA damage. In DT40, USP1 autocleavage is not stimulated by DNA damage, and expressing a noncleavable mutant in the USP1 knockout strain partially rescues crosslinker sensitivity. We conclude that efficient DNA crosslink repair requires FANCD2 deubiquitination, whereas FANCD2 monoubiquitination is not dependent on USP1 autocleavage.", + "authors": { + "abbreviation": "Vibe H Oestergaard, Frederic Langevin, Hendrik J Kuiken, ..., Ketan J Patel", + "authorList": [ + { + "ForeName": "Vibe", + "LastName": "Oestergaard", + "abbrevName": "Oestergaard VH", + "email": null, + "isCollectiveName": false, + "name": "Vibe H Oestergaard" + }, + { + "ForeName": "Frederic", + "LastName": "Langevin", + "abbrevName": "Langevin F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Langevin" + }, + { + "ForeName": "Hendrik", + "LastName": "Kuiken", + "abbrevName": "Kuiken HJ", + "email": null, + "isCollectiveName": false, + "name": "Hendrik J Kuiken" + }, + { + "ForeName": "Paul", + "LastName": "Pace", + "abbrevName": "Pace P", + "email": null, + "isCollectiveName": false, + "name": "Paul Pace" + }, + { + "ForeName": "Wojciech", + "LastName": "Niedzwiedz", + "abbrevName": "Niedzwiedz W", + "email": null, + "isCollectiveName": false, + "name": "Wojciech Niedzwiedz" + }, + { + "ForeName": "Laura", + "LastName": "Simpson", + "abbrevName": "Simpson LJ", + "email": null, + "isCollectiveName": false, + "name": "Laura J Simpson" + }, + { + "ForeName": "Mioko", + "LastName": "Ohzeki", + "abbrevName": "Ohzeki M", + "email": null, + "isCollectiveName": false, + "name": "Mioko Ohzeki" + }, + { + "ForeName": "Minoru", + "LastName": "Takata", + "abbrevName": "Takata M", + "email": null, + "isCollectiveName": false, + "name": "Minoru Takata" + }, + { + "ForeName": "Julian", + "LastName": "Sale", + "abbrevName": "Sale JE", + "email": null, + "isCollectiveName": false, + "name": "Julian E Sale" + }, + { + "ForeName": "Ketan", + "LastName": "Patel", + "abbrevName": "Patel KJ", + "email": null, + "isCollectiveName": false, + "name": "Ketan J Patel" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.020", + "pmid": "18082605", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 28 2007", + "title": "Deubiquitination of FANCD2 is required for DNA crosslink repair." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "17681537", + "pubmed": { + "ISODate": "2007-09-21T00:00:00.000Z", + "abstract": "We discuss basic physical-chemical principles underlying the formation of stable macromolecular complexes, which in many cases are likely to be the biological units performing a certain physiological function. We also consider available theoretical approaches to the calculation of macromolecular affinity and entropy of complexation. The latter is shown to play an important role and make a major effect on complex size and symmetry. We develop a new method, based on chemical thermodynamics, for automatic detection of macromolecular assemblies in the Protein Data Bank (PDB) entries that are the results of X-ray diffraction experiments. As found, biological units may be recovered at 80-90% success rate, which makes X-ray crystallography an important source of experimental data on macromolecular complexes and protein-protein interactions. The method is implemented as a public WWW service.", + "authors": { + "abbreviation": "Evgeny Krissinel, Kim Henrick", + "authorList": [ + { + "ForeName": "Evgeny", + "LastName": "Krissinel", + "abbrevName": "Krissinel E", + "email": null, + "isCollectiveName": false, + "name": "Evgeny Krissinel" + }, + { + "ForeName": "Kim", + "LastName": "Henrick", + "abbrevName": "Henrick K", + "email": null, + "isCollectiveName": false, + "name": "Kim Henrick" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2007.05.022", + "pmid": "17681537", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 372 2007", + "title": "Inference of macromolecular assemblies from crystalline state." + } + }, + { + "pmid": "17545995", + "pubmed": { + "ISODate": "2007-06-01T00:00:00.000Z", + "abstract": "The small ubiquitin-like modifier, SUMO, can be covalently linked to specific proteins and many substrates carrying this modification have been identified. However, for some proteins, the role that SUMO modification imparts remains obscure. Our understanding of SUMO biology and function has been significantly advanced by the recent discovery of proteins and protein domains that contain SUMO-interacting motifs (SIMs), which interact non-covalently with SUMO. Unlike the motifs and domains that mediate ubiquitin binding, the diversity of SIMs seems limited. Nevertheless, SIMs have already increased our understanding of how SUMO affects DNA repair, transcriptional activation, nuclear body formation and protein turnover. This review takes a detailed look at how SIMs were identified, how they specifically bind to SUMO, their crucial roles in multi-step enzymatic processes, and how they direct the assembly and disassembly of dimeric and multimeric protein complexes.", + "authors": { + "abbreviation": "Oliver Kerscher", + "authorList": [ + { + "ForeName": "Oliver", + "LastName": "Kerscher", + "abbrevName": "Kerscher O", + "email": "opkers@wm.edu", + "isCollectiveName": false, + "name": "Oliver Kerscher" + } + ], + "contacts": [ + { + "ForeName": "Oliver", + "LastName": "Kerscher", + "email": [ + "opkers@wm.edu" + ], + "name": "Oliver Kerscher" + } + ] + }, + "doi": "10.1038/sj.embor.7400980", + "pmid": "17545995", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "EMBO Rep 8 2007", + "title": "SUMO junction-what's your function? New insights through SUMO-interacting motifs." + } + }, + { + "pmid": "17460694", + "pubmed": { + "ISODate": "2007-06-01T00:00:00.000Z", + "abstract": "Activation of the Fanconi anemia (FA) DNA damage-response pathway results in the monoubiquitination of FANCD2, which is regulated by the nuclear FA core ubiquitin ligase complex. A FANCD2 protein sequence-based homology search facilitated the discovery of FANCI, a second monoubiquitinated component of the FA pathway. Biallelic mutations in the gene coding for this protein were found in cells from four FA patients, including an FA-I reference cell line.", + "authors": { + "abbreviation": "Ashley E Sims, Elizabeth Spiteri, Robert J Sims, ..., Tony T Huang", + "authorList": [ + { + "ForeName": "Ashley", + "LastName": "Sims", + "abbrevName": "Sims AE", + "email": null, + "isCollectiveName": false, + "name": "Ashley E Sims" + }, + { + "ForeName": "Elizabeth", + "LastName": "Spiteri", + "abbrevName": "Spiteri E", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth Spiteri" + }, + { + "ForeName": "Robert", + "LastName": "Sims", + "abbrevName": "Sims RJ", + "email": null, + "isCollectiveName": false, + "name": "Robert J Sims" + }, + { + "ForeName": "Adriana", + "LastName": "Arita", + "abbrevName": "Arita AG", + "email": null, + "isCollectiveName": false, + "name": "Adriana G Arita" + }, + { + "ForeName": "Francis", + "LastName": "Lach", + "abbrevName": "Lach FP", + "email": null, + "isCollectiveName": false, + "name": "Francis P Lach" + }, + { + "ForeName": "Thomas", + "LastName": "Landers", + "abbrevName": "Landers T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Landers" + }, + { + "ForeName": "Melanie", + "LastName": "Wurm", + "abbrevName": "Wurm M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Wurm" + }, + { + "ForeName": "Marcel", + "LastName": "Freund", + "abbrevName": "Freund M", + "email": null, + "isCollectiveName": false, + "name": "Marcel Freund" + }, + { + "ForeName": "Kornelia", + "LastName": "Neveling", + "abbrevName": "Neveling K", + "email": null, + "isCollectiveName": false, + "name": "Kornelia Neveling" + }, + { + "ForeName": "Helmut", + "LastName": "Hanenberg", + "abbrevName": "Hanenberg H", + "email": null, + "isCollectiveName": false, + "name": "Helmut Hanenberg" + }, + { + "ForeName": "Arleen", + "LastName": "Auerbach", + "abbrevName": "Auerbach AD", + "email": null, + "isCollectiveName": false, + "name": "Arleen D Auerbach" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/nsmb1252", + "pmid": "17460694", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Struct Mol Biol 14 2007", + "title": "FANCI is a second monoubiquitinated member of the Fanconi anemia pathway." + } + }, + { + "pmid": "17412408", + "pubmed": { + "ISODate": "2007-04-20T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a developmental and cancer-predisposition syndrome caused by mutations in genes controlling DNA interstrand crosslink repair. Several FA proteins form a ubiquitin ligase that controls monoubiquitination of the FANCD2 protein in an ATR-dependent manner. Here we describe the FA protein FANCI, identified as an ATM/ATR kinase substrate required for resistance to mitomycin C. FANCI shares sequence similarity with FANCD2, likely evolving from a common ancestral gene. The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. Like FANCD2, FANCI is monoubiquitinated and unexpectedly, ubiquitination of each protein is important for the maintenance of ubiquitin on the other, indicating the existence of a dual ubiquitin-locking mechanism required for ID complex function. Mutation in FANCI is responsible for loss of a functional FA pathway in a patient with Fanconi anemia complementation group I.", + "authors": { + "abbreviation": "Agata Smogorzewska, Shuhei Matsuoka, Patrizia Vinciguerra, ..., Stephen J Elledge", + "authorList": [ + { + "ForeName": "Agata", + "LastName": "Smogorzewska", + "abbrevName": "Smogorzewska A", + "email": null, + "isCollectiveName": false, + "name": "Agata Smogorzewska" + }, + { + "ForeName": "Shuhei", + "LastName": "Matsuoka", + "abbrevName": "Matsuoka S", + "email": null, + "isCollectiveName": false, + "name": "Shuhei Matsuoka" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "E", + "LastName": "McDonald", + "abbrevName": "McDonald ER", + "email": null, + "isCollectiveName": false, + "name": "E Robert McDonald" + }, + { + "ForeName": "Kristen", + "LastName": "Hurov", + "abbrevName": "Hurov KE", + "email": null, + "isCollectiveName": false, + "name": "Kristen E Hurov" + }, + { + "ForeName": "Ji", + "LastName": "Luo", + "abbrevName": "Luo J", + "email": null, + "isCollectiveName": false, + "name": "Ji Luo" + }, + { + "ForeName": "Bryan", + "LastName": "Ballif", + "abbrevName": "Ballif BA", + "email": null, + "isCollectiveName": false, + "name": "Bryan A Ballif" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Kay", + "LastName": "Hofmann", + "abbrevName": "Hofmann K", + "email": null, + "isCollectiveName": false, + "name": "Kay Hofmann" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Stephen", + "LastName": "Elledge", + "abbrevName": "Elledge SJ", + "email": null, + "isCollectiveName": false, + "name": "Stephen J Elledge" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2007.03.009", + "pmid": "17412408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cell 129 2007", + "title": "Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair." + } + }, + { + "pmid": "16626738", + "pubmed": { + "ISODate": "2006-05-26T00:00:00.000Z", + "abstract": "Modification of cellular proteins by the small ubiquitin-like modifier SUMO is important in regulating various cellular events. Many different nuclear proteins are targeted by SUMO, and the functional consequences of this modification are diverse. For most proteins, however, the functional and structural consequences of modification by specific SUMO isomers are unclear. Conjugation of SUMO to thymine-DNA glycosylase (TDG) induces the dissociation of TDG from its product DNA. Structure determination of the TDG central region conjugated to SUMO-1 previously suggested a mechanism in which the SUMOylation-induced conformational change in the C-terminal region of TDG releases TDG from tight binding to its product DNA. Here, we have determined the crystal structure of the central region of TDG conjugated to SUMO-3. The overall structure of SUMO-3-conjugated TDG is similar to the previously reported structure of TDG conjugated to SUMO-1, despite the relatively low level of amino acid sequence similarity between SUMO-3 and SUMO-1. The two structures revealed that the sequence of TDG that resembles the SUMO-binding motif (SBM) can form an intermolecular beta-sheet with either SUMO-1 or SUMO-3. Structural comparison with the canonical SBM shows that this SBM-like sequence of TDG retains all of the characteristic interactions of the SBM, indicating sequence diversity in the SBM.", + "authors": { + "abbreviation": "Daichi Baba, Nobuo Maita, Jun-Goo Jee, ..., Masahiro Shirakawa", + "authorList": [ + { + "ForeName": "Daichi", + "LastName": "Baba", + "abbrevName": "Baba D", + "email": null, + "isCollectiveName": false, + "name": "Daichi Baba" + }, + { + "ForeName": "Nobuo", + "LastName": "Maita", + "abbrevName": "Maita N", + "email": null, + "isCollectiveName": false, + "name": "Nobuo Maita" + }, + { + "ForeName": "Jun-Goo", + "LastName": "Jee", + "abbrevName": "Jee JG", + "email": null, + "isCollectiveName": false, + "name": "Jun-Goo Jee" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Uchimura", + "abbrevName": "Uchimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Uchimura" + }, + { + "ForeName": "Hisato", + "LastName": "Saitoh", + "abbrevName": "Saitoh H", + "email": null, + "isCollectiveName": false, + "name": "Hisato Saitoh" + }, + { + "ForeName": "Kaoru", + "LastName": "Sugasawa", + "abbrevName": "Sugasawa K", + "email": null, + "isCollectiveName": false, + "name": "Kaoru Sugasawa" + }, + { + "ForeName": "Fumio", + "LastName": "Hanaoka", + "abbrevName": "Hanaoka F", + "email": null, + "isCollectiveName": false, + "name": "Fumio Hanaoka" + }, + { + "ForeName": "Hidehito", + "LastName": "Tochio", + "abbrevName": "Tochio H", + "email": null, + "isCollectiveName": false, + "name": "Hidehito Tochio" + }, + { + "ForeName": "Hidekazu", + "LastName": "Hiroaki", + "abbrevName": "Hiroaki H", + "email": null, + "isCollectiveName": false, + "name": "Hidekazu Hiroaki" + }, + { + "ForeName": "Masahiro", + "LastName": "Shirakawa", + "abbrevName": "Shirakawa M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Shirakawa" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2006.03.036", + "pmid": "16626738", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 359 2006", + "title": "Crystal structure of SUMO-3-modified thymine-DNA glycosylase." + } + }, + { + "pmid": "16531995", + "pubmed": { + "ISODate": "2006-04-01T00:00:00.000Z", + "abstract": "Monoubiquitination is a reversible post-translational protein modification that has an important regulatory function in many biological processes, including DNA repair. Deubiquitinating enzymes (DUBs) are proteases that are negative regulators of monoubiquitination, but little is known about their regulation and contribution to the control of conjugated-substrate levels. Here, we show that the DUB ubiquitin specific protease 1 (USP1) deubiquitinates the DNA replication processivity factor, PCNA, as a safeguard against error-prone translesion synthesis (TLS) of DNA. Ultraviolet (UV) irradiation inactivates USP1 through an autocleavage event, thus enabling monoubiquitinated PCNA to accumulate and to activate TLS. Significantly, the site of USP1 cleavage is immediately after a conserved internal ubiquitin-like diglycine (Gly-Gly) motif. This mechanism is reminiscent of the processing of precursors of ubiquitin and ubiquitin-like modifiers by DUBs. Our results define a regulatory mechanism for protein ubiquitination that involves the signal-induced degradation of an inhibitory DUB.", + "authors": { + "abbreviation": "Tony T Huang, Sebastian M B Nijman, Kanchan D Mirchandani, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Sebastian", + "LastName": "Nijman", + "abbrevName": "Nijman SM", + "email": null, + "isCollectiveName": false, + "name": "Sebastian M B Nijman" + }, + { + "ForeName": "Kanchan", + "LastName": "Mirchandani", + "abbrevName": "Mirchandani KD", + "email": null, + "isCollectiveName": false, + "name": "Kanchan D Mirchandani" + }, + { + "ForeName": "Paul", + "LastName": "Galardy", + "abbrevName": "Galardy PJ", + "email": null, + "isCollectiveName": false, + "name": "Paul J Galardy" + }, + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Hidde", + "LastName": "Ploegh", + "abbrevName": "Ploegh HL", + "email": null, + "isCollectiveName": false, + "name": "Hidde L Ploegh" + }, + { + "ForeName": "René", + "LastName": "Bernards", + "abbrevName": "Bernards R", + "email": null, + "isCollectiveName": false, + "name": "René Bernards" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1378", + "pmid": "16531995", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 8 2006", + "title": "Regulation of monoubiquitinated PCNA by DUB autocleavage." + } + }, + { + "pmid": "16182563", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "A new method was developed to acquire images automatically at a series of specimen tilts, as required for tomographic reconstruction. The method uses changes in specimen position at previous tilt angles to predict the position at the current tilt angle. Actual measurement of the position or focus is skipped if the statistical error of the prediction is low enough. This method allows a tilt series to be acquired rapidly when conditions are good but falls back toward the traditional approach of taking focusing and tracking images when necessary. The method has been implemented in a program, SerialEM, that provides an efficient environment for data acquisition. This program includes control of an energy filter as well as a low-dose imaging mode, in which tracking and focusing occur away from the area of interest. The program can automatically acquire a montage of overlapping frames, allowing tomography of areas larger than the field of the CCD camera. It also includes tools for navigating between specimen positions and finding regions of interest.", + "authors": { + "abbreviation": "David N Mastronarde", + "authorList": [ + { + "ForeName": "David", + "LastName": "Mastronarde", + "abbrevName": "Mastronarde DN", + "email": "mast@colorado.edu", + "isCollectiveName": false, + "name": "David N Mastronarde" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Mastronarde", + "email": [ + "mast@colorado.edu" + ], + "name": "David N Mastronarde" + } + ] + }, + "doi": "10.1016/j.jsb.2005.07.007", + "pmid": "16182563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Struct Biol 152 2005", + "title": "Automated electron microscope tomography using robust prediction of specimen movements." + } + }, + { + "pmid": "15694335", + "pubmed": { + "ISODate": "2005-02-04T00:00:00.000Z", + "abstract": "Protein ubiquitination and deubiquitination are dynamic processes implicated in the regulation of numerous cellular pathways. Monoubiquitination of the Fanconi anemia (FA) protein FANCD2 appears to be critical in the repair of DNA damage because many of the proteins that are mutated in FA are required for FANCD2 ubiquitination. By screening a gene family RNAi library, we identify the deubiquitinating enzyme USP1 as a novel component of the Fanconi anemia pathway. Inhibition of USP1 leads to hyperaccumulation of monoubiquitinated FANCD2. Furthermore, USP1 physically associates with FANCD2, and the proteins colocalize in chromatin after DNA damage. Finally, analysis of crosslinker-induced chromosomal aberrations in USP1 knockdown cells suggests a role in DNA repair. We propose that USP1 deubiquitinates FANCD2 when cells exit S phase or recommence cycling after a DNA damage insult and may play a critical role in the FA pathway by recycling FANCD2.", + "authors": { + "abbreviation": "Sebastian M B Nijman, Tony T Huang, Annette M G Dirac, ..., René Bernards", + "authorList": [ + { + "ForeName": "Sebastian", + "LastName": "Nijman", + "abbrevName": "Nijman SM", + "email": null, + "isCollectiveName": false, + "name": "Sebastian M B Nijman" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Annette", + "LastName": "Dirac", + "abbrevName": "Dirac AM", + "email": null, + "isCollectiveName": false, + "name": "Annette M G Dirac" + }, + { + "ForeName": "Thijn", + "LastName": "Brummelkamp", + "abbrevName": "Brummelkamp TR", + "email": null, + "isCollectiveName": false, + "name": "Thijn R Brummelkamp" + }, + { + "ForeName": "Ron", + "LastName": "Kerkhoven", + "abbrevName": "Kerkhoven RM", + "email": null, + "isCollectiveName": false, + "name": "Ron M Kerkhoven" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "René", + "LastName": "Bernards", + "abbrevName": "Bernards R", + "email": null, + "isCollectiveName": false, + "name": "René Bernards" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2005.01.008", + "pmid": "15694335", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Cell 17 2005", + "title": "The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "15264254", + "pubmed": { + "ISODate": "2004-10-01T00:00:00.000Z", + "abstract": "The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.", + "authors": { + "abbreviation": "Eric F Pettersen, Thomas D Goddard, Conrad C Huang, ..., Thomas E Ferrin", + "authorList": [ + { + "ForeName": "Eric", + "LastName": "Pettersen", + "abbrevName": "Pettersen EF", + "email": null, + "isCollectiveName": false, + "name": "Eric F Pettersen" + }, + { + "ForeName": "Thomas", + "LastName": "Goddard", + "abbrevName": "Goddard TD", + "email": null, + "isCollectiveName": false, + "name": "Thomas D Goddard" + }, + { + "ForeName": "Conrad", + "LastName": "Huang", + "abbrevName": "Huang CC", + "email": null, + "isCollectiveName": false, + "name": "Conrad C Huang" + }, + { + "ForeName": "Gregory", + "LastName": "Couch", + "abbrevName": "Couch GS", + "email": null, + "isCollectiveName": false, + "name": "Gregory S Couch" + }, + { + "ForeName": "Daniel", + "LastName": "Greenblatt", + "abbrevName": "Greenblatt DM", + "email": null, + "isCollectiveName": false, + "name": "Daniel M Greenblatt" + }, + { + "ForeName": "Elaine", + "LastName": "Meng", + "abbrevName": "Meng EC", + "email": null, + "isCollectiveName": false, + "name": "Elaine C Meng" + }, + { + "ForeName": "Thomas", + "LastName": "Ferrin", + "abbrevName": "Ferrin TE", + "email": null, + "isCollectiveName": false, + "name": "Thomas E Ferrin" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcc.20084", + "pmid": "15264254", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Comput Chem 25 2004", + "title": "UCSF Chimera--a visualization system for exploratory research and analysis." + } + }, + { + "pmid": "11239454", + "pubmed": { + "ISODate": "2001-02-01T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have been cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1, in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes.", + "authors": { + "abbreviation": "I Garcia-Higuera, T Taniguchi, S Ganesan, ..., A D D'Andrea", + "authorList": [ + { + "ForeName": "I", + "LastName": "Garcia-Higuera", + "abbrevName": "Garcia-Higuera I", + "email": null, + "isCollectiveName": false, + "name": "I Garcia-Higuera" + }, + { + "ForeName": "T", + "LastName": "Taniguchi", + "abbrevName": "Taniguchi T", + "email": null, + "isCollectiveName": false, + "name": "T Taniguchi" + }, + { + "ForeName": "S", + "LastName": "Ganesan", + "abbrevName": "Ganesan S", + "email": null, + "isCollectiveName": false, + "name": "S Ganesan" + }, + { + "ForeName": "M", + "LastName": "Meyn", + "abbrevName": "Meyn MS", + "email": null, + "isCollectiveName": false, + "name": "M S Meyn" + }, + { + "ForeName": "C", + "LastName": "Timmers", + "abbrevName": "Timmers C", + "email": null, + "isCollectiveName": false, + "name": "C Timmers" + }, + { + "ForeName": "J", + "LastName": "Hejna", + "abbrevName": "Hejna J", + "email": null, + "isCollectiveName": false, + "name": "J Hejna" + }, + { + "ForeName": "M", + "LastName": "Grompe", + "abbrevName": "Grompe M", + "email": null, + "isCollectiveName": false, + "name": "M Grompe" + }, + { + "ForeName": "A", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "A D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/s1097-2765(01)00173-3", + "pmid": "11239454", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Cell 7 2001", + "title": "Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway." + } + }, + { + "pmid": "8563639", + "pubmed": { + "ISODate": "1995-11-01T00:00:00.000Z", + "abstract": "The molar absorption coefficient, epsilon, of a protein is usually based on concentrations measured by dry weight, nitrogen, or amino acid analysis. The studies reported here suggest that the Edelhoch method is the best method for measuring epsilon for a protein. (This method is described by Gill and von Hippel [1989, Anal Biochem 182:319-326] and is based on data from Edelhoch [1967, Biochemistry 6:1948-1954]). The absorbance of a protein at 280 nm depends on the content of Trp, Tyr, and cystine (disulfide bonds). The average epsilon values for these chromophores in a sample of 18 well-characterized proteins have been estimated, and the epsilon values in water, propanol, 6 M guanidine hydrochloride (GdnHCl), and 8 M urea have been measured. For Trp, the average epsilon values for the proteins are less than the epsilon values measured in any of the solvents. For Tyr, the average epsilon values for the proteins are intermediate between those measured in 6 M GdnHCl and those measured in propanol. Based on a sample of 116 measured epsilon values for 80 proteins, the epsilon at 280 nm of a folded protein in water, epsilon (280), can best be predicted with this equation: epsilon (280) (M-1 cm-1) = (#Trp)(5,500) + (#Tyr)(1,490) + (#cystine)(125) These epsilon (280) values are quite reliable for proteins containing Trp residues, and less reliable for proteins that do not. However, the Edelhoch method is convenient and accurate, and the best approach is to measure rather than predict epsilon.", + "authors": { + "abbreviation": "C N Pace, F Vajdos, L Fee, ..., T Gray", + "authorList": [ + { + "ForeName": "C", + "LastName": "Pace", + "abbrevName": "Pace CN", + "email": null, + "isCollectiveName": false, + "name": "C N Pace" + }, + { + "ForeName": "F", + "LastName": "Vajdos", + "abbrevName": "Vajdos F", + "email": null, + "isCollectiveName": false, + "name": "F Vajdos" + }, + { + "ForeName": "L", + "LastName": "Fee", + "abbrevName": "Fee L", + "email": null, + "isCollectiveName": false, + "name": "L Fee" + }, + { + "ForeName": "G", + "LastName": "Grimsley", + "abbrevName": "Grimsley G", + "email": null, + "isCollectiveName": false, + "name": "G Grimsley" + }, + { + "ForeName": "T", + "LastName": "Gray", + "abbrevName": "Gray T", + "email": null, + "isCollectiveName": false, + "name": "T Gray" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.5560041120", + "pmid": "8563639", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Protein Sci 4 1995", + "title": "How to measure and predict the molar absorption coefficient of a protein." + } + }, + { + "pmid": "8001157", + "pubmed": { + "ISODate": "1994-12-30T00:00:00.000Z", + "abstract": "The crystal structure of the processivity factor required by eukaryotic DNA polymerase delta, proliferating cell nuclear antigen (PCNA) from S. cerevisiae, has been determined at 2.3 A resolution. Three PCNA molecules, each containing two topologically identical domains, are tightly associated to form a closed ring. The dimensions and electrostatic properties of the ring suggest that PCNA encircles duplex DNA, providing a DNA-bound platform for the attachment of the polymerase. The trimeric PCNA ring is strikingly similar to the dimeric ring formed by the beta subunit (processivity factor) of E. coli DNA polymerase III holoenzyme, with which it shares no significant sequence identity. This structural correspondence further substantiates the mechanistic connection between eukaryotic and prokaryotic DNA replication that has been suggested on biochemical grounds.", + "authors": { + "abbreviation": "T S Krishna, X P Kong, S Gary, ..., J Kuriyan", + "authorList": [ + { + "ForeName": "T", + "LastName": "Krishna", + "abbrevName": "Krishna TS", + "email": null, + "isCollectiveName": false, + "name": "T S Krishna" + }, + { + "ForeName": "X", + "LastName": "Kong", + "abbrevName": "Kong XP", + "email": null, + "isCollectiveName": false, + "name": "X P Kong" + }, + { + "ForeName": "S", + "LastName": "Gary", + "abbrevName": "Gary S", + "email": null, + "isCollectiveName": false, + "name": "S Gary" + }, + { + "ForeName": "P", + "LastName": "Burgers", + "abbrevName": "Burgers PM", + "email": null, + "isCollectiveName": false, + "name": "P M Burgers" + }, + { + "ForeName": "J", + "LastName": "Kuriyan", + "abbrevName": "Kuriyan J", + "email": null, + "isCollectiveName": false, + "name": "J Kuriyan" + } + ], + "contacts": [] + }, + "doi": "10.1016/0092-8674(94)90014-0", + "pmid": "8001157", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Cell 79 1994", + "title": "Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA." + } + } + ], + "relatedPapers": [ + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2021-07-23T11:51:05.955Z", + "_newestOpId": "9efd3183-178c-4927-80ac-91077893d9a8", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "1297c941-b23e-461f-9cc7-46e3457d5ca4" + }, + { + "id": "2af10d33-240c-4a41-94eb-78da690b2d7d" + } + ], + "id": "54641fe7-30f1-4478-abbe-d41531f26948", + "liveId": "8eb06d6f-7c2d-434f-b175-045acf89b8de", + "lock": null, + "locked": false, + "name": "USP1-UAF1 complex", + "position": { + "x": 214.11277330264664, + "y": 162.81012658227826 + }, + "relatedPapers": [ + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + } + ], + "secret": "read-only", + "type": "complex" + }, + { + "_creationTimestamp": "2021-07-23T11:50:59.066Z", + "_newestOpId": "0583f905-401f-438a-a746-c0536c3cc9a6", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "612167" + }, + { + "db": "HGNC", + "id": "HGNC:30914" + }, + { + "db": "Ensembl", + "id": "ENSG00000114742" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.321643, + "id": "57599", + "name": "WDR48", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100, + "shortSynonyms": [ + "WDR48", + "P80", + "SPG60", + "UAF1", + "WD repeat-containing protein 48", + "USP1 associated factor 1", + "WD repeat endosomal protein", + "testicular tissue protein Li 224", + "WD repeat domain 48" + ], + "synonyms": [ + "P80", + "SPG60", + "UAF1", + "WD repeat-containing protein 48", + "USP1 associated factor 1", + "WD repeat endosomal protein", + "testicular tissue protein Li 224", + "WD repeat domain 48" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "1297c941-b23e-461f-9cc7-46e3457d5ca4", + "liveId": "e9a1a62a-c8d3-4431-8621-3626d62f95bb", + "lock": null, + "locked": false, + "name": "UAF1", + "parentId": "54641fe7-30f1-4478-abbe-d41531f26948", + "position": { + "x": 360.6260069044879, + "y": 172.69965477560396 + }, + "relatedPapers": [ + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-07-23T11:50:28.981Z", + "_newestOpId": "f5b07da0-0c00-44e4-b14e-b6c41ce78c20", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "613984" + }, + { + "db": "HGNC", + "id": "HGNC:3585" + }, + { + "db": "Ensembl", + "id": "ENSG00000144554" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 10.918428, + "id": "2177", + "name": "FANCD2", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "FA-D2", + "FA4", + "FACD", + "FAD", + "FAD2", + "FANCD", + "Fanconi anemia group D2 protein", + "Fanconi anemia complementation group D2", + "FA complementation group D2" + ], + "synonyms": [ + "FA-D2", + "FA4", + "FACD", + "FAD", + "FAD2", + "FANCD", + "Fanconi anemia group D2 protein", + "Fanconi anemia complementation group D2", + "FA complementation group D2" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "87ed3eb8-aff7-463b-bd2d-494aede66d78", + "liveId": "73c5f49c-bd35-42ec-a741-4ce0bb44fed7", + "lock": null, + "locked": false, + "name": "FANCD2", + "parentId": "bafa60d9-cae7-4b27-85c7-c92e4d4fb68a", + "position": { + "x": 308.55696202531647, + "y": 132.34982738780207 + }, + "relatedPapers": [ + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-07-23T11:50:47.765Z", + "_newestOpId": "d6e4bff4-e521-4991-98b7-3bc6c3b409bf", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "603478" + }, + { + "db": "HGNC", + "id": "HGNC:12607" + }, + { + "db": "Ensembl", + "id": "ENSG00000162607" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 10.929575, + "id": "7398", + "name": "USP1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "UBP", + "ubiquitin carboxyl-terminal hydrolase 1", + "deubiquitinating enzyme 1", + "hUBP", + "ubiquitin specific processing protease 1", + "ubiquitin specific protease 1", + "ubiquitin thioesterase 1", + "ubiquitin thiolesterase 1", + "ubiquitin specific peptidase 1" + ], + "synonyms": [ + "UBP", + "ubiquitin carboxyl-terminal hydrolase 1", + "deubiquitinating enzyme 1", + "hUBP", + "ubiquitin specific processing protease 1", + "ubiquitin specific protease 1", + "ubiquitin thioesterase 1", + "ubiquitin thiolesterase 1", + "ubiquitin specific peptidase 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "2af10d33-240c-4a41-94eb-78da690b2d7d", + "liveId": "b5ae14e2-28a1-4fb0-ba62-389684106f41", + "lock": null, + "locked": false, + "name": "USP1", + "parentId": "54641fe7-30f1-4478-abbe-d41531f26948", + "position": { + "x": 311.9631760644418, + "y": 174.01150747986176 + }, + "relatedPapers": [ + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-07-23T11:50:40.655Z", + "_newestOpId": "6ea1e61b-ef1f-4b96-8613-e8adbadabcb8", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "53abc3ba-4d9b-431f-a100-9a6411450218" + }, + { + "id": "87ed3eb8-aff7-463b-bd2d-494aede66d78" + } + ], + "id": "bafa60d9-cae7-4b27-85c7-c92e4d4fb68a", + "liveId": "72658656-4a1e-44ee-b03a-d70bc45b82b1", + "lock": null, + "locked": false, + "name": "ID2 complex (ubiquitin on FANCD2)", + "position": { + "x": 333.16398158803224, + "y": 93.14844649021865 + }, + "relatedPapers": [ + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + } + ], + "secret": "read-only", + "type": "complex" + }, + { + "_creationTimestamp": "2021-07-23T13:02:39.714Z", + "_newestOpId": "31c42ca8-0a5d-43c6-af59-61f59f8ed960", + "_ops": [], + "association": "deubiquitination", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "2af10d33-240c-4a41-94eb-78da690b2d7d" + }, + { + "group": "unsigned", + "id": "87ed3eb8-aff7-463b-bd2d-494aede66d78" + } + ], + "id": "8ee9fb94-b3b8-4212-bddc-d46f1a079164", + "liveId": "2e191f7a-5766-48d8-9538-6d231abb6f2f", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": -3.619677790563685, + "y": 54.04746835443038 + }, + "relatedPapers": [ + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + } + ], + "secret": "read-only", + "type": "deubiquitination" + }, + { + "_creationTimestamp": "2021-07-23T11:50:36.410Z", + "_newestOpId": "60cc6402-2a7c-455c-b0b7-e130ea99c7b7", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "611360" + }, + { + "db": "HGNC", + "id": "HGNC:25568" + }, + { + "db": "Ensembl", + "id": "ENSG00000140525" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.4404, + "id": "55215", + "name": "FANCI", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "KIAA1794", + "Fanconi anemia group I protein", + "Fanconi anemia complementation group I", + "FA complementation group I" + ], + "synonyms": [ + "KIAA1794", + "Fanconi anemia group I protein", + "Fanconi anemia complementation group I", + "FA complementation group I" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "53abc3ba-4d9b-431f-a100-9a6411450218", + "liveId": "41db090c-27bd-4fa0-a8cb-6a7d782340db", + "lock": null, + "locked": false, + "name": "FANCI", + "parentId": "bafa60d9-cae7-4b27-85c7-c92e4d4fb68a", + "position": { + "x": 360.58918296892983, + "y": 132.49252013808976 + }, + "relatedPapers": [ + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + }, + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-07-23T12:24:02.683Z", + "_newestOpId": "cbd0a755-edc7-4f61-a17b-a4919bc68b90", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "1297c941-b23e-461f-9cc7-46e3457d5ca4" + }, + { + "group": "unsigned", + "id": "53abc3ba-4d9b-431f-a100-9a6411450218" + } + ], + "id": "b38116a2-5002-48b0-b156-32bcbff764a4", + "liveId": "0830d748-2b35-4a09-a336-b58f352fca59", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": -8.346950517836541, + "y": 61.68383199079401 + }, + "relatedPapers": [ + { + "pmid": "27463890", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interaction-deficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.", + "authors": { + "abbreviation": "Scott Cukras, Euiho Lee, Emily Palumbo, ..., Younghoon Kee", + "authorList": [ + { + "ForeName": "Scott", + "LastName": "Cukras", + "abbrevName": "Cukras S", + "email": null, + "isCollectiveName": false, + "name": "Scott Cukras" + }, + { + "ForeName": "Euiho", + "LastName": "Lee", + "abbrevName": "Lee E", + "email": null, + "isCollectiveName": false, + "name": "Euiho Lee" + }, + { + "ForeName": "Emily", + "LastName": "Palumbo", + "abbrevName": "Palumbo E", + "email": null, + "isCollectiveName": false, + "name": "Emily Palumbo" + }, + { + "ForeName": "Pamela", + "LastName": "Benavidez", + "abbrevName": "Benavidez P", + "email": null, + "isCollectiveName": false, + "name": "Pamela Benavidez" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Younghoon", + "LastName": "Kee", + "abbrevName": "Kee Y", + "email": null, + "isCollectiveName": false, + "name": "Younghoon Kee" + } + ], + "contacts": [] + }, + "doi": "10.1080/15384101.2016.1209613", + "pmid": "27463890", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Cycle 15 2016", + "title": "The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair." + } + }, + { + "pmid": "21896657", + "pubmed": { + "ISODate": "2011-09-01T00:00:00.000Z", + "abstract": "The USP1/UAF1 complex deubiquitinates the Fanconi anemia protein FANCD2, thereby promoting homologous recombination and DNA cross-link repair. How USP1/UAF1 is targeted to the FANCD2/FANCI heterodimer has remained unknown. Here we show that UAF1 contains a tandem repeat of SUMO-like domains in its C terminus (SLD1 and SLD2). SLD2 binds directly to a SUMO-like domain-interacting motif (SIM) on FANCI. Deletion of the SLD2 sequence of UAF1 or mutation of the SIM on FANCI disrupts UAF1/FANCI binding and inhibits FANCD2 deubiquitination and DNA repair. The USP1/UAF1 complex also deubiquitinates PCNA-Ub, and deubiquitination requires the PCNA-binding protein hELG1. The SLD2 sequence of UAF1 binds to a SIM on hELG1, thus targeting the USP1/UAF1 complex to its PCNA-Ub substrate. We propose that the regulated targeting of USP1/UAF1 to its DNA repair substrates, FANCD2-Ub and PCNA-Ub, by SLD-SIM interactions coordinates homologous recombination and translesion DNA synthesis.", + "authors": { + "abbreviation": "Kailin Yang, George-Lucian Moldovan, Patrizia Vinciguerra, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "George-Lucian", + "LastName": "Moldovan", + "abbrevName": "Moldovan GL", + "email": null, + "isCollectiveName": false, + "name": "George-Lucian Moldovan" + }, + { + "ForeName": "Patrizia", + "LastName": "Vinciguerra", + "abbrevName": "Vinciguerra P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Vinciguerra" + }, + { + "ForeName": "Junko", + "LastName": "Murai", + "abbrevName": "Murai J", + "email": null, + "isCollectiveName": false, + "name": "Junko Murai" + }, + { + "ForeName": "Shunichi", + "LastName": "Takeda", + "abbrevName": "Takeda S", + "email": null, + "isCollectiveName": false, + "name": "Shunichi Takeda" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.17020911", + "pmid": "21896657", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genes Dev 25 2011", + "title": "Regulation of the Fanconi anemia pathway by a SUMO-like delivery network." + } + }, + { + "pmid": "18082604", + "pubmed": { + "ISODate": "2007-12-14T00:00:00.000Z", + "abstract": "The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2, a key protein of the Fanconi anemia DNA repair pathway. Here we report the purification of a USP1 multisubunit protein complex from HeLa cells containing stoichiometric amounts of a WD40 repeat-containing protein, USP1 associated factor 1 (UAF1). In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). Moreover, we show that DNA damage results in an immediate shutoff of transcription of the USP1 gene, leading to a rapid decline in the USP1/UAF1 protein complex. Taken together, our results describe a mechanism of regulation of the deubiquitinating enzyme, USP1, and of DNA repair.", + "authors": { + "abbreviation": "Martin A Cohn, Przemyslaw Kowal, Kailin Yang, ..., Alan D D'Andrea", + "authorList": [ + { + "ForeName": "Martin", + "LastName": "Cohn", + "abbrevName": "Cohn MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Cohn" + }, + { + "ForeName": "Przemyslaw", + "LastName": "Kowal", + "abbrevName": "Kowal P", + "email": null, + "isCollectiveName": false, + "name": "Przemyslaw Kowal" + }, + { + "ForeName": "Kailin", + "LastName": "Yang", + "abbrevName": "Yang K", + "email": null, + "isCollectiveName": false, + "name": "Kailin Yang" + }, + { + "ForeName": "Wilhelm", + "LastName": "Haas", + "abbrevName": "Haas W", + "email": null, + "isCollectiveName": false, + "name": "Wilhelm Haas" + }, + { + "ForeName": "Tony", + "LastName": "Huang", + "abbrevName": "Huang TT", + "email": null, + "isCollectiveName": false, + "name": "Tony T Huang" + }, + { + "ForeName": "Steven", + "LastName": "Gygi", + "abbrevName": "Gygi SP", + "email": null, + "isCollectiveName": false, + "name": "Steven P Gygi" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2007.09.031", + "pmid": "18082604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Cell 28 2007", + "title": "A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway." + } + }, + { + "pmid": "30456385", + "pubmed": { + "ISODate": "2018-10-01T00:00:00.000Z", + "abstract": "The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin-substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP.", + "authors": { + "abbreviation": "Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden", + "authorList": [ + { + "ForeName": "Connor", + "LastName": "Arkinson", + "abbrevName": "Arkinson C", + "email": null, + "isCollectiveName": false, + "name": "Connor Arkinson" + }, + { + "ForeName": "Viduth", + "LastName": "Chaugule", + "abbrevName": "Chaugule VK", + "email": null, + "isCollectiveName": false, + "name": "Viduth K Chaugule" + }, + { + "ForeName": "Rachel", + "LastName": "Toth", + "abbrevName": "Toth R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Toth" + }, + { + "ForeName": "Helen", + "LastName": "Walden", + "abbrevName": "Walden H", + "email": null, + "isCollectiveName": false, + "name": "Helen Walden" + } + ], + "contacts": [] + }, + "doi": "10.26508/lsa.201800162", + "pmid": "30456385", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Life Sci Alliance 1 2018", + "title": "Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1." + } + }, + { + "pmid": "27986592", + "pubmed": { + "ISODate": "2017-01-17T00:00:00.000Z", + "abstract": "Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.", + "authors": { + "abbreviation": "Paolo Swuec, Ludovic Renault, Aaron Borg, ..., Alessandro Costa", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Swuec", + "abbrevName": "Swuec P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Swuec" + }, + { + "ForeName": "Ludovic", + "LastName": "Renault", + "abbrevName": "Renault L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Renault" + }, + { + "ForeName": "Aaron", + "LastName": "Borg", + "abbrevName": "Borg A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Borg" + }, + { + "ForeName": "Fenil", + "LastName": "Shah", + "abbrevName": "Shah F", + "email": null, + "isCollectiveName": false, + "name": "Fenil Shah" + }, + { + "ForeName": "Vincent", + "LastName": "Murphy", + "abbrevName": "Murphy VJ", + "email": null, + "isCollectiveName": false, + "name": "Vincent J Murphy" + }, + { + "ForeName": "Sylvie", + "LastName": "van Twest", + "abbrevName": "van Twest S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie van Twest" + }, + { + "ForeName": "Ambrosius", + "LastName": "Snijders", + "abbrevName": "Snijders AP", + "email": null, + "isCollectiveName": false, + "name": "Ambrosius P Snijders" + }, + { + "ForeName": "Andrew", + "LastName": "Deans", + "abbrevName": "Deans AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Deans" + }, + { + "ForeName": "Alessandro", + "LastName": "Costa", + "abbrevName": "Costa A", + "email": "alessandro.costa@crick.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Costa" + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Costa", + "email": [ + "alessandro.costa@crick.ac.uk" + ], + "name": "Alessandro Costa" + } + ] + }, + "doi": "10.1016/j.celrep.2016.11.013", + "pmid": "27986592", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 18 2017", + "title": "The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2." + } + }, + { + "pmid": "27373336", + "pubmed": { + "ISODate": "2016-07-21T00:00:00.000Z", + "abstract": "Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.", + "authors": { + "abbreviation": "Heng Li, Kah Suan Lim, Hyungjin Kim, ..., Ning Zheng", + "authorList": [ + { + "ForeName": "Heng", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Heng Li" + }, + { + "ForeName": "Kah", + "LastName": "Lim", + "abbrevName": "Lim KS", + "email": null, + "isCollectiveName": false, + "name": "Kah Suan Lim" + }, + { + "ForeName": "Hyungjin", + "LastName": "Kim", + "abbrevName": "Kim H", + "email": null, + "isCollectiveName": false, + "name": "Hyungjin Kim" + }, + { + "ForeName": "Thomas", + "LastName": "Hinds", + "abbrevName": "Hinds TR", + "email": null, + "isCollectiveName": false, + "name": "Thomas R Hinds" + }, + { + "ForeName": "Ukhyun", + "LastName": "Jo", + "abbrevName": "Jo U", + "email": null, + "isCollectiveName": false, + "name": "Ukhyun Jo" + }, + { + "ForeName": "Haibin", + "LastName": "Mao", + "abbrevName": "Mao H", + "email": null, + "isCollectiveName": false, + "name": "Haibin Mao" + }, + { + "ForeName": "Caroline", + "LastName": "Weller", + "abbrevName": "Weller CE", + "email": null, + "isCollectiveName": false, + "name": "Caroline E Weller" + }, + { + "ForeName": "Ji", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Ji Sun" + }, + { + "ForeName": "Champak", + "LastName": "Chatterjee", + "abbrevName": "Chatterjee C", + "email": null, + "isCollectiveName": false, + "name": "Champak Chatterjee" + }, + { + "ForeName": "Alan", + "LastName": "D'Andrea", + "abbrevName": "D'Andrea AD", + "email": null, + "isCollectiveName": false, + "name": "Alan D D'Andrea" + }, + { + "ForeName": "Ning", + "LastName": "Zheng", + "abbrevName": "Zheng N", + "email": "nzheng@uw.edu", + "isCollectiveName": false, + "name": "Ning Zheng" + } + ], + "contacts": [ + { + "ForeName": "Ning", + "LastName": "Zheng", + "email": [ + "nzheng@uw.edu" + ], + "name": "Ning Zheng" + } + ] + }, + "doi": "10.1016/j.molcel.2016.05.031", + "pmid": "27373336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 63 2016", + "title": "Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20." + } + }, + { + "pmid": "24623813", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions. ", + "authors": { + "abbreviation": "Simonne Longerich, Youngho Kwon, Miaw-Sheue Tsai, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Youngho", + "LastName": "Kwon", + "abbrevName": "Kwon Y", + "email": null, + "isCollectiveName": false, + "name": "Youngho Kwon" + }, + { + "ForeName": "Miaw-Sheue", + "LastName": "Tsai", + "abbrevName": "Tsai MS", + "email": null, + "isCollectiveName": false, + "name": "Miaw-Sheue Tsai" + }, + { + "ForeName": "Aye", + "LastName": "Hlaing", + "abbrevName": "Hlaing AS", + "email": null, + "isCollectiveName": false, + "name": "Aye Su Hlaing" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": null, + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "patrick.sung@yale.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "patrick.sung@yale.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1093/nar/gku198", + "pmid": "24623813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 42 2014", + "title": "Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA." + } + }, + { + "pmid": "31253762", + "pubmed": { + "ISODate": "2019-06-28T00:00:00.000Z", + "abstract": "Fanconi anemia (FA) is a multigenic disease of bone marrow failure and cancer susceptibility stemming from a failure to remove DNA crosslinks and other chromosomal lesions. Within the FA DNA damage response pathway, DNA-dependent monoubiquitinaton of FANCD2 licenses downstream events, while timely FANCD2 deubiquitination serves to extinguish the response. Here, we show with reconstituted biochemical systems, which we developed, that efficient FANCD2 deubiquitination by the USP1-UAF1 complex is dependent on DNA and DNA binding by UAF1. Surprisingly, we find that the DNA binding activity of the UAF1-associated protein RAD51AP1 can substitute for that of UAF1 in FANCD2 deubiquitination in our biochemical system. We also reveal the importance of DNA binding by UAF1 and RAD51AP1 in FANCD2 deubiquitination in the cellular setting. Our results provide insights into a key step in the FA pathway and help define the multifaceted role of the USP1-UAF1-RAD51AP1 complex in DNA damage tolerance and genome repair.", + "authors": { + "abbreviation": "Fengshan Liang, Adam S Miller, Simonne Longerich, ..., Patrick Sung", + "authorList": [ + { + "ForeName": "Fengshan", + "LastName": "Liang", + "abbrevName": "Liang F", + "email": null, + "isCollectiveName": false, + "name": "Fengshan Liang" + }, + { + "ForeName": "Adam", + "LastName": "Miller", + "abbrevName": "Miller AS", + "email": null, + "isCollectiveName": false, + "name": "Adam S Miller" + }, + { + "ForeName": "Simonne", + "LastName": "Longerich", + "abbrevName": "Longerich S", + "email": null, + "isCollectiveName": false, + "name": "Simonne Longerich" + }, + { + "ForeName": "Caroline", + "LastName": "Tang", + "abbrevName": "Tang C", + "email": null, + "isCollectiveName": false, + "name": "Caroline Tang" + }, + { + "ForeName": "David", + "LastName": "Maranon", + "abbrevName": "Maranon D", + "email": null, + "isCollectiveName": false, + "name": "David Maranon" + }, + { + "ForeName": "Elizabeth", + "LastName": "Williamson", + "abbrevName": "Williamson EA", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth A Williamson" + }, + { + "ForeName": "Robert", + "LastName": "Hromas", + "abbrevName": "Hromas R", + "email": null, + "isCollectiveName": false, + "name": "Robert Hromas" + }, + { + "ForeName": "Claudia", + "LastName": "Wiese", + "abbrevName": "Wiese C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Wiese" + }, + { + "ForeName": "Gary", + "LastName": "Kupfer", + "abbrevName": "Kupfer GM", + "email": "gary.kupfer@yale.edu", + "isCollectiveName": false, + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "abbrevName": "Sung P", + "email": "sungp@uthscsa.edu", + "isCollectiveName": false, + "name": "Patrick Sung" + } + ], + "contacts": [ + { + "ForeName": "Gary", + "LastName": "Kupfer", + "email": [ + "gary.kupfer@yale.edu" + ], + "name": "Gary M Kupfer" + }, + { + "ForeName": "Patrick", + "LastName": "Sung", + "email": [ + "sungp@uthscsa.edu" + ], + "name": "Patrick Sung" + } + ] + }, + "doi": "10.1038/s41467-019-10408-5", + "pmid": "31253762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response." + } + }, + { + "pmid": "27650958", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8Å and of UAF1 at 2.3Å. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.", + "authors": { + "abbreviation": "Shreya Dharadhar, Marcello Clerici, Willem J van Dijk, ..., Titia K Sixma", + "authorList": [ + { + "ForeName": "Shreya", + "LastName": "Dharadhar", + "abbrevName": "Dharadhar S", + "email": null, + "isCollectiveName": false, + "name": "Shreya Dharadhar" + }, + { + "ForeName": "Marcello", + "LastName": "Clerici", + "abbrevName": "Clerici M", + "email": null, + "isCollectiveName": false, + "name": "Marcello Clerici" + }, + { + "ForeName": "Willem", + "LastName": "van Dijk", + "abbrevName": "van Dijk WJ", + "email": null, + "isCollectiveName": false, + "name": "Willem J van Dijk" + }, + { + "ForeName": "Alexander", + "LastName": "Fish", + "abbrevName": "Fish A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Fish" + }, + { + "ForeName": "Titia", + "LastName": "Sixma", + "abbrevName": "Sixma TK", + "email": "t.sixma@nki.nl", + "isCollectiveName": false, + "name": "Titia K Sixma" + } + ], + "contacts": [ + { + "ForeName": "Titia", + "LastName": "Sixma", + "email": [ + "t.sixma@nki.nl" + ], + "name": "Titia K Sixma" + } + ] + }, + "doi": "10.1016/j.jsb.2016.09.011", + "pmid": "27650958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Struct Biol 196 2016", + "title": "A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme." + } + } + ], + "secret": "read-only", + "type": "binding" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/complex_tests_5.json b/neo4j-test/document/complex_tests_5.json new file mode 100644 index 000000000..404ddd42f --- /dev/null +++ b/neo4j-test/document/complex_tests_5.json @@ -0,0 +1,34488 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-12-06T20:11:53.019Z", + "_newestOpId": "922d6c2e-0517-495c-98b6-f334925de24a", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole-genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and type I necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1γ) to complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1γ fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g-/- mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo.", + "ArticleTitle": "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + }, + { + "Affiliation": "Department of Clinical Immunology, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jingchun", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-0571-7444" + } + ], + "Initials": "J", + "LastName": "Du" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + }, + { + "Affiliation": "Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ, 85040, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Yougui", + "Identifier": [], + "Initials": "Y", + "LastName": "Xiang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + }, + { + "Affiliation": "School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330006, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Hua", + "Identifier": [], + "Initials": "H", + "LastName": "Liu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Shuzhen", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-0602-3217" + } + ], + "Initials": "S", + "LastName": "Liu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ashwani", + "Identifier": [], + "Initials": "A", + "LastName": "Kumar" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + }, + { + "Affiliation": "Department of Bioinformatics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + }, + { + "Affiliation": "Department of Population and Data Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Chao", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-1838-0502" + } + ], + "Initials": "C", + "LastName": "Xing" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. zhigao@usf.edu.", + "email": [ + "zhigao@usf.edu" + ] + }, + { + "Affiliation": "Center for Regenerative Medicine, Heart Institute, Department of Internal Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL, 33602, USA. zhigao@usf.edu.", + "email": [ + "zhigao@usf.edu" + ] + } + ], + "CollectiveName": null, + "ForeName": "Zhigao", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-6544-4302" + } + ], + "Initials": "Z", + "LastName": "Wang" + } + 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Science. 2014;345:1184–1188." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Jingchun", + "LastName": "Du", + "abbrevName": "Du J", + "email": null, + "isCollectiveName": false, + "name": "Jingchun Du", + "orcid": "0000-0002-0571-7444" + }, + { + "ForeName": "Yougui", + "LastName": "Xiang", + "abbrevName": "Xiang Y", + "email": null, + "isCollectiveName": false, + "name": "Yougui Xiang", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hua Liu", + "orcid": null + }, + { + "ForeName": "Shuzhen", + "LastName": "Liu", + "abbrevName": "Liu S", + "email": null, + "isCollectiveName": false, + "name": "Shuzhen Liu", + "orcid": "0000-0002-0602-3217" + }, + { + "ForeName": "Ashwani", + "LastName": "Kumar", + "abbrevName": "Kumar A", + "email": null, + "isCollectiveName": false, + "name": "Ashwani Kumar", + "orcid": null + }, + { + "ForeName": "Chao", + "LastName": "Xing", + "abbrevName": "Xing C", + "email": null, + "isCollectiveName": false, + "name": "Chao Xing", + "orcid": "0000-0002-1838-0502" + }, + { + "ForeName": "Zhigao", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": "zhigao@usf.edu", + "isCollectiveName": false, + "name": "Zhigao Wang", + "orcid": "0000-0002-6544-4302" + } + ], + "caption": "apoptosis and necroptosis", + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1670357513, + "entries": [ + { + "id": "3e669fd7-8018-4098-b305-f050f090099e" + }, + { + "id": "e4355ec8-9c2f-43c4-bbc4-f54ea7b6318d" + }, + { + "id": "b2483833-8ca2-4246-8125-7cff29dec7ae" + }, + { + "id": "f9673773-0fa4-4c6c-bae3-8dc7373bc9d7" + }, + { + "id": "80f93da0-91c1-41f4-b549-6e99a2eb870c" + } + ], + "id": "4638c40d-200d-4fa6-906b-2f567a3cbe06", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1670357976, + "liveId": "6a7edb50-3567-4ac5-8bcb-eb25ee1f7652", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "31932442", + "pubmed": { + "ISODate": "2020-01-28T00:00:00.000Z", + "abstract": "Necroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.", + "authors": { + "abbreviation": "Sarah Hanna-Addams, Shuzhen Liu, Hua Liu, ..., Zhigao Wang", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Hanna-Addams", + "abbrevName": "Hanna-Addams S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Hanna-Addams", + "orcid": null + }, + { + "ForeName": "Shuzhen", + "LastName": "Liu", + "abbrevName": "Liu S", + "email": null, + "isCollectiveName": false, + "name": "Shuzhen Liu", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hua Liu", + "orcid": null + }, + { + "ForeName": "She", + "LastName": "Chen", + "abbrevName": "Chen S", + "email": null, + "isCollectiveName": false, + "name": "She Chen", + "orcid": null + }, + { + "ForeName": "Zhigao", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": "zhigao.wang@utsouthwestern.edu", + "isCollectiveName": false, + "name": "Zhigao Wang", + "orcid": "0000-0002-6544-4302" + } + ], + "contacts": [ + { + "ForeName": "Zhigao", + "LastName": "Wang", + "email": [ + "zhigao.wang@utsouthwestern.edu" + ], + "name": "Zhigao Wang" + } + ] + }, + "doi": "10.1073/pnas.1917112117", + "pmid": "31932442", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 117 2020", + "title": "CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis." + } + }, + { + "pmid": "31827281", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.", + "authors": { + "abbreviation": "Najoua Lalaoui, Steven E Boyden, Hirotsugu Oda, ..., John Silke", + "authorList": [ + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": "lalaoui@wehi.edu.au", + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Steven", + "LastName": "Boyden", + "abbrevName": "Boyden SE", + "email": "steven.boyden@genetics.utah.edu", + "isCollectiveName": false, + "name": "Steven E Boyden", + "orcid": null + }, + { + "ForeName": "Hirotsugu", + "LastName": "Oda", + "abbrevName": "Oda H", + "email": null, + "isCollectiveName": false, + "name": "Hirotsugu Oda", + "orcid": null + }, + { + "ForeName": "Geryl", + "LastName": "Wood", + "abbrevName": "Wood GM", + "email": null, + "isCollectiveName": false, + "name": "Geryl M Wood", + "orcid": null + }, + { + "ForeName": "Deborah", + "LastName": "Stone", + "abbrevName": "Stone DL", + "email": null, + "isCollectiveName": false, + "name": "Deborah L Stone", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lin Liu", + "orcid": null + }, + { + "ForeName": "Monique", + "LastName": "Stoffels", + "abbrevName": "Stoffels M", + "email": null, + "isCollectiveName": false, + "name": "Monique Stoffels", + "orcid": null + }, + { + "ForeName": "Tobias", + "LastName": "Kratina", + "abbrevName": "Kratina T", + "email": null, + "isCollectiveName": false, + "name": "Tobias Kratina", + "orcid": null + }, + { + "ForeName": "Kate", + "LastName": "Lawlor", + "abbrevName": "Lawlor KE", + "email": null, + "isCollectiveName": false, + "name": "Kate E Lawlor", + "orcid": null + }, + { + "ForeName": "Kristien", + "LastName": "Zaal", + "abbrevName": "Zaal KJM", + "email": null, + "isCollectiveName": false, + "name": "Kristien J M Zaal", + "orcid": null + }, + { + "ForeName": "Patrycja", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann PM", + "email": null, + "isCollectiveName": false, + "name": "Patrycja M Hoffmann", + "orcid": null + }, + { + "ForeName": "Nima", + "LastName": "Etemadi", + "abbrevName": "Etemadi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Etemadi", + "orcid": null + }, + { + "ForeName": "Kristy", + "LastName": "Shield-Artin", + "abbrevName": "Shield-Artin K", + "email": null, + "isCollectiveName": false, + "name": "Kristy Shield-Artin", + "orcid": null + }, + { + "ForeName": "Christine", + "LastName": "Biben", + "abbrevName": "Biben C", + "email": null, + "isCollectiveName": false, + "name": "Christine Biben", + "orcid": null + }, + { + "ForeName": "Wanxia", + "LastName": "Tsai", + "abbrevName": "Tsai WL", + "email": null, + "isCollectiveName": false, + "name": "Wanxia Li Tsai", + "orcid": null + }, + { + "ForeName": "Mary", + "LastName": "Blake", + "abbrevName": "Blake MD", + "email": null, + "isCollectiveName": false, + "name": "Mary D Blake", + "orcid": null + }, + { + "ForeName": "Hye", + "LastName": "Kuehn", + "abbrevName": "Kuehn HS", + "email": null, + "isCollectiveName": false, + "name": "Hye Sun Kuehn", + "orcid": null + }, + { + "ForeName": "Dan", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Dan Yang", + "orcid": null + }, + { + "ForeName": "Holly", + "LastName": "Anderton", + "abbrevName": "Anderton H", + "email": null, + "isCollectiveName": false, + "name": "Holly Anderton", + "orcid": null + }, + { + "ForeName": "Natasha", + "LastName": "Silke", + "abbrevName": "Silke N", + "email": null, + "isCollectiveName": false, + "name": "Natasha Silke", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Lixin", + "LastName": "Zheng", + "abbrevName": "Zheng L", + "email": null, + "isCollectiveName": false, + "name": "Lixin Zheng", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Moura", + "abbrevName": "Moura NS", + "email": null, + "isCollectiveName": false, + "name": "Natalia Sampaio Moura", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Beck", + "abbrevName": "Beck DB", + "email": null, + "isCollectiveName": false, + "name": "David B Beck", + "orcid": null + }, + { + "ForeName": "Gustavo", + "LastName": "Gutierrez-Cruz", + "abbrevName": "Gutierrez-Cruz G", + "email": null, + "isCollectiveName": false, + "name": "Gustavo Gutierrez-Cruz", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ombrello", + "abbrevName": "Ombrello AK", + "email": null, + "isCollectiveName": false, + "name": "Amanda K Ombrello", + "orcid": null + }, + { + "ForeName": "Gineth", + "LastName": "Pinto-Patarroyo", + "abbrevName": "Pinto-Patarroyo GP", + "email": null, + "isCollectiveName": false, + "name": "Gineth P Pinto-Patarroyo", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Kueh", + "abbrevName": "Kueh AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Kueh", + "orcid": null + }, + { + "ForeName": "Marco", + "LastName": "Herold", + "abbrevName": "Herold MJ", + "email": null, + "isCollectiveName": false, + "name": "Marco J Herold", + "orcid": null + }, + { + "ForeName": "Cathrine", + "LastName": "Hall", + "abbrevName": "Hall C", + "email": null, + "isCollectiveName": false, + "name": "Cathrine Hall", + "orcid": null + }, + { + "ForeName": "Hongying", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hongying Wang", + "orcid": null + }, + { + "ForeName": "Jae", + "LastName": "Chae", + "abbrevName": "Chae JJ", + "email": null, + "isCollectiveName": false, + "name": "Jae Jin Chae", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Dmitrieva", + "abbrevName": "Dmitrieva NI", + "email": null, + "isCollectiveName": false, + "name": "Natalia I Dmitrieva", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "McKenzie", + "abbrevName": "McKenzie M", + "email": null, + "isCollectiveName": false, + "name": "Mark McKenzie", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Light", + "abbrevName": "Light A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Light", + "orcid": null + }, + { + "ForeName": "Beverly", + "LastName": "Barham", + "abbrevName": "Barham BK", + "email": null, + "isCollectiveName": false, + "name": "Beverly K Barham", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Jones", + "abbrevName": "Jones A", + "email": null, + "isCollectiveName": false, + "name": "Anne Jones", + "orcid": null + }, + { + "ForeName": "Tina", + "LastName": "Romeo", + "abbrevName": "Romeo TM", + "email": null, + "isCollectiveName": false, + "name": "Tina M Romeo", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhou", + "abbrevName": "Zhou Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhou", + "orcid": null + }, + { + "ForeName": "Ivona", + "LastName": "Aksentijevich", + "abbrevName": "Aksentijevich I", + "email": null, + "isCollectiveName": false, + "name": "Ivona Aksentijevich", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Mullikin", + "abbrevName": "Mullikin JC", + "email": null, + "isCollectiveName": false, + "name": "James C Mullikin", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Gross", + "abbrevName": "Gross AJ", + "email": null, + "isCollectiveName": false, + "name": "Andrew J Gross", + "orcid": null + }, + { + "ForeName": "Anthony", + "LastName": "Shum", + "abbrevName": "Shum AK", + "email": null, + "isCollectiveName": false, + "name": "Anthony K Shum", + "orcid": null + }, + { + "ForeName": "Edwin", + "LastName": "Hawkins", + "abbrevName": "Hawkins ED", + "email": null, + "isCollectiveName": false, + "name": "Edwin D Hawkins", + "orcid": null + }, + { + "ForeName": "Seth", + "LastName": "Masters", + "abbrevName": "Masters SL", + "email": null, + "isCollectiveName": false, + "name": "Seth L Masters", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Lenardo", + "abbrevName": "Lenardo MJ", + "email": null, + "isCollectiveName": false, + "name": "Michael J Lenardo", + "orcid": null + }, + { + "ForeName": "Manfred", + "LastName": "Boehm", + "abbrevName": "Boehm M", + "email": null, + "isCollectiveName": false, + "name": "Manfred Boehm", + "orcid": null + }, + { + "ForeName": "Sergio", + "LastName": "Rosenzweig", + "abbrevName": "Rosenzweig SD", + "email": null, + "isCollectiveName": false, + "name": "Sergio D Rosenzweig", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Voss", + "abbrevName": "Voss AK", + "email": null, + "isCollectiveName": false, + "name": "Anne K Voss", + "orcid": null + }, + { + "ForeName": "Massimo", + "LastName": "Gadina", + "abbrevName": "Gadina M", + "email": null, + "isCollectiveName": false, + "name": "Massimo Gadina", + "orcid": null + }, + { + "ForeName": "Daniel", + "LastName": "Kastner", + "abbrevName": "Kastner DL", + "email": "kastnerd@mail.nih.gov", + "isCollectiveName": false, + "name": "Daniel L Kastner", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "email": [ + "lalaoui@wehi.edu.au" + ], + "name": "Najoua Lalaoui" + }, + { + "ForeName": "Steven", + "LastName": "Boyden", + "email": [ + "steven.boyden@genetics.utah.edu" + ], + "name": "Steven E Boyden" + }, + { + "ForeName": "Daniel", + "LastName": "Kastner", + "email": [ + "kastnerd@mail.nih.gov" + ], + "name": "Daniel L Kastner" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + } + ] + }, + "doi": "10.1038/s41586-019-1828-5", + "pmid": "31827281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 577 2020", + "title": "Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease." + } + }, + { + "pmid": "31827280", + "pubmed": { + "ISODate": "2020-01-01T00:00:00.000Z", + "abstract": "Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.", + "authors": { + "abbreviation": "Panfeng Tao, Jinqiao Sun, Zheming Wu, ..., Qing Zhou", + "authorList": [ + { + "ForeName": "Panfeng", + "LastName": "Tao", + "abbrevName": "Tao P", + "email": null, + "isCollectiveName": false, + "name": "Panfeng Tao", + "orcid": null + }, + { + "ForeName": "Jinqiao", + "LastName": "Sun", + "abbrevName": "Sun J", + "email": null, + "isCollectiveName": false, + "name": "Jinqiao Sun", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Shihao", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shihao Wang", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Wang", + "orcid": null + }, + { + "ForeName": "Wanjin", + "LastName": "Li", + "abbrevName": "Li W", + "email": null, + "isCollectiveName": false, + "name": "Wanjin Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Renkui", + "LastName": "Bai", + "abbrevName": "Bai R", + "email": null, + "isCollectiveName": false, + "name": "Renkui Bai", + "orcid": null + }, + { + "ForeName": "Jiahui", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jiahui Zhang", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Wang", + "orcid": null + }, + { + "ForeName": "Pui", + "LastName": "Lee", + "abbrevName": "Lee PY", + "email": null, + "isCollectiveName": false, + "name": "Pui Y Lee", + "orcid": null + }, + { + "ForeName": "Wenjing", + "LastName": "Ying", + "abbrevName": "Ying W", + "email": null, + "isCollectiveName": false, + "name": "Wenjing Ying", + "orcid": null + }, + { + "ForeName": "Qinhua", + "LastName": "Zhou", + "abbrevName": "Zhou Q", + "email": null, + "isCollectiveName": false, + "name": "Qinhua Zhou", + "orcid": null + }, + { + "ForeName": "Jia", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jia Hou", + "orcid": null + }, + { + "ForeName": "Wenjie", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wenjie Wang", + "orcid": null + }, + { + "ForeName": "Bijun", + "LastName": "Sun", + "abbrevName": "Sun B", + "email": null, + "isCollectiveName": false, + "name": "Bijun Sun", + "orcid": null + }, + { + "ForeName": "Mi", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mi Yang", + "orcid": null + }, + { + "ForeName": "Danru", + "LastName": "Liu", + "abbrevName": "Liu D", + "email": null, + "isCollectiveName": false, + "name": "Danru Liu", + "orcid": null + }, + { + "ForeName": "Ran", + "LastName": "Fang", + "abbrevName": "Fang R", + "email": null, + "isCollectiveName": false, + "name": "Ran Fang", + "orcid": null + }, + { + "ForeName": "Huan", + "LastName": "Han", + "abbrevName": "Han H", + "email": null, + "isCollectiveName": false, + "name": "Huan Han", + "orcid": null + }, + { + "ForeName": "Zhaohui", + "LastName": "Yang", + "abbrevName": "Yang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaohui Yang", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xin Huang", + "orcid": null + }, + { + "ForeName": "Haibo", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Haibo Li", + "orcid": null + }, + { + "ForeName": "Natalie", + "LastName": "Deuitch", + "abbrevName": "Deuitch N", + "email": null, + "isCollectiveName": false, + "name": "Natalie Deuitch", + "orcid": null + }, + { + "ForeName": "Yuan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Zhang", + "orcid": null + }, + { + "ForeName": "Dilan", + "LastName": "Dissanayake", + "abbrevName": "Dissanayake D", + "email": null, + "isCollectiveName": false, + "name": "Dilan Dissanayake", + "orcid": null + }, + { + "ForeName": "Katrina", + "LastName": "Haude", + "abbrevName": "Haude K", + "email": null, + "isCollectiveName": false, + "name": "Katrina Haude", + "orcid": null + }, + { + "ForeName": "Kirsty", + "LastName": "McWalter", + "abbrevName": "McWalter K", + "email": null, + "isCollectiveName": false, + "name": "Kirsty McWalter", + "orcid": null + }, + { + "ForeName": "Chelsea", + "LastName": "Roadhouse", + "abbrevName": "Roadhouse C", + "email": null, + "isCollectiveName": false, + "name": "Chelsea Roadhouse", + "orcid": null + }, + { + "ForeName": "Jennifer", + "LastName": "MacKenzie", + "abbrevName": "MacKenzie JJ", + "email": null, + "isCollectiveName": false, + "name": "Jennifer J MacKenzie", + "orcid": null + }, + { + "ForeName": "Ronald", + "LastName": "Laxer", + "abbrevName": "Laxer RM", + "email": null, + "isCollectiveName": false, + "name": "Ronald M Laxer", + "orcid": null + }, + { + "ForeName": "Ivona", + "LastName": "Aksentijevich", + "abbrevName": "Aksentijevich I", + "email": null, + "isCollectiveName": false, + "name": "Ivona Aksentijevich", + "orcid": null + }, + { + "ForeName": "Xiaomin", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": "yuxiaomin78@gmail.com", + "isCollectiveName": false, + "name": "Xiaomin Yu", + "orcid": null + }, + { + "ForeName": "Xiaochuan", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": "xchwang@shmu.edu.cn", + "isCollectiveName": false, + "name": "Xiaochuan Wang", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Zhou", + "abbrevName": "Zhou Q", + "email": "zhouq2@zju.edu.cn", + "isCollectiveName": false, + "name": "Qing Zhou", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Xiaomin", + "LastName": "Yu", + "email": [ + "yuxiaomin78@gmail.com" + ], + "name": "Xiaomin Yu" + }, + { + "ForeName": "Xiaochuan", + "LastName": "Wang", + "email": [ + "xchwang@shmu.edu.cn" + ], + "name": "Xiaochuan Wang" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + }, + { + "ForeName": "Qing", + "LastName": "Zhou", + "email": [ + "zhouq2@zju.edu.cn" + ], + "name": "Qing Zhou" + } + ] + }, + "doi": "10.1038/s41586-019-1830-y", + "pmid": "31827280", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 577 2020", + "title": "A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1." + } + }, + { + "pmid": "31048504", + "pubmed": { + "ISODate": "2019-05-14T00:00:00.000Z", + "abstract": "RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood-brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer's disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central nervous systems.", + "authors": { + "abbreviation": "Alexei Degterev, Dimitry Ofengeim, Junying Yuan", + "authorList": [ + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1901179116", + "pmid": "31048504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Proc Natl Acad Sci U S A 116 2019", + "title": "Targeting RIPK1 for the treatment of human diseases." + } + }, + { + "pmid": "30988283", + "pubmed": { + "ISODate": "2019-04-15T00:00:00.000Z", + "abstract": "RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Dario Priem, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Meghan", + "LastName": "Wynosky-Dolfi", + "abbrevName": "Wynosky-Dolfi MA", + "email": null, + "isCollectiveName": false, + "name": "Meghan A Wynosky-Dolfi", + "orcid": "0000-0002-2985-3918" + }, + { + "ForeName": "Daniel", + "LastName": "Sorobetea", + "abbrevName": "Sorobetea D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Sorobetea", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": null + }, + { + "ForeName": "Piero", + "LastName": "Giansanti", + "abbrevName": "Giansanti P", + "email": null, + "isCollectiveName": false, + "name": "Piero Giansanti", + "orcid": null + }, + { + "ForeName": "Ria", + "LastName": "Roelandt", + "abbrevName": "Roelandt R", + "email": null, + "isCollectiveName": false, + "name": "Ria Roelandt", + "orcid": null + }, + { + "ForeName": "Julia", + "LastName": "Gropengiesser", + "abbrevName": "Gropengiesser J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengiesser", + "orcid": null + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + }, + { + "ForeName": "Savvas", + "LastName": "Savvides", + "abbrevName": "Savvides SN", + "email": null, + "isCollectiveName": false, + "name": "Savvas N Savvides", + "orcid": "0000-0003-3420-5947" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJR", + "email": null, + "isCollectiveName": false, + "name": "Albert J R Heck", + "orcid": "0000-0002-2405-4404" + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Igor", + "LastName": "Brodsky", + "abbrevName": "Brodsky IE", + "email": null, + "isCollectiveName": false, + "name": "Igor E Brodsky", + "orcid": "0000-0001-7970-872X" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41467-019-09690-0", + "pmid": "30988283", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 10 2019", + "title": "Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation." + } + }, + { + "pmid": "30591564", + "pubmed": { + "ISODate": "2019-01-15T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.", + "authors": { + "abbreviation": "Yue Li, Marita Führer, Ehsan Bahrami, ..., Daniel Kotlarz", + "authorList": [ + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li", + "orcid": null + }, + { + "ForeName": "Marita", + "LastName": "Führer", + "abbrevName": "Führer M", + "email": null, + "isCollectiveName": false, + "name": "Marita Führer", + "orcid": null + }, + { + "ForeName": "Ehsan", + "LastName": "Bahrami", + "abbrevName": "Bahrami E", + "email": null, + "isCollectiveName": false, + "name": "Ehsan Bahrami", + "orcid": null + }, + { + "ForeName": "Piotr", + "LastName": "Socha", + "abbrevName": "Socha P", + "email": null, + "isCollectiveName": false, + "name": "Piotr Socha", + "orcid": null + }, + { + "ForeName": "Maja", + "LastName": "Klaudel-Dreszler", + "abbrevName": "Klaudel-Dreszler M", + "email": null, + "isCollectiveName": false, + "name": "Maja Klaudel-Dreszler", + "orcid": null + }, + { + "ForeName": "Amira", + "LastName": "Bouzidi", + "abbrevName": "Bouzidi A", + "email": null, + "isCollectiveName": false, + "name": "Amira Bouzidi", + "orcid": null + }, + { + "ForeName": "Yanshan", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanshan Liu", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Lehle", + "abbrevName": "Lehle AS", + "email": null, + "isCollectiveName": false, + "name": "Anna S Lehle", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Magg", + "abbrevName": "Magg T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Magg", + "orcid": null + }, + { + "ForeName": "Sebastian", + "LastName": "Hollizeck", + "abbrevName": "Hollizeck S", + "email": null, + "isCollectiveName": false, + "name": "Sebastian Hollizeck", + "orcid": null + }, + { + "ForeName": "Meino", + "LastName": "Rohlfs", + "abbrevName": "Rohlfs M", + "email": null, + "isCollectiveName": false, + "name": "Meino Rohlfs", + "orcid": null + }, + { + "ForeName": "Raffaele", + "LastName": "Conca", + "abbrevName": "Conca R", + "email": null, + "isCollectiveName": false, + "name": "Raffaele Conca", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Field", + "abbrevName": "Field M", + "email": null, + "isCollectiveName": false, + "name": "Michael Field", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Warner", + "abbrevName": "Warner N", + "email": null, + "isCollectiveName": false, + "name": "Neil Warner", + "orcid": null + }, + { + "ForeName": "Slae", + "LastName": "Mordechai", + "abbrevName": "Mordechai S", + "email": null, + "isCollectiveName": false, + "name": "Slae Mordechai", + "orcid": null + }, + { + "ForeName": "Eyal", + "LastName": "Shteyer", + "abbrevName": "Shteyer E", + "email": null, + "isCollectiveName": false, + "name": "Eyal Shteyer", + "orcid": null + }, + { + "ForeName": "Dan", + "LastName": "Turner", + "abbrevName": "Turner D", + "email": null, + "isCollectiveName": false, + "name": "Dan Turner", + "orcid": null + }, + { + "ForeName": "Rachida", + "LastName": "Boukari", + "abbrevName": "Boukari R", + "email": null, + "isCollectiveName": false, + "name": "Rachida Boukari", + "orcid": null + }, + { + "ForeName": "Reda", + "LastName": "Belbouab", + "abbrevName": "Belbouab R", + "email": null, + "isCollectiveName": false, + "name": "Reda Belbouab", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Walz", + "abbrevName": "Walz C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Walz", + "orcid": null + }, + { + "ForeName": "Moritz", + "LastName": "Gaidt", + "abbrevName": "Gaidt MM", + "email": null, + "isCollectiveName": false, + "name": "Moritz M Gaidt", + "orcid": null + }, + { + "ForeName": "Veit", + "LastName": "Hornung", + "abbrevName": "Hornung V", + "email": null, + "isCollectiveName": false, + "name": "Veit Hornung", + "orcid": null + }, + { + "ForeName": "Bernd", + "LastName": "Baumann", + "abbrevName": "Baumann B", + "email": null, + "isCollectiveName": false, + "name": "Bernd Baumann", + "orcid": null + }, + { + "ForeName": "Ulrich", + "LastName": "Pannicke", + "abbrevName": "Pannicke U", + "email": null, + "isCollectiveName": false, + "name": "Ulrich Pannicke", + "orcid": null + }, + { + "ForeName": "Eman", + "LastName": "Al Idrissi", + "abbrevName": "Al Idrissi E", + "email": null, + "isCollectiveName": false, + "name": "Eman Al Idrissi", + "orcid": null + }, + { + "ForeName": "Hamza", + "LastName": "Ali Alghamdi", + "abbrevName": "Ali Alghamdi H", + "email": null, + "isCollectiveName": false, + "name": "Hamza Ali Alghamdi", + "orcid": null + }, + { + "ForeName": "Fernando", + "LastName": "Sepulveda", + "abbrevName": "Sepulveda FE", + "email": null, + "isCollectiveName": false, + "name": "Fernando E Sepulveda", + "orcid": null + }, + { + "ForeName": "Marine", + "LastName": "Gil", + "abbrevName": "Gil M", + "email": null, + "isCollectiveName": false, + "name": "Marine Gil", + "orcid": null + }, + { + "ForeName": "Geneviève", + "LastName": "de Saint Basile", + "abbrevName": "de Saint Basile G", + "email": null, + "isCollectiveName": false, + "name": "Geneviève de Saint Basile", + "orcid": null + }, + { + "ForeName": "Manfred", + "LastName": "Hönig", + "abbrevName": "Hönig M", + "email": null, + "isCollectiveName": false, + "name": "Manfred Hönig", + "orcid": null + }, + { + "ForeName": "Sibylle", + "LastName": "Koletzko", + "abbrevName": "Koletzko S", + "email": null, + "isCollectiveName": false, + "name": "Sibylle Koletzko", + "orcid": null + }, + { + "ForeName": "Aleixo", + "LastName": "Muise", + "abbrevName": "Muise AM", + "email": null, + "isCollectiveName": false, + "name": "Aleixo M Muise", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Snapper", + "abbrevName": "Snapper SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Snapper", + "orcid": null + }, + { + "ForeName": "Klaus", + "LastName": "Schwarz", + "abbrevName": "Schwarz K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Schwarz", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Klein", + "abbrevName": "Klein C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Klein", + "orcid": null + }, + { + "ForeName": "Daniel", + "LastName": "Kotlarz", + "abbrevName": "Kotlarz D", + "email": "daniel.kotlarz@med.uni-muenchen.de", + "isCollectiveName": false, + "name": "Daniel Kotlarz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daniel", + "LastName": "Kotlarz", + "email": [ + "daniel.kotlarz@med.uni-muenchen.de" + ], + "name": "Daniel Kotlarz" + } + ] + }, + "doi": "10.1073/pnas.1813582116", + "pmid": "30591564", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 116 2019", + "title": "Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases." + } + }, + { + "pmid": "30420664", + "pubmed": { + "ISODate": "2018-12-01T00:00:00.000Z", + "abstract": "The linear-ubiquitin chain assembly complex (LUBAC) modulates signalling via various immune receptors. In tumour necrosis factor (TNF) signalling, linear (also known as M1) ubiquitin enables full gene activation and prevents cell death. However, the mechanisms underlying cell death prevention remain ill-defined. Here, we show that LUBAC activity enables TBK1 and IKKε recruitment to and activation at the TNF receptor 1 signalling complex (TNFR1-SC). While exerting only limited effects on TNF-induced gene activation, TBK1 and IKKε are essential to prevent TNF-induced cell death. Mechanistically, TBK1 and IKKε phosphorylate the kinase RIPK1 in the TNFR1-SC, thereby preventing RIPK1-dependent cell death. This activity is essential in vivo, as it prevents TNF-induced lethal shock. Strikingly, NEMO (also known as IKKγ), which mostly, but not exclusively, binds the TNFR1-SC via M1 ubiquitin, mediates the recruitment of the adaptors TANK and NAP1 (also known as AZI2). TANK is constitutively associated with both TBK1 and IKKε, while NAP1 is associated with TBK1. We discovered a previously unrecognized cell death checkpoint that is mediated by TBK1 and IKKε, and uncovered an essential survival function for NEMO, whereby it enables the recruitment and activation of these non-canonical IKKs to prevent TNF-induced cell death.", + "authors": { + "abbreviation": "Elodie Lafont, Peter Draber, Eva Rieser, ..., Henning Walczak", + "authorList": [ + { + "ForeName": "Elodie", + "LastName": "Lafont", + "abbrevName": "Lafont E", + "email": null, + "isCollectiveName": false, + "name": "Elodie Lafont", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Draber", + "abbrevName": "Draber P", + "email": null, + "isCollectiveName": false, + "name": "Peter Draber", + "orcid": null + }, + { + "ForeName": "Eva", + "LastName": "Rieser", + "abbrevName": "Rieser E", + "email": null, + "isCollectiveName": false, + "name": "Eva Rieser", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Reichert", + "abbrevName": "Reichert M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Reichert", + "orcid": null + }, + { + "ForeName": "Sebastian", + "LastName": "Kupka", + "abbrevName": "Kupka S", + "email": null, + "isCollectiveName": false, + "name": "Sebastian Kupka", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "de Miguel", + "abbrevName": "de Miguel D", + "email": null, + "isCollectiveName": false, + "name": "Diego de Miguel", + "orcid": null + }, + { + "ForeName": "Helena", + "LastName": "Draberova", + "abbrevName": "Draberova H", + "email": null, + "isCollectiveName": false, + "name": "Helena Draberova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "von Mässenhausen", + "abbrevName": "von Mässenhausen A", + "email": null, + "isCollectiveName": false, + "name": "Anne von Mässenhausen", + "orcid": null + }, + { + "ForeName": "Amandeep", + "LastName": "Bhamra", + "abbrevName": "Bhamra A", + "email": null, + "isCollectiveName": false, + "name": "Amandeep Bhamra", + "orcid": null + }, + { + "ForeName": "Stephen", + "LastName": "Henderson", + "abbrevName": "Henderson S", + "email": null, + "isCollectiveName": false, + "name": "Stephen Henderson", + "orcid": "0000-0002-9032-3828" + }, + { + "ForeName": "Katarzyna", + "LastName": "Wojdyla", + "abbrevName": "Wojdyla K", + "email": null, + "isCollectiveName": false, + "name": "Katarzyna Wojdyla", + "orcid": null + }, + { + "ForeName": "Avigayil", + "LastName": "Chalk", + "abbrevName": "Chalk A", + "email": null, + "isCollectiveName": false, + "name": "Avigayil Chalk", + "orcid": null + }, + { + "ForeName": "Silvia", + "LastName": "Surinova", + "abbrevName": "Surinova S", + "email": null, + "isCollectiveName": false, + "name": "Silvia Surinova", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Linkermann", + "abbrevName": "Linkermann A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Linkermann", + "orcid": "0000-0001-6287-9725" + }, + { + "ForeName": "Henning", + "LastName": "Walczak", + "abbrevName": "Walczak H", + "email": "h.walczak@ucl.ac.uk", + "isCollectiveName": false, + "name": "Henning Walczak", + "orcid": "0000-0002-6312-4591" + } + ], + "contacts": [ + { + "ForeName": "Henning", + "LastName": "Walczak", + "email": [ + "h.walczak@ucl.ac.uk" + ], + "name": "Henning Walczak" + } + ] + }, + "doi": "10.1038/s41556-018-0229-6", + "pmid": "30420664", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation." + } + }, + { + "pmid": "30146158", + "pubmed": { + "ISODate": "2018-09-06T00:00:00.000Z", + "abstract": "Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss, and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.", + "authors": { + "abbreviation": "Daichao Xu, Taijie Jin, Hong Zhu, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Hongbo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongbo Chen", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": null, + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Lauren", + "LastName": "Mifflin", + "abbrevName": "Mifflin L", + "email": null, + "isCollectiveName": false, + "name": "Lauren Mifflin", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Wanjin", + "LastName": "Li", + "abbrevName": "Li W", + "email": null, + "isCollectiveName": false, + "name": "Wanjin Li", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Masanori", + "LastName": "Naito", + "abbrevName": "Naito MG", + "email": null, + "isCollectiveName": false, + "name": "Masanori Gomi Naito", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Liviu", + "LastName": "Aron", + "abbrevName": "Aron L", + "email": null, + "isCollectiveName": false, + "name": "Liviu Aron", + "orcid": null + }, + { + "ForeName": "Xian", + "LastName": "Adiconis", + "abbrevName": "Adiconis X", + "email": null, + "isCollectiveName": false, + "name": "Xian Adiconis", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Levin", + "abbrevName": "Levin JZ", + "email": null, + "isCollectiveName": false, + "name": "Joshua Z Levin", + "orcid": null + }, + { + "ForeName": "Bruce", + "LastName": "Yankner", + "abbrevName": "Yankner BA", + "email": null, + "isCollectiveName": false, + "name": "Bruce A Yankner", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1016/j.cell.2018.07.041", + "pmid": "30146158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 174 2018", + "title": "TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging." + } + }, + { + "pmid": "30131615", + "pubmed": { + "ISODate": "2018-09-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein (RIP) kinases, in particular RIPK1, RIPK2 and RIPK3, have emerged as pleiotropic modulators of inflammatory responses that act either by directly regulating intracellular inflammatory signaling pathways or by causing apoptotic or necrotic cell death. In this Review, we discuss the signaling pathways and immunological functions of these RIP kinases in the inflammatory response to microbial infection and tissue injury, as well as their potential roles in the pathogenesis of inflammatory disease and aging.", + "authors": { + "abbreviation": "Sudan He, Xiaodong Wang", + "authorList": [ + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan@suda.edu.cn", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + }, + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": "wangxiaodong@nibs.ac.cn", + "isCollectiveName": false, + "name": "Xiaodong Wang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan@suda.edu.cn" + ], + "name": "Sudan He" + }, + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "email": [ + "wangxiaodong@nibs.ac.cn" + ], + "name": "Xiaodong Wang" + } + ] + }, + "doi": "10.1038/s41590-018-0188-x", + "pmid": "30131615", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Immunol 19 2018", + "title": "RIP kinases as modulators of inflammation and immunity." + } + }, + { + "pmid": "30115685", + "pubmed": { + "ISODate": "2018-09-28T00:00:00.000Z", + "abstract": "The protein Ser/Thr phosphatase PP1 catalyzes an important fraction of protein dephosphorylation events and forms highly specific holoenzymes through an association with regulatory interactors of protein phosphatase one (RIPPOs). The functional characterization of individual PP1 holoenzymes is hampered by the lack of straightforward strategies for substrate mapping. Because efficient substrate recruitment often involves binding to both PP1 and its associated RIPPO, here we examined whether PP1-RIPPO fusions can be used to trap substrates for further analysis. Fusions of an hypoactive point mutant of PP1 and either of four tested RIPPOs accumulated in HEK293T cells with their associated substrates and were co-immunoprecipitated for subsequent identification of the substrates by immunoblotting or MS analysis. Hypoactive fusions were also used to study RIPPOs themselves as substrates for associated PP1. In contrast, substrate trapping was barely detected with active PP1-RIPPO fusions or with nonfused PP1 or RIPPO subunits. Our results suggest that hypoactive fusions of PP1 subunits represent an easy-to-use tool for substrate identification of individual holoenzymes.", + "authors": { + "abbreviation": "Dan Wu, Veerle De Wever, Rita Derua, ..., Mathieu Bollen", + "authorList": [ + { + "ForeName": "Dan", + "LastName": "Wu", + "abbrevName": "Wu D", + "email": null, + "isCollectiveName": false, + "name": "Dan Wu", + "orcid": null + }, + { + "ForeName": "Veerle", + "LastName": "De Wever", + "abbrevName": "De Wever V", + "email": null, + "isCollectiveName": false, + "name": "Veerle De Wever", + "orcid": null + }, + { + "ForeName": "Rita", + "LastName": "Derua", + "abbrevName": "Derua R", + "email": null, + "isCollectiveName": false, + "name": "Rita Derua", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Winkler", + "abbrevName": "Winkler C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Winkler", + "orcid": null + }, + { + "ForeName": "Monique", + "LastName": "Beullens", + "abbrevName": "Beullens M", + "email": null, + "isCollectiveName": false, + "name": "Monique Beullens", + "orcid": null + }, + { + "ForeName": "Aleyde", + "LastName": "Van Eynde", + "abbrevName": "Van Eynde A", + "email": null, + "isCollectiveName": false, + "name": "Aleyde Van Eynde", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bollen", + "abbrevName": "Bollen M", + "email": "Mathieu.Bollen@kuleuven.be", + "isCollectiveName": false, + "name": "Mathieu Bollen", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bollen", + "email": [ + "Mathieu.Bollen@kuleuven.be" + ], + "name": "Mathieu Bollen" + } + ] + }, + "doi": "10.1074/jbc.RA118.004132", + "pmid": "30115685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "A substrate-trapping strategy for protein phosphatase PP1 holoenzymes using hypoactive subunit fusions." + } + }, + { + "pmid": "30056088", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": "Protein phosphatase 1 (PP1) catalyzes more than half of all phosphoserine/threonine dephosphorylation reactions in mammalian cells. In vivo PP1 does not exist as a free catalytic subunit but is always associated with at least one regulatory PP1-interacting protein (PIP) to generate a large set of distinct holoenzymes. Each PP1 complex controls the dephosphorylation of only a small subset of PP1 substrates. We screened the literature for genetically engineered mouse models and identified models for all PP1 isoforms and 104 PIPs. PP1 itself and at least 49 PIPs were connected to human disease-associated phenotypes. Additionally, phenotypes related to 17 PIPs were clearly linked to altered PP1 function, while such information was lacking for 32 other PIPs. We propose structural reverse genetics, which combines structural characterization of proteins with mouse genetics, to identify new PP1-related therapeutic targets. The available mouse models confirm the pleiotropic action of PP1 in health and diseases.", + "authors": { + "abbreviation": "Mónica Ferreira, Monique Beullens, Mathieu Bollen, Aleyde Van Eynde", + "authorList": [ + { + "ForeName": "Mónica", + "LastName": "Ferreira", + "abbrevName": "Ferreira M", + "email": null, + "isCollectiveName": false, + "name": "Mónica Ferreira", + "orcid": null + }, + { + "ForeName": "Monique", + "LastName": "Beullens", + "abbrevName": "Beullens M", + "email": null, + "isCollectiveName": false, + "name": "Monique Beullens", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bollen", + "abbrevName": "Bollen M", + "email": null, + "isCollectiveName": false, + "name": "Mathieu Bollen", + "orcid": null + }, + { + "ForeName": "Aleyde", + "LastName": "Van Eynde", + "abbrevName": "Van Eynde A", + "email": "Aleyde.VanEynde@kuleuven.be", + "isCollectiveName": false, + "name": "Aleyde Van Eynde", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Aleyde", + "LastName": "Van Eynde", + "email": [ + "Aleyde.VanEynde@kuleuven.be" + ], + "name": "Aleyde Van Eynde" + } + ] + }, + "doi": "10.1016/j.bbamcr.2018.07.019", + "pmid": "30056088", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochim Biophys Acta Mol Cell Res 1866 2019", + "title": "Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics." + } + }, + { + "pmid": "30026316", + "pubmed": { + "ISODate": "2018-08-24T00:00:00.000Z", + "abstract": "RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.", + "authors": { + "abbreviation": "Delphine Cuchet-Lourenço, Davide Eletto, Changxin Wu, ..., Sergey Nejentsev", + "authorList": [ + { + "ForeName": "Delphine", + "LastName": "Cuchet-Lourenço", + "abbrevName": "Cuchet-Lourenço D", + "email": null, + "isCollectiveName": false, + "name": "Delphine Cuchet-Lourenço", + "orcid": "0000-0002-9501-6122" + }, + { + "ForeName": "Davide", + "LastName": "Eletto", + "abbrevName": "Eletto D", + "email": null, + "isCollectiveName": false, + "name": "Davide Eletto", + "orcid": "0000-0002-2650-1968" + }, + { + "ForeName": "Changxin", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": null, + "isCollectiveName": false, + "name": "Changxin Wu", + "orcid": null + }, + { + "ForeName": "Vincent", + "LastName": "Plagnol", + "abbrevName": "Plagnol V", + "email": null, + "isCollectiveName": false, + "name": "Vincent Plagnol", + "orcid": "0000-0002-5597-9215" + }, + { + "ForeName": "Olivier", + "LastName": "Papapietro", + "abbrevName": "Papapietro O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Papapietro", + "orcid": "0000-0001-5072-5235" + }, + { + "ForeName": "James", + "LastName": "Curtis", + "abbrevName": "Curtis J", + "email": null, + "isCollectiveName": false, + "name": "James Curtis", + "orcid": null + }, + { + "ForeName": "Lourdes", + "LastName": "Ceron-Gutierrez", + "abbrevName": "Ceron-Gutierrez L", + "email": null, + "isCollectiveName": false, + "name": "Lourdes Ceron-Gutierrez", + "orcid": null + }, + { + "ForeName": "Chris", + "LastName": "Bacon", + "abbrevName": "Bacon CM", + "email": null, + "isCollectiveName": false, + "name": "Chris M Bacon", + "orcid": "0000-0002-8268-2812" + }, + { + "ForeName": "Scott", + "LastName": "Hackett", + "abbrevName": "Hackett S", + "email": null, + "isCollectiveName": false, + "name": "Scott Hackett", + "orcid": null + }, + { + "ForeName": "Badr", + "LastName": "Alsaleem", + "abbrevName": "Alsaleem B", + "email": null, + "isCollectiveName": false, + "name": "Badr Alsaleem", + "orcid": "0000-0003-3348-4550" + }, + { + "ForeName": "Mailis", + "LastName": "Maes", + "abbrevName": "Maes M", + "email": null, + "isCollectiveName": false, + "name": "Mailis Maes", + "orcid": "0000-0002-0266-6557" + }, + { + "ForeName": "Miguel", + "LastName": "Gaspar", + "abbrevName": "Gaspar M", + "email": null, + "isCollectiveName": false, + "name": "Miguel Gaspar", + "orcid": null + }, + { + "ForeName": "Ali", + "LastName": "Alisaac", + "abbrevName": "Alisaac A", + "email": null, + "isCollectiveName": false, + "name": "Ali Alisaac", + "orcid": "0000-0003-1463-4488" + }, + { + "ForeName": "Emma", + "LastName": "Goss", + "abbrevName": "Goss E", + "email": null, + "isCollectiveName": false, + "name": "Emma Goss", + "orcid": "0000-0002-5277-4249" + }, + { + "ForeName": "Eman", + "LastName": "AlIdrissi", + "abbrevName": "AlIdrissi E", + "email": null, + "isCollectiveName": false, + "name": "Eman AlIdrissi", + "orcid": "0000-0003-2462-3571" + }, + { + "ForeName": "Daniela", + "LastName": "Siegmund", + "abbrevName": "Siegmund D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Siegmund", + "orcid": null + }, + { + "ForeName": "Harald", + "LastName": "Wajant", + "abbrevName": "Wajant H", + "email": null, + "isCollectiveName": false, + "name": "Harald Wajant", + "orcid": "0000-0002-2005-3949" + }, + { + "ForeName": "Dinakantha", + "LastName": "Kumararatne", + "abbrevName": "Kumararatne D", + "email": null, + "isCollectiveName": false, + "name": "Dinakantha Kumararatne", + "orcid": "0000-0001-8438-4686" + }, + { + "ForeName": "Mofareh", + "LastName": "AlZahrani", + "abbrevName": "AlZahrani MS", + "email": null, + "isCollectiveName": false, + "name": "Mofareh S AlZahrani", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Arkwright", + "abbrevName": "Arkwright PD", + "email": null, + "isCollectiveName": false, + "name": "Peter D Arkwright", + "orcid": "0000-0002-7411-5375" + }, + { + "ForeName": "Mario", + "LastName": "Abinun", + "abbrevName": "Abinun M", + "email": null, + "isCollectiveName": false, + "name": "Mario Abinun", + "orcid": "0000-0002-7050-3565" + }, + { + "ForeName": "Rainer", + "LastName": "Doffinger", + "abbrevName": "Doffinger R", + "email": null, + "isCollectiveName": false, + "name": "Rainer Doffinger", + "orcid": "0000-0002-9841-3617" + }, + { + "ForeName": "Sergey", + "LastName": "Nejentsev", + "abbrevName": "Nejentsev S", + "email": "sn262@cam.ac.uk", + "isCollectiveName": false, + "name": "Sergey Nejentsev", + "orcid": "0000-0002-7528-4461" + } + ], + "contacts": [ + { + "ForeName": "Sergey", + "LastName": "Nejentsev", + "email": [ + "sn262@cam.ac.uk" + ], + "name": "Sergey Nejentsev" + } + ] + }, + "doi": "10.1126/science.aar2641", + "pmid": "30026316", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 361 2018", + "title": "Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "29362479", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.", + "authors": { + "abbreviation": "Lorenzo Galluzzi, Ilio Vitale, Stuart A Aaronson, ..., Guido Kroemer", + "authorList": [ + { + "ForeName": "Lorenzo", + "LastName": "Galluzzi", + "abbrevName": "Galluzzi L", + "email": "deadoc@vodafone.it", + "isCollectiveName": false, + "name": "Lorenzo Galluzzi", + "orcid": null + }, + { + "ForeName": "Ilio", + "LastName": "Vitale", + "abbrevName": "Vitale I", + "email": null, + "isCollectiveName": false, + "name": "Ilio Vitale", + "orcid": null + }, + { + "ForeName": "Stuart", + "LastName": "Aaronson", + "abbrevName": "Aaronson SA", + "email": null, + "isCollectiveName": false, + "name": "Stuart A Aaronson", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Abrams", + "abbrevName": "Abrams JM", + "email": null, + "isCollectiveName": false, + "name": "John M Abrams", + "orcid": null + }, + { + "ForeName": "Dieter", + "LastName": "Adam", + "abbrevName": "Adam D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Adam", + "orcid": null + }, + { + "ForeName": "Patrizia", + "LastName": "Agostinis", + "abbrevName": "Agostinis P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Agostinis", + "orcid": null + }, + { + "ForeName": "Emad", + "LastName": "Alnemri", + "abbrevName": "Alnemri ES", + "email": null, + "isCollectiveName": false, + "name": "Emad S Alnemri", + "orcid": null + }, + { + "ForeName": "Lucia", + "LastName": "Altucci", + "abbrevName": "Altucci L", + "email": null, + "isCollectiveName": false, + "name": "Lucia Altucci", + "orcid": null + }, + { + "ForeName": "Ivano", + "LastName": "Amelio", + "abbrevName": "Amelio I", + "email": null, + "isCollectiveName": false, + "name": "Ivano Amelio", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Andrews", + "abbrevName": "Andrews DW", + "email": null, + "isCollectiveName": false, + "name": "David W Andrews", + "orcid": null + }, + { + "ForeName": "Margherita", + "LastName": "Annicchiarico-Petruzzelli", + "abbrevName": "Annicchiarico-Petruzzelli M", + "email": null, + "isCollectiveName": false, + "name": "Margherita Annicchiarico-Petruzzelli", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Antonov", + "abbrevName": "Antonov AV", + "email": null, + "isCollectiveName": false, + "name": "Alexey V Antonov", + "orcid": null + }, + { + "ForeName": "Eli", + "LastName": "Arama", + "abbrevName": "Arama E", + "email": null, + "isCollectiveName": false, + "name": "Eli Arama", + "orcid": null + }, + { + "ForeName": "Eric", + "LastName": "Baehrecke", + "abbrevName": "Baehrecke EH", + "email": null, + "isCollectiveName": false, + "name": "Eric H Baehrecke", + "orcid": null + }, + { + "ForeName": "Nickolai", + "LastName": "Barlev", + "abbrevName": "Barlev NA", + "email": null, + "isCollectiveName": false, + "name": "Nickolai A Barlev", + "orcid": null + }, + { 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+ "isCollectiveName": false, + "name": "David Wallach", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Wang", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Wells", + "abbrevName": "Wells JA", + "email": null, + "isCollectiveName": false, + "name": "James A Wells", + "orcid": null + }, + { + "ForeName": "Will", + "LastName": "Wood", + "abbrevName": "Wood W", + "email": null, + "isCollectiveName": false, + "name": "Will Wood", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Zahra", + "LastName": "Zakeri", + "abbrevName": "Zakeri Z", + "email": null, + "isCollectiveName": false, + "name": "Zahra Zakeri", + "orcid": null + }, + { + "ForeName": "Boris", + "LastName": "Zhivotovsky", + "abbrevName": "Zhivotovsky B", + "email": null, + "isCollectiveName": false, + "name": "Boris Zhivotovsky", + "orcid": null + }, + { + "ForeName": "Laurence", + "LastName": "Zitvogel", + "abbrevName": "Zitvogel L", + "email": null, + "isCollectiveName": false, + "name": "Laurence Zitvogel", + "orcid": null + }, + { + "ForeName": "Gerry", + "LastName": "Melino", + "abbrevName": "Melino G", + "email": null, + "isCollectiveName": false, + "name": "Gerry Melino", + "orcid": null + }, + { + "ForeName": "Guido", + "LastName": "Kroemer", + "abbrevName": "Kroemer G", + "email": "kroemer@orange.fr", + "isCollectiveName": false, + "name": "Guido Kroemer", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Lorenzo", + "LastName": "Galluzzi", + "email": [ + "deadoc@vodafone.it" + ], + "name": "Lorenzo Galluzzi" + }, + { + "ForeName": "Guido", + "LastName": "Kroemer", + "email": [ + "kroemer@orange.fr" + ], + "name": "Guido Kroemer" + } + ] + }, + "doi": "10.1038/s41418-017-0012-4", + "pmid": "29362479", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell Death Differ 25 2018", + "title": "Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018." + } + }, + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + }, + { + "pmid": "28827318", + "pubmed": { + "ISODate": "2017-09-05T00:00:00.000Z", + "abstract": "Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α-induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.", + "authors": { + "abbreviation": "Shuzhen Liu, Hua Liu, Andrea Johnston, ..., Zhigao Wang", + "authorList": [ + { + "ForeName": "Shuzhen", + "LastName": "Liu", + "abbrevName": "Liu S", + "email": null, + "isCollectiveName": false, + "name": "Shuzhen Liu", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hua Liu", + "orcid": null + }, + { + "ForeName": "Andrea", + "LastName": "Johnston", + "abbrevName": "Johnston A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Johnston", + "orcid": null + }, + { + "ForeName": "Sarah", + "LastName": "Hanna-Addams", + "abbrevName": "Hanna-Addams S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Hanna-Addams", + "orcid": null + }, + { + "ForeName": "Eduardo", + "LastName": "Reynoso", + "abbrevName": "Reynoso E", + "email": null, + "isCollectiveName": false, + "name": "Eduardo Reynoso", + "orcid": null + }, + { + "ForeName": "Yougui", + "LastName": "Xiang", + "abbrevName": "Xiang Y", + "email": null, + "isCollectiveName": false, + "name": "Yougui Xiang", + "orcid": null + }, + { + "ForeName": "Zhigao", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": "zhigao.wang@utsouthwestern.edu", + "isCollectiveName": false, + "name": "Zhigao Wang", + "orcid": "0000-0002-6544-4302" + } + ], + "contacts": [ + { + "ForeName": "Zhigao", + "LastName": "Wang", + "email": [ + "zhigao.wang@utsouthwestern.edu" + ], + "name": "Zhigao Wang" + } + ] + }, + "doi": "10.1073/pnas.1707531114", + "pmid": "28827318", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + }, + { + "pmid": "28202662", + "pubmed": { + "ISODate": "2017-02-08T00:00:00.000Z", + "abstract": "Protein phosphatase 1 (PP1) is expressed in all eukaryotic cells and catalyzes a substantial fraction of phosphoserine/threonine dephosphorylation reactions. It forms stable complexes with PP1-interacting proteins (PIPs) that guide the phosphatase throughout its life cycle and control its fate and function. The diversity of PIPs is huge (≈200 in vertebrates), and most of them combine short linear motifs to form large and unique interaction interfaces with PP1. Many PIPs have separate domains for PP1 anchoring, PP1 regulation, substrate recruitment and subcellular targeting, which enable them to direct associated PP1 to a specific subset of substrates and mediate acute activity control. Hence, PP1 functions as the catalytic subunit of a large number of multimeric holoenzymes, each with its own subset of substrates and mechanism(s) of regulation.", + "authors": { + "abbreviation": "Iris Verbinnen, Monica Ferreira, Mathieu Bollen", + "authorList": [ + { + "ForeName": "Iris", + "LastName": "Verbinnen", + "abbrevName": "Verbinnen I", + "email": null, + "isCollectiveName": false, + "name": "Iris Verbinnen", + "orcid": null + }, + { + "ForeName": "Monica", + "LastName": "Ferreira", + "abbrevName": "Ferreira M", + "email": null, + "isCollectiveName": false, + "name": "Monica Ferreira", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bollen", + "abbrevName": "Bollen M", + "email": "mathieu.bollen@kuleuven.be", + "isCollectiveName": false, + "name": "Mathieu Bollen", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bollen", + "email": [ + "mathieu.bollen@kuleuven.be" + ], + "name": "Mathieu Bollen" + } + ] + }, + "doi": "10.1042/BST20160154", + "pmid": "28202662", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochem Soc Trans 45 2017", + "title": "Biogenesis and activity regulation of protein phosphatase 1." + } + }, + { + "pmid": "28176780", + "pubmed": { + "ISODate": "2017-02-08T00:00:00.000Z", + "abstract": "Necroptosis is a type of programmed cell death with great significance in many pathological processes. Tumour necrosis factor-α(TNF), a proinflammatory cytokine, is a prototypic trigger of necroptosis. It is known that mitochondrial reactive oxygen species (ROS) promote necroptosis, and that kinase activity of receptor interacting protein 1 (RIP1) is required for TNF-induced necroptosis. However, how ROS function and what RIP1 phosphorylates to promote necroptosis are largely unknown. Here we show that three crucial cysteines in RIP1 are required for sensing ROS, and ROS subsequently activates RIP1 autophosphorylation on serine residue 161 (S161). The major function of RIP1 kinase activity in TNF-induced necroptosis is to autophosphorylate S161. This specific phosphorylation then enables RIP1 to recruit RIP3 and form a functional necrosome, a central controller of necroptosis. Since ROS induction is known to require necrosomal RIP3, ROS therefore function in a positive feedback circuit that ensures effective induction of necroptosis.", + "authors": { + "abbreviation": "Yingying Zhang, Sheng Sean Su, Shubo Zhao, ..., Jiahuai Han", + "authorList": [ + { + "ForeName": "Yingying", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingying Zhang", + "orcid": null + }, + { + "ForeName": "Sheng", + "LastName": "Su", + "abbrevName": "Su SS", + "email": null, + "isCollectiveName": false, + "name": "Sheng Sean Su", + "orcid": null + }, + { + "ForeName": "Shubo", + "LastName": "Zhao", + "abbrevName": "Zhao S", + "email": null, + "isCollectiveName": false, + "name": "Shubo Zhao", + "orcid": null + }, + { + "ForeName": "Zhentao", + "LastName": "Yang", + "abbrevName": "Yang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhentao Yang", + "orcid": null + }, + { + "ForeName": "Chuan-Qi", + "LastName": "Zhong", + "abbrevName": "Zhong CQ", + "email": null, + "isCollectiveName": false, + "name": "Chuan-Qi Zhong", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xin Chen", + "orcid": null + }, + { + "ForeName": "Qixu", + "LastName": "Cai", + "abbrevName": "Cai Q", + "email": null, + "isCollectiveName": false, + "name": "Qixu Cai", + "orcid": null + }, + { + "ForeName": "Zhang-Hua", + "LastName": "Yang", + "abbrevName": "Yang ZH", + "email": null, + "isCollectiveName": false, + "name": "Zhang-Hua Yang", + "orcid": null + }, + { + "ForeName": "Deli", + "LastName": "Huang", + "abbrevName": "Huang D", + "email": null, + "isCollectiveName": false, + "name": "Deli Huang", + "orcid": null + }, + { + "ForeName": "Rui", + "LastName": "Wu", + "abbrevName": "Wu R", + "email": null, + "isCollectiveName": false, + "name": "Rui Wu", + "orcid": null + }, + { + "ForeName": "Jiahuai", + "LastName": "Han", + "abbrevName": "Han J", + "email": null, + "isCollectiveName": false, + "name": "Jiahuai Han", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms14329", + "pmid": "28176780", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome." + } + }, + { + "pmid": "27999438", + "pubmed": { + "ISODate": "2017-02-01T00:00:00.000Z", + "abstract": "In the early 2000s, receptor-interacting serine/threonine protein kinase 1 (RIPK1), a molecule already recognized as an important regulator of cell survival, inflammation and disease, was attributed an additional function: the regulation of a novel cell death pathway that came to be known as necroptosis. Subsequently, the related kinase RIPK3 and its substrate mixed-lineage kinase domain-like protein (MLKL) were also implicated in the necroptotic pathway, and links between this pathway and apoptosis were established. In this Timeline article, we outline the discoveries that have helped to identify the roles of RIPK1, RIPK3, MLKL and other regulators of necroptosis, and how they interact to determine cell fate.", + "authors": { + "abbreviation": "Ricardo Weinlich, Andrew Oberst, Helen M Beere, Douglas R Green", + "authorList": [ + { + "ForeName": "Ricardo", + "LastName": "Weinlich", + "abbrevName": "Weinlich R", + "email": null, + "isCollectiveName": false, + "name": "Ricardo Weinlich", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Oberst", + "abbrevName": "Oberst A", + "email": null, + "isCollectiveName": false, + "name": "Andrew Oberst", + "orcid": null + }, + { + "ForeName": "Helen", + "LastName": "Beere", + "abbrevName": "Beere HM", + "email": null, + "isCollectiveName": false, + "name": "Helen M Beere", + "orcid": null + }, + { + "ForeName": "Douglas", + "LastName": "Green", + "abbrevName": "Green DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Green", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm.2016.149", + "pmid": "27999438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 18 2017", + "title": "Necroptosis in development, inflammation and disease." + } + }, + { + "pmid": "27815211", + "pubmed": { + "ISODate": "2017-01-05T00:00:00.000Z", + "abstract": "Glycogen and triglyceride are two major forms of energy storage in the body and provide the fuel during different phases of food deprivation. However, how glycogen metabolism is linked to fat deposition in adipose tissue has not been clearly characterized. We generated a mouse model with whole-body deletion of PPP1R3G, a glycogen-targeting subunit of protein phosphatase-1 required for glycogen synthesis. Upon feeding with high-fat diet, the body weight and fat composition are significantly reduced in the PPP1R3G-/- mice compared to the wild type controls. The metabolic rate of the mice as measured by O2 consumption and CO2 production is accelerated by PPP1R3G deletion. The high-fat diet-induced liver steatosis is also slightly relieved by PPP1R3G deletion. The glycogen level in adipose tissue is reduced by PPP1R3G deletion. In 3T3L1 cells, overexpression of PPP1R3G leads to increases of both glycogen and triglyceride levels. In conclusion, our study indicates that glycogen is actively involved in fat accumulation in adipose tissue and obesity development upon high-fat diet. Our study also suggests that PPP1R3G is an important player that links glycogen metabolism to lipid metabolism in vivo.", + "authors": { + "abbreviation": "Yongxian Zhang, Jin Gu, Lin Wang, ..., Yan Chen", + "authorList": [ + { + "ForeName": "Yongxian", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yongxian Zhang", + "orcid": null + }, + { + "ForeName": "Jin", + "LastName": "Gu", + "abbrevName": "Gu J", + "email": null, + "isCollectiveName": false, + "name": "Jin Gu", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Lin Wang", + "orcid": null + }, + { + "ForeName": "Zilong", + "LastName": "Zhao", + "abbrevName": "Zhao Z", + "email": null, + "isCollectiveName": false, + "name": "Zilong Zhao", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Pan", + "abbrevName": "Pan Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Pan", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": "ychen3@sibs.ac.cn", + "isCollectiveName": false, + "name": "Yan Chen", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Yan", + "LastName": "Chen", + "email": [ + "ychen3@sibs.ac.cn" + ], + "name": "Yan Chen" + } + ] + }, + "doi": "10.1016/j.mce.2016.10.036", + "pmid": "27815211", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Endocrinol 439 2017", + "title": "Ablation of PPP1R3G reduces glycogen deposition and mitigates high-fat diet induced obesity." + } + }, + { + "pmid": "27308513", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "Our current knowledge of the molecular mechanisms regulating the signaling pathways leading to cell survival, cell death, and inflammation has shed light on the tight mutual interplays between these processes. Moreover, the fact that both apoptosis and necrosis can be molecularly controlled has greatly increased our interest in the roles that these types of cell death play in the control of general processes such as development, homeostasis, and inflammation. In this review, we provide a brief update on the different cell death modalities and describe in more detail the intracellular crosstalk between survival, apoptotic, necroptotic, and inflammatory pathways that are activated downstream of death receptors. An important concept is that the different cell death processes modulate each other by mutual inhibitory mechanisms, serve as alternative back-up death routes in the case of a defect in the first-line cell death response, and are controlled by multiple feedback loops. We conclude by discussing future perspectives and challenges in the field of cell death and inflammation research.", + "authors": { + "abbreviation": "Tom Vanden Berghe, William J Kaiser, Mathieu Jm Bertrand, Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Kaiser", + "abbrevName": "Kaiser WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Kaiser", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu Jm Bertrand", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.4161/23723556.2014.975093", + "pmid": "27308513", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Mol Cell Oncol 2 2015", + "title": "Molecular crosstalk between apoptosis, necroptosis, and survival signaling." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "25751141", + "pubmed": { + "ISODate": "2015-04-01T00:00:00.000Z", + "abstract": "The auto-phosphorylation of murine receptor-interacting protein 3 (Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how Rip3 phosphorylation is regulated is still largely unknown. Here we identified protein phosphatase 1B (Ppm1b) as a Rip3 phosphatase and found that Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by Rip3 auto-phosphorylation in resting cells, and tumour necrosis factor-α (TNF)-induced necroptosis in cultured cells. We revealed that Ppm1b selectively suppresses necroptosis through the dephosphorylation of Rip3, which then prevents the recruitment of mixed lineage kinase domain-like protein (Mlkl) to the necrosome. We further showed that Ppm1b deficiency (Ppm1b(d/d)) in mice enhanced TNF-induced death in a Rip3-dependent manner, and the role of Ppm1b in inhibiting necroptosis was evidenced by elevated Rip3 phosphorylation and tissue damage in the caecum of TNF-treated Ppm1b(d/d) mice. These data indicate that Ppm1b negatively regulates necroptosis through dephosphorylating Rip3 in vitro and in vivo.", + "authors": { + "abbreviation": "Wanze Chen, Jianfeng Wu, Lisheng Li, ..., Jiahuai Han", + "authorList": [ + { + "ForeName": "Wanze", + "LastName": "Chen", + "abbrevName": "Chen W", + "email": null, + "isCollectiveName": false, + "name": "Wanze Chen", + "orcid": null + }, + { + "ForeName": "Jianfeng", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jianfeng Wu", + "orcid": null + }, + { + "ForeName": "Lisheng", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Lisheng Li", + "orcid": null + }, + { + "ForeName": "Zhengmao", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhengmao Zhang", + "orcid": null + }, + { + "ForeName": "Junming", + "LastName": "Ren", + "abbrevName": "Ren J", + "email": null, + "isCollectiveName": false, + "name": "Junming Ren", + "orcid": null + }, + { + "ForeName": "Yaoji", + "LastName": "Liang", + "abbrevName": "Liang Y", + "email": null, + "isCollectiveName": false, + "name": "Yaoji Liang", + "orcid": null + }, + { + "ForeName": "Fenfang", + "LastName": "Chen", + "abbrevName": "Chen F", + "email": null, + "isCollectiveName": false, + "name": "Fenfang Chen", + "orcid": null + }, + { + "ForeName": "Chao", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Chao Yang", + "orcid": null + }, + { + "ForeName": "Zhenru", + "LastName": "Zhou", + "abbrevName": "Zhou Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenru Zhou", + "orcid": null + }, + { + "ForeName": "Sheng", + "LastName": "Su", + "abbrevName": "Su SS", + "email": null, + "isCollectiveName": false, + "name": "Sheng Sean Su", + "orcid": null + }, + { + "ForeName": "Xinru", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xinru Zheng", + "orcid": null + }, + { + "ForeName": "Zhirong", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhirong Zhang", + "orcid": null + }, + { + "ForeName": "Chuan-Qi", + "LastName": "Zhong", + "abbrevName": "Zhong CQ", + "email": null, + "isCollectiveName": false, + "name": "Chuan-Qi Zhong", + "orcid": null + }, + { + "ForeName": "Haoqiang", + "LastName": "Wan", + "abbrevName": "Wan H", + "email": null, + "isCollectiveName": false, + "name": "Haoqiang Wan", + "orcid": null + }, + { + "ForeName": "Mu", + "LastName": "Xiao", + "abbrevName": "Xiao M", + "email": null, + "isCollectiveName": false, + "name": "Mu Xiao", + "orcid": null + }, + { + "ForeName": "Xia", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": null, + "isCollectiveName": false, + "name": "Xia Lin", + "orcid": null + }, + { + "ForeName": "Xin-Hua", + "LastName": "Feng", + "abbrevName": "Feng XH", + "email": null, + "isCollectiveName": false, + "name": "Xin-Hua Feng", + "orcid": null + }, + { + "ForeName": "Jiahuai", + "LastName": "Han", + "abbrevName": "Han J", + "email": null, + "isCollectiveName": false, + "name": "Jiahuai Han", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3120", + "pmid": "25751141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 17 2015", + "title": "Ppm1b negatively regulates necroptosis through dephosphorylating Rip3." + } + }, + { + "pmid": "25476604", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "We propose the Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK) method for prioritizing single-guide RNAs, genes and pathways in genome-scale CRISPR/Cas9 knockout screens. MAGeCK demonstrates better performance compared with existing methods, identifies both positively and negatively selected genes simultaneously, and reports robust results across different experimental conditions. Using public datasets, MAGeCK identified novel essential genes and pathways, including EGFR in vemurafenib-treated A375 cells harboring a BRAF mutation. MAGeCK also detected cell type-specific essential genes, including BCR and ABL1, in KBM7 cells bearing a BCR-ABL fusion, and IGF1R in HL-60 cells, which depends on the insulin signaling pathway for proliferation.", + "authors": { + "abbreviation": "Wei Li, Han Xu, Tengfei Xiao, ..., X Shirley Liu", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Li", + "abbrevName": "Li W", + "email": null, + "isCollectiveName": false, + "name": "Wei Li", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Xu", + "abbrevName": "Xu H", + "email": null, + "isCollectiveName": false, + "name": "Han Xu", + "orcid": null + }, + { + "ForeName": "Tengfei", + "LastName": "Xiao", + "abbrevName": "Xiao T", + "email": null, + "isCollectiveName": false, + "name": "Tengfei Xiao", + "orcid": null + }, + { + "ForeName": "Le", + "LastName": "Cong", + "abbrevName": "Cong L", + "email": null, + "isCollectiveName": false, + "name": "Le Cong", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Love", + "abbrevName": "Love MI", + "email": null, + "isCollectiveName": false, + "name": "Michael I Love", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Zhang", + "abbrevName": "Zhang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Zhang", + "orcid": null + }, + { + "ForeName": "Rafael", + "LastName": "Irizarry", + "abbrevName": "Irizarry RA", + "email": null, + "isCollectiveName": false, + "name": "Rafael A Irizarry", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Liu", + "abbrevName": "Liu JS", + "email": null, + "isCollectiveName": false, + "name": "Jun S Liu", + "orcid": null + }, + { + "ForeName": "Myles", + "LastName": "Brown", + "abbrevName": "Brown M", + "email": null, + "isCollectiveName": false, + "name": "Myles Brown", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XS", + "email": null, + "isCollectiveName": false, + "name": "X Shirley Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1186/s13059-014-0554-4", + "pmid": "25476604", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genome Biol 15 2014", + "title": "MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens." + } + }, + { + "pmid": "25288762", + "pubmed": { + "ISODate": "2014-10-21T00:00:00.000Z", + "abstract": "Necroptosis is considered to be complementary to the classical caspase-dependent programmed cell death pathway, apoptosis. The pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) is an essential effector protein in the necroptotic cell death pathway downstream of the protein kinase Receptor Interacting Protein Kinase-3 (RIPK3). How MLKL causes cell death is unclear, however RIPK3-mediated phosphorylation of the activation loop in MLKL trips a molecular switch to induce necroptotic cell death. Here, we show that the MLKL pseudokinase domain acts as a latch to restrain the N-terminal four-helix bundle (4HB) domain and that unleashing this domain results in formation of a high-molecular-weight, membrane-localized complex and cell death. Using alanine-scanning mutagenesis, we identified two clusters of residues on opposing faces of the 4HB domain that were required for the 4HB domain to kill cells. The integrity of one cluster was essential for membrane localization, whereas MLKL mutations in the other cluster did not prevent membrane translocation but prevented killing; this demonstrates that membrane localization is necessary, but insufficient, to induce cell death. Finally, we identified a small molecule that binds the nucleotide binding site within the MLKL pseudokinase domain and retards MLKL translocation to membranes, thereby preventing necroptosis. This inhibitor provides a novel tool to investigate necroptosis and demonstrates the feasibility of using small molecules to target the nucleotide binding site of pseudokinases to modulate signal transduction.", + "authors": { + "abbreviation": "Joanne M Hildebrand, Maria C Tanzer, Isabelle S Lucet, ..., John Silke", + "authorList": [ + { + "ForeName": "Joanne", + "LastName": "Hildebrand", + "abbrevName": "Hildebrand JM", + "email": null, + "isCollectiveName": false, + "name": "Joanne M Hildebrand", + "orcid": null + }, + { + "ForeName": "Maria", + "LastName": "Tanzer", + "abbrevName": "Tanzer MC", + "email": null, + "isCollectiveName": false, + "name": "Maria C Tanzer", + "orcid": null + }, + { + "ForeName": "Isabelle", + "LastName": "Lucet", + "abbrevName": "Lucet IS", + "email": null, + "isCollectiveName": false, + "name": "Isabelle S Lucet", + "orcid": null + }, + { + "ForeName": "Samuel", + "LastName": "Young", + "abbrevName": "Young SN", + "email": null, + "isCollectiveName": false, + "name": "Samuel N Young", + "orcid": null + }, + { + "ForeName": "Sukhdeep", + "LastName": "Spall", + "abbrevName": "Spall SK", + "email": null, + "isCollectiveName": false, + "name": "Sukhdeep K Spall", + "orcid": null + }, + { + "ForeName": "Pooja", + "LastName": "Sharma", + "abbrevName": "Sharma P", + "email": null, + "isCollectiveName": false, + "name": "Pooja Sharma", + "orcid": null + }, + { + "ForeName": "Catia", + "LastName": "Pierotti", + "abbrevName": "Pierotti C", + "email": null, + "isCollectiveName": false, + "name": "Catia Pierotti", + "orcid": null + }, + { + "ForeName": "Jean-Marc", + "LastName": "Garnier", + "abbrevName": "Garnier JM", + "email": null, + "isCollectiveName": false, + "name": "Jean-Marc Garnier", + "orcid": null + }, + { + "ForeName": "Renwick", + "LastName": "Dobson", + "abbrevName": "Dobson RC", + "email": null, + "isCollectiveName": false, + "name": "Renwick C J Dobson", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Webb", + "abbrevName": "Webb AI", + "email": null, + "isCollectiveName": false, + "name": "Andrew I Webb", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Tripaydonis", + "abbrevName": "Tripaydonis A", + "email": null, + "isCollectiveName": false, + "name": "Anne Tripaydonis", + "orcid": null + }, + { + "ForeName": "Jeffrey", + "LastName": "Babon", + "abbrevName": "Babon JJ", + "email": null, + "isCollectiveName": false, + "name": "Jeffrey J Babon", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "Mulcair", + "abbrevName": "Mulcair MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Mulcair", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Scanlon", + "abbrevName": "Scanlon MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Scanlon", + "orcid": null + }, + { + "ForeName": "Warren", + "LastName": "Alexander", + "abbrevName": "Alexander WS", + "email": null, + "isCollectiveName": false, + "name": "Warren S Alexander", + "orcid": null + }, + { + "ForeName": "Andrew", + "LastName": "Wilks", + "abbrevName": "Wilks AF", + "email": null, + "isCollectiveName": false, + "name": "Andrew F Wilks", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Czabotar", + "abbrevName": "Czabotar PE", + "email": null, + "isCollectiveName": false, + "name": "Peter E Czabotar", + "orcid": null + }, + { + "ForeName": "Guillaume", + "LastName": "Lessene", + "abbrevName": "Lessene G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Lessene", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": "jamesm@wehi.edu.au", + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "jamesm@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "James", + "LastName": "Murphy", + "email": [ + "jamesm@wehi.edu.au", + "silke@wehi.edu.au" + ], + "name": "James M Murphy" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "jamesm@wehi.edu.au", + "silke@wehi.edu.au" + ], + "name": "John Silke" + } + ] + }, + "doi": "10.1073/pnas.1408987111", + "pmid": "25288762", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 111 2014", + "title": "Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death." + } + }, + { + "pmid": "25150011", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "Cell turnover is a fundamental feature in metazoans. Cells can die passively, as a consequence of severe damage to their structural integrity, or actively, owing to a more confined biological disruption such as DNA damage. Passive cell death is uncontrolled and often harmful to the organism. In contrast, active cell death is tightly regulated and serves to support the organism's life. Apoptosis-the primary form of regulated cell death-is relatively well defined. Necroptosis-an alternative, distinct kind of regulated cell death discovered more recently-is less well understood. Apoptosis and necroptosis can be triggered either from within the cell or by extracellular stimuli. Certain signaling components, including several death ligands and receptors, can regulate both processes. Whereas apoptosis is triggered and executed via intracellular proteases called caspases, necroptosis is suppressed by caspase activity. Here we highlight current understanding of the key signaling mechanisms that control regulated cell death.", + "authors": { + "abbreviation": "Avi Ashkenazi, Guy Salvesen", + "authorList": [ + { + "ForeName": "Avi", + "LastName": "Ashkenazi", + "abbrevName": "Ashkenazi A", + "email": "aa@gene.com", + "isCollectiveName": false, + "name": "Avi Ashkenazi", + "orcid": null + }, + { + "ForeName": "Guy", + "LastName": "Salvesen", + "abbrevName": "Salvesen G", + "email": null, + "isCollectiveName": false, + "name": "Guy Salvesen", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Avi", + "LastName": "Ashkenazi", + "email": [ + "aa@gene.com" + ], + "name": "Avi Ashkenazi" + } + ] + }, + "doi": "10.1146/annurev-cellbio-100913-013226", + "pmid": "25150011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Annu Rev Cell Dev Biol 30 2014", + "title": "Regulated cell death: signaling and mechanisms." + } + }, + { + "pmid": "25123483", + "pubmed": { + "ISODate": "2014-09-05T00:00:00.000Z", + "abstract": "Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. DMD is characterized by progressive muscle weakness and a shortened life span, and there is no effective treatment. We used clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9)-mediated genome editing to correct the dystrophin gene (Dmd) mutation in the germ line of mdx mice, a model for DMD, and then monitored muscle structure and function. Genome editing produced genetically mosaic animals containing 2 to 100% correction of the Dmd gene. The degree of muscle phenotypic rescue in mosaic mice exceeded the efficiency of gene correction, likely reflecting an advantage of the corrected cells and their contribution to regenerating muscle. With the anticipated technological advances that will facilitate genome editing of postnatal somatic cells, this strategy may one day allow correction of disease-causing mutations in the muscle tissue of patients with DMD.", + "authors": { + "abbreviation": "Chengzu Long, John R McAnally, John M Shelton, ..., Eric N Olson", + "authorList": [ + { + "ForeName": "Chengzu", + "LastName": "Long", + "abbrevName": "Long C", + "email": null, + "isCollectiveName": false, + "name": "Chengzu Long", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "McAnally", + "abbrevName": "McAnally JR", + "email": null, + "isCollectiveName": false, + "name": "John R McAnally", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Shelton", + "abbrevName": "Shelton JM", + "email": null, + "isCollectiveName": false, + "name": "John M Shelton", + "orcid": null + }, + { + "ForeName": "Alex", + "LastName": "Mireault", + "abbrevName": "Mireault AA", + "email": null, + "isCollectiveName": false, + "name": "Alex A Mireault", + "orcid": null + }, + { + "ForeName": "Rhonda", + "LastName": "Bassel-Duby", + "abbrevName": "Bassel-Duby R", + "email": null, + "isCollectiveName": false, + "name": "Rhonda Bassel-Duby", + "orcid": null + }, + { + "ForeName": "Eric", + "LastName": "Olson", + "abbrevName": "Olson EN", + "email": null, + "isCollectiveName": false, + "name": "Eric N Olson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1254445", + "pmid": "25123483", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 345 2014", + "title": "Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA." + } + }, + { + "pmid": "25075903", + "pubmed": { + "ISODate": "2014-08-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Neville E Sanjana, Ophir Shalem, Feng Zhang", + "authorList": [ + { + "ForeName": "Neville", + "LastName": "Sanjana", + "abbrevName": "Sanjana NE", + "email": null, + "isCollectiveName": false, + "name": "Neville E Sanjana", + "orcid": null + }, + { + "ForeName": "Ophir", + "LastName": "Shalem", + "abbrevName": "Shalem O", + "email": null, + "isCollectiveName": false, + "name": "Ophir Shalem", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Zhang", + "abbrevName": "Zhang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Zhang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth.3047", + "pmid": "25075903", + "pubTypes": [ + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Nat Methods 11 2014", + "title": "Improved vectors and genome-wide libraries for CRISPR screening." + } + }, + { + "pmid": "24813885", + "pubmed": { + "ISODate": "2014-05-22T00:00:00.000Z", + "abstract": "Although mixed lineage kinase domain-like (MLKL) protein has emerged as a specific and crucial protein for necroptosis induction, how MLKL transduces the death signal remains poorly understood. Here, we demonstrate that the full four-helical bundle domain (4HBD) in the N-terminal region of MLKL is required and sufficient to induce its oligomerization and trigger cell death. Moreover, we found that a patch of positively charged amino acids on the surface of the 4HBD binds to phosphatidylinositol phosphates (PIPs) and allows recruitment of MLKL to the plasma membrane. Importantly, we found that recombinant MLKL, but not a mutant lacking these positive charges, induces leakage of PIP-containing liposomes as potently as BAX, supporting a model in which MLKL induces necroptosis by directly permeabilizing the plasma membrane. Accordingly, we found that inhibiting the formation of PI(5)P and PI(4,5)P2 specifically inhibits tumor necrosis factor (TNF)-mediated necroptosis but not apoptosis.", + "authors": { + "abbreviation": "Yves Dondelinger, Wim Declercq, Sylvie Montessuit, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Montessuit", + "abbrevName": "Montessuit S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Montessuit", + "orcid": null + }, + { + "ForeName": "Ria", + "LastName": "Roelandt", + "abbrevName": "Roelandt R", + "email": null, + "isCollectiveName": false, + "name": "Ria Roelandt", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Goncalves", + "abbrevName": "Goncalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Goncalves", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Paco", + "LastName": "Hulpiau", + "abbrevName": "Hulpiau P", + "email": null, + "isCollectiveName": false, + "name": "Paco Hulpiau", + "orcid": null + }, + { + "ForeName": "Kathrin", + "LastName": "Weber", + "abbrevName": "Weber K", + "email": null, + "isCollectiveName": false, + "name": "Kathrin Weber", + "orcid": null + }, + { + "ForeName": "Clark", + "LastName": "Sehon", + "abbrevName": "Sehon CA", + "email": null, + "isCollectiveName": false, + "name": "Clark A Sehon", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Marquis", + "abbrevName": "Marquis RW", + "email": null, + "isCollectiveName": false, + "name": "Robert W Marquis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Savvas", + "LastName": "Savvides", + "abbrevName": "Savvides S", + "email": null, + "isCollectiveName": false, + "name": "Savvas Savvides", + "orcid": null + }, + { + "ForeName": "Jean-Claude", + "LastName": "Martinou", + "abbrevName": "Martinou JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Claude Martinou", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": "peter.vandenabeele@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "email": [ + "peter.vandenabeele@irc.vib-ugent.be" + ], + "name": "Peter Vandenabeele" + } + ] + }, + "doi": "10.1016/j.celrep.2014.04.026", + "pmid": "24813885", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 7 2014", + "title": "MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates." + } + }, + { + "pmid": "24703947", + "pubmed": { + "ISODate": "2014-04-10T00:00:00.000Z", + "abstract": "Programmed necrotic cell death induced by the tumor necrosis factor alpha (TNF-α) family of cytokines is dependent on a kinase cascade consisting of receptor-interacting kinases RIP1 and RIP3. How these kinase activities cause cells to die by necrosis is not known. The mixed lineage kinase domain-like protein MLKL is a functional RIP3 substrate that binds to RIP3 through its kinase-like domain but lacks kinase activity of its own. RIP3 phosphorylates MLKL at the T357 and S358 sites. Reported here is the development of a monoclonal antibody that specifically recognizes phosphorylated MLKL in cells dying of this pathway and in human liver biopsy samples from patients suffering from drug-induced liver injury. The phosphorylated MLKL forms an oligomer that binds to phosphatidylinositol lipids and cardiolipin. This property allows MLKL to move from the cytosol to the plasma and intracellular membranes, where it directly disrupts membrane integrity, resulting in necrotic death.", + "authors": { + "abbreviation": "Huayi Wang, Liming Sun, Lijing Su, ..., Xiaodong Wang", + "authorList": [ + { + "ForeName": "Huayi", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huayi Wang", + "orcid": null + }, + { + "ForeName": "Liming", + "LastName": "Sun", + "abbrevName": "Sun L", + "email": null, + "isCollectiveName": false, + "name": "Liming Sun", + "orcid": null + }, + { + "ForeName": "Lijing", + "LastName": "Su", + "abbrevName": "Su L", + "email": null, + "isCollectiveName": false, + "name": "Lijing Su", + "orcid": null + }, + { + "ForeName": "Josep", + "LastName": "Rizo", + "abbrevName": "Rizo J", + "email": null, + "isCollectiveName": false, + "name": "Josep Rizo", + "orcid": null + }, + { + "ForeName": "Lei", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lei Liu", + "orcid": null + }, + { + "ForeName": "Li-Feng", + "LastName": "Wang", + "abbrevName": "Wang LF", + "email": null, + "isCollectiveName": false, + "name": "Li-Feng Wang", + "orcid": null + }, + { + "ForeName": "Fu-Sheng", + "LastName": "Wang", + "abbrevName": "Wang FS", + "email": null, + "isCollectiveName": false, + "name": "Fu-Sheng Wang", + "orcid": null + }, + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": "wangxiaodong@nibs.ac.cn", + "isCollectiveName": false, + "name": "Xiaodong Wang", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "email": [ + "wangxiaodong@nibs.ac.cn" + ], + "name": "Xiaodong Wang" + } + ] + }, + "doi": "10.1016/j.molcel.2014.03.003", + "pmid": "24703947", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 54 2014", + "title": "Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3." + } + }, + { + "pmid": "24586659", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "Innate immune sensors such as Toll-like receptors (TLRs) differentially utilize adaptor proteins and additional molecular mediators to ensure robust and precise immune responses to pathogen challenge. Through a gain-of-function genetic screen, we identified the gamma catalytic subunit of protein phosphatase 1 (PP1-γ) as a positive regulator of MyD88-dependent proinflammatory innate immune activation. PP1-γ physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKKγ, whereas enzymatically inactive PP1-γ represses these events. Importantly, these activities were found to be critical for cellular innate responses to pathogen challenge and microbial clearance in both mouse macrophages and human monocyte lines. These data indicate that PP1-γ phosphatase activity regulates overall TRAF6 E3 ubiquitin ligase function and promotes NF-κB-mediated innate signaling responses.", + "authors": { + "abbreviation": "Amanda M Opaluch, Monika Schneider, Chih-yuan Chiang, ..., Sumit K Chanda", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Opaluch", + "abbrevName": "Opaluch AM", + "email": null, + "isCollectiveName": false, + "name": "Amanda M Opaluch", + "orcid": null + }, + { + "ForeName": "Monika", + "LastName": "Schneider", + "abbrevName": "Schneider M", + "email": null, + "isCollectiveName": false, + "name": "Monika Schneider", + "orcid": null + }, + { + "ForeName": "Chih-yuan", + "LastName": "Chiang", + "abbrevName": "Chiang CY", + "email": null, + "isCollectiveName": false, + "name": "Chih-yuan Chiang", + "orcid": null + }, + { + "ForeName": "Quy", + "LastName": "Nguyen", + "abbrevName": "Nguyen QT", + "email": null, + "isCollectiveName": false, + "name": "Quy T Nguyen", + "orcid": null + }, + { + "ForeName": "Ana", + "LastName": "Maestre", + "abbrevName": "Maestre AM", + "email": null, + "isCollectiveName": false, + "name": "Ana M Maestre", + "orcid": null + }, + { + "ForeName": "Lubbertus", + "LastName": "Mulder", + "abbrevName": "Mulder LC", + "email": null, + "isCollectiveName": false, + "name": "Lubbertus C F Mulder", + "orcid": null + }, + { + "ForeName": "Ismael", + "LastName": "Secundino", + "abbrevName": "Secundino I", + "email": null, + "isCollectiveName": false, + "name": "Ismael Secundino", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "De Jesus", + "abbrevName": "De Jesus PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D De Jesus", + "orcid": null + }, + { + "ForeName": "Renate", + "LastName": "König", + "abbrevName": "König R", + "email": null, + "isCollectiveName": false, + "name": "Renate König", + "orcid": null + }, + { + "ForeName": "Viviana", + "LastName": "Simon", + "abbrevName": "Simon V", + "email": null, + "isCollectiveName": false, + "name": "Viviana Simon", + "orcid": null + }, + { + "ForeName": "Victor", + "LastName": "Nizet", + "abbrevName": "Nizet V", + "email": null, + "isCollectiveName": false, + "name": "Victor Nizet", + "orcid": null + }, + { + "ForeName": "Graham", + "LastName": "MacLeod", + "abbrevName": "MacLeod G", + "email": null, + "isCollectiveName": false, + "name": "Graham MacLeod", + "orcid": null + }, + { + "ForeName": "Susannah", + "LastName": "Varmuza", + "abbrevName": "Varmuza S", + "email": null, + "isCollectiveName": false, + "name": "Susannah Varmuza", + "orcid": null + }, + { + "ForeName": "Ana", + "LastName": "Fernandez-Sesma", + "abbrevName": "Fernandez-Sesma A", + "email": null, + "isCollectiveName": false, + "name": "Ana Fernandez-Sesma", + "orcid": null + }, + { + "ForeName": "Sumit", + "LastName": "Chanda", + "abbrevName": "Chanda SK", + "email": null, + "isCollectiveName": false, + "name": "Sumit K Chanda", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0089284", + "pmid": "24586659", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 9 2014", + "title": "Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-γ." + } + }, + { + "pmid": "24366341", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain (HBD*) triggers necroptosis. Notably, forcing together the N-terminal domain (ND) but not the C-terminal kinase domain of MLKL causes necroptosis. Further deletion analysis showed that the four-α-helix bundle of MLKL (1-130 amino acids) is sufficient to trigger necroptosis. Both the HBD*-mediated and TNF-induced complexes of MLKL(ND) or MLKL are tetramers, and translocation of these complexes to lipid rafts of the plasma membrane precedes cell death. The homo-oligomerization is required for MLKL translocation and the signal sequence for plasma membrane location is located in the junction of the first and second α-helices of MLKL. The plasma membrane translocation of MLKL or MLKL(ND) leads to sodium influx, and depletion of sodium from the cell culture medium inhibits necroptosis. All of the above phenomena were not seen in apoptosis. Thus, the MLKL oligomerization leads to translocation of MLKL to lipid rafts of plasma membrane, and the plasma membrane MLKL complex acts either by itself or via other proteins to increase the sodium influx, which increases osmotic pressure, eventually leading to membrane rupture.", + "authors": { + "abbreviation": "Xin Chen, Wenjuan Li, Junming Ren, ..., Jiahuai Han", + "authorList": [ + { + "ForeName": "Xin", + "LastName": "Chen", + "abbrevName": "Chen X", + "email": null, + "isCollectiveName": false, + "name": "Xin Chen", + "orcid": null + }, + { + "ForeName": "Wenjuan", + "LastName": "Li", + "abbrevName": "Li W", + "email": null, + "isCollectiveName": false, + "name": "Wenjuan Li", + "orcid": null + }, + { + "ForeName": "Junming", + "LastName": "Ren", + "abbrevName": "Ren J", + "email": null, + "isCollectiveName": false, + "name": "Junming Ren", + "orcid": null + }, + { + "ForeName": "Deli", + "LastName": "Huang", + "abbrevName": "Huang D", + "email": null, + "isCollectiveName": false, + "name": "Deli Huang", + "orcid": null + }, + { + "ForeName": "Wan-Ting", + "LastName": "He", + "abbrevName": "He WT", + "email": null, + "isCollectiveName": false, + "name": "Wan-Ting He", + "orcid": null + }, + { + "ForeName": "Yunlong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yunlong Song", + "orcid": null + }, + { + "ForeName": "Chao", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Chao Yang", + "orcid": null + }, + { + "ForeName": "Wanyun", + "LastName": "Li", + "abbrevName": "Li W", + "email": null, + "isCollectiveName": false, + "name": "Wanyun Li", + "orcid": null + }, + { + "ForeName": "Xinru", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xinru Zheng", + "orcid": null + }, + { + "ForeName": "Pengda", + "LastName": "Chen", + "abbrevName": "Chen P", + "email": null, + "isCollectiveName": false, + "name": "Pengda Chen", + "orcid": null + }, + { + "ForeName": "Jiahuai", + "LastName": "Han", + "abbrevName": "Han J", + "email": null, + "isCollectiveName": false, + "name": "Jiahuai Han", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cr.2013.171", + "pmid": "24366341", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Res 24 2014", + "title": "Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death." + } + }, + { + "pmid": "24336571", + "pubmed": { + "ISODate": "2014-01-03T00:00:00.000Z", + "abstract": "The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.", + "authors": { + "abbreviation": "Ophir Shalem, Neville E Sanjana, Ella Hartenian, ..., Feng Zhang", + "authorList": [ + { + "ForeName": "Ophir", + "LastName": "Shalem", + "abbrevName": "Shalem O", + "email": null, + "isCollectiveName": false, + "name": "Ophir Shalem", + "orcid": null + }, + { + "ForeName": "Neville", + "LastName": "Sanjana", + "abbrevName": "Sanjana NE", + "email": null, + "isCollectiveName": false, + "name": "Neville E Sanjana", + "orcid": null + }, + { + "ForeName": "Ella", + "LastName": "Hartenian", + "abbrevName": "Hartenian E", + "email": null, + "isCollectiveName": false, + "name": "Ella Hartenian", + "orcid": null + }, + { + "ForeName": "Xi", + "LastName": "Shi", + "abbrevName": "Shi X", + "email": null, + "isCollectiveName": false, + "name": "Xi Shi", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Scott", + "abbrevName": "Scott DA", + "email": null, + "isCollectiveName": false, + "name": "David A Scott", + "orcid": null + }, + { + "ForeName": "Tarjei", + "LastName": "Mikkelson", + "abbrevName": "Mikkelson T", + "email": null, + "isCollectiveName": false, + "name": "Tarjei Mikkelson", + "orcid": null + }, + { + "ForeName": "Dirk", + "LastName": "Heckl", + "abbrevName": "Heckl D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Heckl", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Ebert", + "abbrevName": "Ebert BL", + "email": null, + "isCollectiveName": false, + "name": "Benjamin L Ebert", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Root", + "abbrevName": "Root DE", + "email": null, + "isCollectiveName": false, + "name": "David E Root", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Doench", + "abbrevName": "Doench JG", + "email": null, + "isCollectiveName": false, + "name": "John G Doench", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Zhang", + "abbrevName": "Zhang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Zhang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1247005", + "pmid": "24336571", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 343 2014", + "title": "Genome-scale CRISPR-Cas9 knockout screening in human cells." + } + }, + { + "pmid": "24316671", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.", + "authors": { + "abbreviation": "Zhenyu Cai, Siriporn Jitkaew, Jie Zhao, ..., Zheng-Gang Liu", + "authorList": [ + { + "ForeName": "Zhenyu", + "LastName": "Cai", + "abbrevName": "Cai Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenyu Cai", + "orcid": null + }, + { + "ForeName": "Siriporn", + "LastName": "Jitkaew", + "abbrevName": "Jitkaew S", + "email": null, + "isCollectiveName": false, + "name": "Siriporn Jitkaew", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhao", + "abbrevName": "Zhao J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhao", + "orcid": null + }, + { + "ForeName": "Hsueh-Cheng", + "LastName": "Chiang", + "abbrevName": "Chiang HC", + "email": null, + "isCollectiveName": false, + "name": "Hsueh-Cheng Chiang", + "orcid": null + }, + { + "ForeName": "Swati", + "LastName": "Choksi", + "abbrevName": "Choksi S", + "email": null, + "isCollectiveName": false, + "name": "Swati Choksi", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jie Liu", + "orcid": null + }, + { + "ForeName": "Yvona", + "LastName": "Ward", + "abbrevName": "Ward Y", + "email": null, + "isCollectiveName": false, + "name": "Yvona Ward", + "orcid": null + }, + { + "ForeName": "Ling-Gang", + "LastName": "Wu", + "abbrevName": "Wu LG", + "email": null, + "isCollectiveName": false, + "name": "Ling-Gang Wu", + "orcid": null + }, + { + "ForeName": "Zheng-Gang", + "LastName": "Liu", + "abbrevName": "Liu ZG", + "email": null, + "isCollectiveName": false, + "name": "Zheng-Gang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2883", + "pmid": "24316671", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis." + } + }, + { + "pmid": "24059293", + "pubmed": { + "ISODate": "2013-12-15T00:00:00.000Z", + "abstract": "Programmed necrosis or necroptosis is controlled by the action of two serine/threonine kinases, RIP1 (receptor-interacting serine/threonine protein kinase 1; also known as RIPK1) and RIP3. The phosphorylation of RIP1 and RIP3 is critical for assembly of the necrosome, an amyloid-like complex that initiates transmission of the pro-necrotic signal. In the present study, we used site-directed mutagenesis to systematically examine the effects of putative phosphoacceptor sites on RIP1 and RIP3 on TNF (tumour necrosis factor)-induced programmed necrosis. We found that mutation of individual serine residues in the kinase domain of RIP1 had little effect on RIP1 kinase activity and TNF-induced programmed necrosis. Surprisingly, an alanine residue substitution for Ser(89) enhanced RIP1 kinase activity and TNF-induced programmed necrosis without affecting RIP1-RIP3 necrosome formation. This indicates that Ser(89) is an inhibitory phosphoacceptor site that can dampen the pro-necrotic function of RIP1. In addition, we show that a phosphomimetic mutant of RIP3, S204D, led to programmed necrosis that was refractory to RIP1 siRNA and insensitive to necrostatin-1 inhibition. Our results show that programmed necrosis is regulated by positive and inhibitory phosphorylation events.", + "authors": { + "abbreviation": "Thomas McQuade, Youngsik Cho, Francis Ka-Ming Chan", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "McQuade", + "abbrevName": "McQuade T", + "email": null, + "isCollectiveName": false, + "name": "Thomas McQuade", + "orcid": null + }, + { + "ForeName": "Youngsik", + "LastName": "Cho", + "abbrevName": "Cho Y", + "email": null, + "isCollectiveName": false, + "name": "Youngsik Cho", + "orcid": null + }, + { + "ForeName": "Francis", + "LastName": "Chan", + "abbrevName": "Chan FK", + "email": null, + "isCollectiveName": false, + "name": "Francis Ka-Ming Chan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1042/BJ20130860", + "pmid": "24059293", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochem J 456 2013", + "title": "Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis." + } + }, + { + "pmid": "23758787", + "pubmed": { + "ISODate": "2013-06-13T00:00:00.000Z", + "abstract": "The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily. The past decade has witnessed rapid expansion of receptor families identified to employ TRAFs for signaling. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), T cell receptor, IL-1 receptor family, IL-17 receptors, IFN receptors and TGFβ receptors. In addition to their role as adaptor proteins, most TRAFs also act as E3 ubiquitin ligases to activate downstream signaling events. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-κBs (NF-κBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). Compelling evidence obtained from germ-line and cell-specific TRAF-deficient mice demonstrates that each TRAF plays indispensable and non-redundant physiological roles, regulating innate and adaptive immunity, embryonic development, tissue homeostasis, stress response, and bone metabolism. Notably, mounting evidence implicates TRAFs in the pathogenesis of human diseases such as cancers and autoimmune diseases, which has sparked new appreciation and interest in TRAF research. This review presents an overview of the current knowledge of TRAFs, with an emphasis on recent findings concerning TRAF molecules in signaling and in human diseases.", + "authors": { + "abbreviation": "Ping Xie", + "authorList": [ + { + "ForeName": "Ping", + "LastName": "Xie", + "abbrevName": "Xie P", + "email": "xiep@rci.rutgers.edu", + "isCollectiveName": false, + "name": "Ping Xie", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Ping", + "LastName": "Xie", + "email": [ + "xiep@rci.rutgers.edu" + ], + "name": "Ping Xie" + } + ] + }, + "doi": "10.1186/1750-2187-8-7", + "pmid": "23758787", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Mol Signal 8 2013", + "title": "TRAF molecules in cell signaling and in human diseases." + } + }, + { + "pmid": "23499489", + "pubmed": { + "ISODate": "2013-03-21T00:00:00.000Z", + "abstract": "RIG-I and MDA5 have emerged as key cytosolic sensors for the detection of RNA viruses and lead to antiviral interferon (IFN) production. Recent studies have highlighted the importance of posttranslational modifications for controlling RIG-I antiviral activity. However, the regulation of MDA5 signal-transducing ability remains unclear. Here, we show that MDA5 signaling activity is regulated by a dynamic balance between phosphorylation and dephosphorylation of its caspase recruitment domains (CARDs). Employing a phosphatome RNAi screen, we identified PP1α and PP1γ as the primary phosphatases that are responsible for MDA5 and RIG-I dephosphorylation and that lead to their activation. Silencing of PP1α and PP1γ enhanced RIG-I and MDA5 CARD phosphorylation and reduced antiviral IFN-β production. PP1α- and PP1γ-depleted cells were impaired in their ability to induce IFN-stimulated gene expression, which resulted in enhanced RNA virus replication. This work identifies PP1α and PP1γ as regulators of antiviral innate immune responses to various RNA viruses, including influenza virus, paramyxovirus, dengue virus, and picornavirus.", + "authors": { + "abbreviation": "Effi Wies, May K Wang, Natalya P Maharaj, ..., Michaela U Gack", + "authorList": [ + { + "ForeName": "Effi", + "LastName": "Wies", + "abbrevName": "Wies E", + "email": null, + "isCollectiveName": false, + "name": "Effi Wies", + "orcid": null + }, + { + "ForeName": "May", + "LastName": "Wang", + "abbrevName": "Wang MK", + "email": null, + "isCollectiveName": false, + "name": "May K Wang", + "orcid": null + }, + { + "ForeName": "Natalya", + "LastName": "Maharaj", + "abbrevName": "Maharaj NP", + "email": null, + "isCollectiveName": false, + "name": "Natalya P Maharaj", + "orcid": null + }, + { + "ForeName": "Kan", + "LastName": "Chen", + "abbrevName": "Chen K", + "email": null, + "isCollectiveName": false, + "name": "Kan Chen", + "orcid": null + }, + { + "ForeName": "Shenghua", + "LastName": "Zhou", + "abbrevName": "Zhou S", + "email": null, + "isCollectiveName": false, + "name": "Shenghua Zhou", + "orcid": null + }, + { + "ForeName": "Robert", + "LastName": "Finberg", + "abbrevName": "Finberg RW", + "email": null, + "isCollectiveName": false, + "name": "Robert W Finberg", + "orcid": null + }, + { + "ForeName": "Michaela", + "LastName": "Gack", + "abbrevName": "Gack MU", + "email": null, + "isCollectiveName": false, + "name": "Michaela U Gack", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.immuni.2012.11.018", + "pmid": "23499489", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Immunity 38 2013", + "title": "Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling." + } + }, + { + "pmid": "22421439", + "pubmed": { + "ISODate": "2012-04-03T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) is an important inflammatory cytokine and induces many cellular responses, including inflammation, cell proliferation, apoptosis, and necrosis. It is known that receptor interacting protein (RIP) kinases, RIP1 and RIP3, are key effectors of TNF-induced necrosis, but little is known about how these two RIP kinases mediate this process, although reactive oxygen species (ROS) generation and JNK activation have been suggested to be two downstream events of RIP kinases. Here we report the identification of mixed lineage kinase domain-like, MLKL, as a key RIP3 downstream component of TNF-induced necrosis. Through screening a kinase/phosphatase shRNA library in human colon adenocarcinoma HT-29 cells, we found that knockdown of MLKL blocked TNF-induced necrosis. Our data suggest that MLKL functions downstream of RIP1 and RIP3 and is recruited to the necrosome through its interaction with RIP3. Finally, we found that MLKL is required for the generation of ROS and the late-phase activation of JNK during TNF-induced necrosis. However, because these two events are not involved in TNF-induced necrosis in HT-29 cells, the target of MLKL during TNF-induced necrosis remains elusive. Taken together, our study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death.", + "authors": { + "abbreviation": "Jie Zhao, Siriporn Jitkaew, Zhenyu Cai, ..., Zheng-Gang Liu", + "authorList": [ + { + "ForeName": "Jie", + "LastName": "Zhao", + "abbrevName": "Zhao J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhao", + "orcid": null + }, + { + "ForeName": "Siriporn", + "LastName": "Jitkaew", + "abbrevName": "Jitkaew S", + "email": null, + "isCollectiveName": false, + "name": "Siriporn Jitkaew", + "orcid": null + }, + { + "ForeName": "Zhenyu", + "LastName": "Cai", + "abbrevName": "Cai Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenyu Cai", + "orcid": null + }, + { + "ForeName": "Swati", + "LastName": "Choksi", + "abbrevName": "Choksi S", + "email": null, + "isCollectiveName": false, + "name": "Swati Choksi", + "orcid": null + }, + { + "ForeName": "Qiuning", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qiuning Li", + "orcid": null + }, + { + "ForeName": "Ji", + "LastName": "Luo", + "abbrevName": "Luo J", + "email": null, + "isCollectiveName": false, + "name": "Ji Luo", + "orcid": null + }, + { + "ForeName": "Zheng-Gang", + "LastName": "Liu", + "abbrevName": "Liu ZG", + "email": null, + "isCollectiveName": false, + "name": "Zheng-Gang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1200012109", + "pmid": "22421439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 109 2012", + "title": "Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis." + } + }, + { + "pmid": "22371307", + "pubmed": { + "ISODate": "2012-05-09T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor (TNFR) signaling may result in survival, apoptosis or programmed necrosis. The latter is called necroptosis if the receptor-interacting protein 1 (RIP1) inhibitor necrostatin-1 (Nec-1) or genetic knockout of RIP3 prevents it. In the lethal mouse model of TNFα-mediated shock, addition of the pan-caspase inhibitor zVAD-fmk (zVAD) accelerates time to death. Here, we demonstrate that RIP3-deficient mice are protected markedly from TNFα-mediated shock in the presence and absence of caspase inhibition. We further show that the fusion protein TAT-crmA, previously demonstrated to inhibit apoptosis, also prevents necroptosis in L929, HT29 and FADD-deficient Jurkat cells. In contrast to RIP3-deficient mice, blocking necroptosis by Nec-1 or TAT-crmA did not protect from TNFα/zVAD-mediated shock, but further accelerated time to death. Even in the absence of caspase inhibition, Nec-1 application led to similar kinetics. Depletion of macrophages, natural killer (NK) cells, granulocytes or genetic deficiency for T lymphocytes did not influence this model. Because RIP3-deficient mice are known to be protected from cerulein-induced pancreatitis (CIP), we applied Nec-1 and TAT-crmA in this model and demonstrated the deterioration of pancreatic damage upon addition of these substances. These data highlight the importance of separating genetic RIP3 deficiency from RIP1 inhibition by Nec-1 application in vivo and challenge the current definition of necroptosis.", + "authors": { + "abbreviation": "Andreas Linkermann, Jan H Bräsen, Federica De Zen, ..., Stefan Krautwald", + "authorList": [ + { + "ForeName": "Andreas", + "LastName": "Linkermann", + "abbrevName": "Linkermann A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Linkermann", + "orcid": null + }, + { + "ForeName": "Jan", + "LastName": "Bräsen", + "abbrevName": "Bräsen JH", + "email": null, + "isCollectiveName": false, + "name": "Jan H Bräsen", + "orcid": null + }, + { + "ForeName": "Federica", + "LastName": "De Zen", + "abbrevName": "De Zen F", + "email": null, + "isCollectiveName": false, + "name": "Federica De Zen", + "orcid": null + }, + { + "ForeName": "Ricardo", + "LastName": "Weinlich", + "abbrevName": "Weinlich R", + "email": null, + "isCollectiveName": false, + "name": "Ricardo Weinlich", + "orcid": null + }, + { + "ForeName": "Reto", + "LastName": "Schwendener", + "abbrevName": "Schwendener RA", + "email": null, + "isCollectiveName": false, + "name": "Reto A Schwendener", + "orcid": null + }, + { + "ForeName": "Douglas", + "LastName": "Green", + "abbrevName": "Green DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Green", + "orcid": null + }, + { + "ForeName": "Ulrich", + "LastName": "Kunzendorf", + "abbrevName": "Kunzendorf U", + "email": null, + "isCollectiveName": false, + "name": "Ulrich Kunzendorf", + "orcid": null + }, + { + "ForeName": "Stefan", + "LastName": "Krautwald", + "abbrevName": "Krautwald S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Krautwald", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2119/molmed.2011.00423", + "pmid": "22371307", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Med 18 2012", + "title": "Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-α-induced shock." + } + }, + { + "pmid": "22265413", + "pubmed": { + "ISODate": "2012-01-20T00:00:00.000Z", + "abstract": "The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide--hereafter referred to as necrosulfonamide--that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.", + "authors": { + "abbreviation": "Liming Sun, Huayi Wang, Zhigao Wang, ..., Xiaodong Wang", + "authorList": [ + { + "ForeName": "Liming", + "LastName": "Sun", + "abbrevName": "Sun L", + "email": null, + "isCollectiveName": false, + "name": "Liming Sun", + "orcid": null + }, + { + "ForeName": "Huayi", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huayi Wang", + "orcid": null + }, + { + "ForeName": "Zhigao", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhigao Wang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": null, + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + }, + { + "ForeName": "She", + "LastName": "Chen", + "abbrevName": "Chen S", + "email": null, + "isCollectiveName": false, + "name": "She Chen", + "orcid": null + }, + { + "ForeName": "Daohong", + "LastName": "Liao", + "abbrevName": "Liao D", + "email": null, + "isCollectiveName": false, + "name": "Daohong Liao", + "orcid": null + }, + { + "ForeName": "Lai", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Lai Wang", + "orcid": null + }, + { + "ForeName": "Jiacong", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jiacong Yan", + "orcid": null + }, + { + "ForeName": "Weilong", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Weilong Liu", + "orcid": null + }, + { + "ForeName": "Xiaoguang", + "LastName": "Lei", + "abbrevName": "Lei X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoguang Lei", + "orcid": null + }, + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaodong Wang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2011.11.031", + "pmid": "22265413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 148 2012", + "title": "Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase." + } + }, + { + "pmid": "22195746", + "pubmed": { + "ISODate": "2011-12-23T00:00:00.000Z", + "abstract": "Engagement of tumor necrosis factor receptor 1 signals two diametrically opposed pathways: survival-inflammation and cell death. An additional switch decides, depending on the cellular context, between caspase-dependent apoptosis and RIP kinase (RIPK)-mediated necrosis, also termed necroptosis. We explored the contribution of both cell death pathways in TNF-induced systemic inflammatory response syndrome (SIRS). Deletion of apoptotic executioner caspases (caspase-3 or -7) or inflammatory caspase-1 had no impact on lethal SIRS. However, deletion of RIPK3 conferred complete protection against lethal SIRS and reduced the amounts of circulating damage-associated molecular patterns. Pretreatment with the RIPK1 kinase inhibitor, necrostatin-1, provided a similar effect. These results suggest that RIPK1-RIPK3-mediated cellular damage by necrosis drives mortality during TNF-induced SIRS. RIPK3 deficiency also protected against cecal ligation and puncture, underscoring the clinical relevance of RIPK kinase inhibition in sepsis and identifying components of the necroptotic pathway that are potential therapeutic targets for treatment of SIRS and sepsis.", + "authors": { + "abbreviation": "Linde Duprez, Nozomi Takahashi, Filip Van Hauwermeiren, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Filip", + "LastName": "Van Hauwermeiren", + "abbrevName": "Van Hauwermeiren F", + "email": null, + "isCollectiveName": false, + "name": "Filip Van Hauwermeiren", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Vandendriessche", + "abbrevName": "Vandendriessche B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Vandendriessche", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Claude", + "LastName": "Libert", + "abbrevName": "Libert C", + "email": null, + "isCollectiveName": false, + "name": "Claude Libert", + "orcid": null + }, + { + "ForeName": "Anje", + "LastName": "Cauwels", + "abbrevName": "Cauwels A", + "email": null, + "isCollectiveName": false, + "name": "Anje Cauwels", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.immuni.2011.09.020", + "pmid": "22195746", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Immunity 35 2011", + "title": "RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome." + } + }, + { + "pmid": "21471512", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "OBJECTIVE: Most animals experience fasting-feeding cycles throughout their lives. It is well known that the liver plays a central role in regulating glycogen metabolism. However, how hepatic glycogenesis is coordinated with the fasting-feeding cycle to control postprandial glucose homeostasis remains largely unknown. This study determines the molecular mechanism underlying the coupling of hepatic glycogenesis with the fasting-feeding cycle. RESEARCH DESIGN AND METHODS: Through a series of molecular, cellular, and animal studies, we investigated how PPP1R3G, a glycogen-targeting regulatory subunit of protein phosphatase 1 (PP1), is implicated in regulating hepatic glycogenesis and glucose homeostasis in a manner tightly orchestrated with the fasting-feeding cycle. RESULTS: PPP1R3G in the liver is upregulated during fasting and downregulated after feeding. PPP1R3G associates with glycogen pellet, interacts with the catalytic subunit of PP1, and regulates glycogen synthase (GS) activity. Fasting glucose level is reduced when PPP1R3G is overexpressed in the liver. Hepatic knockdown of PPP1R3G reduces postprandial elevation of GS activity, decreases postprandial accumulation of liver glycogen, and decelerates postprandial clearance of blood glucose. Other glycogen-targeting regulatory subunits of PP1, such as PPP1R3B, PPP1R3C, and PPP1R3D, are downregulated by fasting and increased by feeding in the liver. CONCLUSIONS: We propose that the opposite expression pattern of PPP1R3G versus other PP1 regulatory subunits comprise an intricate regulatory machinery to control hepatic glycogenesis during the fasting-feeding cycle. Because of its unique expression pattern, PPP1R3G plays a major role to control postprandial glucose homeostasis during the fasting-feeding transition via its regulation on liver glycogenesis.", + "authors": { + "abbreviation": "Xiaolin Luo, Yongxian Zhang, Xiangbo Ruan, ..., Yan Chen", + "authorList": [ + { + "ForeName": "Xiaolin", + "LastName": "Luo", + "abbrevName": "Luo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolin Luo", + "orcid": null + }, + { + "ForeName": "Yongxian", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yongxian Zhang", + "orcid": null + }, + { + "ForeName": "Xiangbo", + "LastName": "Ruan", + "abbrevName": "Ruan X", + "email": null, + "isCollectiveName": false, + "name": "Xiangbo Ruan", + "orcid": null + }, + { + "ForeName": "Xiaomeng", + "LastName": "Jiang", + "abbrevName": "Jiang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaomeng Jiang", + "orcid": null + }, + { + "ForeName": "Lu", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Lu Zhu", + "orcid": null + }, + { + "ForeName": "Xiao", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiao Wang", + "orcid": null + }, + { + "ForeName": "Qiurong", + "LastName": "Ding", + "abbrevName": "Ding Q", + "email": null, + "isCollectiveName": false, + "name": "Qiurong Ding", + "orcid": null + }, + { + "ForeName": "Weizhong", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Weizhong Liu", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Pan", + "abbrevName": "Pan Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Pan", + "orcid": null + }, + { + "ForeName": "Zhenzhen", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenzhen Wang", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2337/db10-1663", + "pmid": "21471512", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Diabetes 60 2011", + "title": "Fasting-induced protein phosphatase 1 regulatory subunit contributes to postprandial blood glucose homeostasis via regulation of hepatic glycogenesis." + } + }, + { + "pmid": "20005846", + "pubmed": { + "ISODate": "2009-12-11T00:00:00.000Z", + "abstract": "TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, and is required for efficient TNF-induced activation of NF-kappaB and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC.", + "authors": { + "abbreviation": "Tobias L Haas, Christoph H Emmerich, Björn Gerlach, ..., Henning Walczak", + "authorList": [ + { + "ForeName": "Tobias", + "LastName": "Haas", + "abbrevName": "Haas TL", + "email": null, + "isCollectiveName": false, + "name": "Tobias L Haas", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Emmerich", + "abbrevName": "Emmerich CH", + "email": null, + "isCollectiveName": false, + "name": "Christoph H Emmerich", + "orcid": null + }, + { + "ForeName": "Björn", + "LastName": "Gerlach", + "abbrevName": "Gerlach B", + "email": null, + "isCollectiveName": false, + "name": "Björn Gerlach", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Schmukle", + "abbrevName": "Schmukle AC", + "email": null, + "isCollectiveName": false, + "name": "Anna C Schmukle", + "orcid": null + }, + { + "ForeName": "Stefanie", + "LastName": "Cordier", + "abbrevName": "Cordier SM", + "email": null, + "isCollectiveName": false, + "name": "Stefanie M Cordier", + "orcid": null + }, + { + "ForeName": "Eva", + "LastName": "Rieser", + "abbrevName": "Rieser E", + "email": null, + "isCollectiveName": false, + "name": "Eva Rieser", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Vince", + "abbrevName": "Vince J", + "email": null, + "isCollectiveName": false, + "name": "James Vince", + "orcid": null + }, + { + "ForeName": "Uwe", + "LastName": "Warnken", + "abbrevName": "Warnken U", + "email": null, + "isCollectiveName": false, + "name": "Uwe Warnken", + "orcid": null + }, + { + "ForeName": "Till", + "LastName": "Wenger", + "abbrevName": "Wenger T", + "email": null, + "isCollectiveName": false, + "name": "Till Wenger", + "orcid": null + }, + { + "ForeName": "Ronald", + "LastName": "Koschny", + "abbrevName": "Koschny R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Koschny", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Henning", + "LastName": "Walczak", + "abbrevName": "Walczak H", + "email": null, + "isCollectiveName": false, + "name": "Henning Walczak", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2009.10.013", + "pmid": "20005846", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 36 2009", + "title": "Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction." + } + }, + { + "pmid": "19524513", + "pubmed": { + "ISODate": "2009-06-12T00:00:00.000Z", + "abstract": "Programmed necrosis is a form of caspase-independent cell death whose molecular regulation is poorly understood. The kinase RIP1 is crucial for programmed necrosis, but also mediates activation of the prosurvival transcription factor NF-kappaB. We postulated that additional molecules are required to specifically activate programmed necrosis. Using a RNA interference screen, we identified the kinase RIP3 as a crucial activator for programmed necrosis induced by TNF and during virus infection. RIP3 regulates necrosis-specific RIP1 phosphorylation. The phosphorylation of RIP1 and RIP3 stabilizes their association within the pronecrotic complex, activates the pronecrotic kinase activity, and triggers downstream reactive oxygen species production. The pronecrotic RIP1-RIP3 complex is induced during vaccinia virus infection. Consequently, RIP3(-/-) mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. Our findings suggest that RIP3 controls programmed necrosis by initiating the pronecrotic kinase cascade, and that this is necessary for the inflammatory response against virus infections.", + "authors": { + "abbreviation": "Young Sik Cho, Sreerupa Challa, David Moquin, ..., Francis Ka-Ming Chan", + "authorList": [ + { + "ForeName": "Young", + "LastName": "Cho", + "abbrevName": "Cho YS", + "email": null, + "isCollectiveName": false, + "name": "Young Sik Cho", + "orcid": null + }, + { + "ForeName": "Sreerupa", + "LastName": "Challa", + "abbrevName": "Challa S", + "email": null, + "isCollectiveName": false, + "name": "Sreerupa Challa", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moquin", + "abbrevName": "Moquin D", + "email": null, + "isCollectiveName": false, + "name": "David Moquin", + "orcid": null + }, + { + "ForeName": "Ryan", + "LastName": "Genga", + "abbrevName": "Genga R", + "email": null, + "isCollectiveName": false, + "name": "Ryan Genga", + "orcid": null + }, + { + "ForeName": "Tathagat", + "LastName": "Ray", + "abbrevName": "Ray TD", + "email": null, + "isCollectiveName": false, + "name": "Tathagat Dutta Ray", + "orcid": null + }, + { + "ForeName": "Melissa", + "LastName": "Guildford", + "abbrevName": "Guildford M", + "email": null, + "isCollectiveName": false, + "name": "Melissa Guildford", + "orcid": null + }, + { + "ForeName": "Francis", + "LastName": "Chan", + "abbrevName": "Chan FK", + "email": null, + "isCollectiveName": false, + "name": "Francis Ka-Ming Chan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2009.05.037", + "pmid": "19524513", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 137 2009", + "title": "Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation." + } + }, + { + "pmid": "19524512", + "pubmed": { + "ISODate": "2009-06-12T00:00:00.000Z", + "abstract": "Smac mimetics induce apoptosis synergistically with TNF-alpha by triggering the formation of a caspase-8-activating complex containing receptor interacting protein kinase-1 (RIPK1). Caspase inhibitors block this form of apoptosis in many types of cells. However, in several other cell lines, caspase inhibitors switch the apoptotic response to necrosis. A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. The kinase activity of RIP3 is essential for necrosis execution. Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. Embryonic fibroblasts from RIP3 knockout mice are resistant to necrosis and RIP3 knockout animals are devoid of inflammation inflicted tissue damage in an acute pancreatitis model. These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines.", + "authors": { + "abbreviation": "Sudan He, Lai Wang, Lin Miao, ..., Xiaodong Wang", + "authorList": [ + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": null, + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + }, + { + "ForeName": "Lai", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Lai Wang", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Miao", + "abbrevName": "Miao L", + "email": null, + "isCollectiveName": false, + "name": "Lin Miao", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Wang", + "orcid": null + }, + { + "ForeName": "Fenghe", + "LastName": "Du", + "abbrevName": "Du F", + "email": null, + "isCollectiveName": false, + "name": "Fenghe Du", + "orcid": null + }, + { + "ForeName": "Liping", + "LastName": "Zhao", + "abbrevName": "Zhao L", + "email": null, + "isCollectiveName": false, + "name": "Liping Zhao", + "orcid": null + }, + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaodong Wang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2009.05.021", + "pmid": "19524512", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 137 2009", + "title": "Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha." + } + }, + { + "pmid": "19498109", + "pubmed": { + "ISODate": "2009-07-17T00:00:00.000Z", + "abstract": "Necrosis can be induced by stimulating death receptors with tumor necrosis factor (TNF) or other agonists; however, the underlying mechanism differentiating necrosis from apoptosis is largely unknown. We identified the protein kinase receptor-interacting protein 3 (RIP3) as a molecular switch between TNF-induced apoptosis and necrosis in NIH 3T3 cells and found that RIP3 was required for necrosis in other cells. RIP3 did not affect RIP1-mediated apoptosis but was required for RIP1-mediated necrosis and the enhancement of necrosis by the caspase inhibitor zVAD. By activating key enzymes of metabolic pathways, RIP3 regulates TNF-induced reactive oxygen species production, which partially accounts for RIP3's ability to promote necrosis. Our data suggest that modulation of energy metabolism in response to death stimuli has an important role in the choice between apoptosis and necrosis.", + "authors": { + "abbreviation": "Duan-Wu Zhang, Jing Shao, Juan Lin, ..., Jiahuai Han", + "authorList": [ + { + "ForeName": "Duan-Wu", + "LastName": "Zhang", + "abbrevName": "Zhang DW", + "email": null, + "isCollectiveName": false, + "name": "Duan-Wu Zhang", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Shao", + "abbrevName": "Shao J", + "email": null, + "isCollectiveName": false, + "name": "Jing Shao", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Na", + "LastName": "Zhang", + "abbrevName": "Zhang N", + "email": null, + "isCollectiveName": false, + "name": "Na Zhang", + "orcid": null + }, + { + "ForeName": "Bao-Ju", + "LastName": "Lu", + "abbrevName": "Lu BJ", + "email": null, + "isCollectiveName": false, + "name": "Bao-Ju Lu", + "orcid": null + }, + { + "ForeName": "Sheng-Cai", + "LastName": "Lin", + "abbrevName": "Lin SC", + "email": null, + "isCollectiveName": false, + "name": "Sheng-Cai Lin", + "orcid": null + }, + { + "ForeName": "Meng-Qiu", + "LastName": "Dong", + "abbrevName": "Dong MQ", + "email": null, + "isCollectiveName": false, + "name": "Meng-Qiu Dong", + "orcid": null + }, + { + "ForeName": "Jiahuai", + "LastName": "Han", + "abbrevName": "Han J", + "email": null, + "isCollectiveName": false, + "name": "Jiahuai Han", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1172308", + "pmid": "19498109", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Science 325 2009", + "title": "RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis." + } + }, + { + "pmid": "19136968", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Nuclear factor-kappaB (NF-kappaB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-kappaB pathway. We have found that the LUBAC ligase complex, composed of the two RING finger proteins HOIL-1L and HOIP, conjugates a head-to-tail-linked linear polyubiquitin chain to substrates. Here, we demonstrate that LUBAC activates the canonical NF-kappaB pathway by binding to NEMO (NF-kappaB essential modulator, also called IKKgamma) and conjugates linear polyubiquitin chains onto specific Lys residues in the CC2-LZ domain of NEMO in a Ubc13-independent manner. Moreover, in HOIL-1 knockout mice and cells derived from these mice, NF-kappaB signalling induced by pro-inflammatory cytokines such as TNF-alpha and IL-1beta was suppressed, resulting in enhanced TNF-alpha-induced apoptosis in hepatocytes of HOIL-1 knockout mice. These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-kappaB activation pathway through linear polyubiquitylation of NEMO.", + "authors": { + "abbreviation": "Fuminori Tokunaga, Shin-ichi Sakata, Yasushi Saeki, ..., Kazuhiro Iwai", + "authorList": [ + { + "ForeName": "Fuminori", + "LastName": "Tokunaga", + "abbrevName": "Tokunaga F", + "email": null, + "isCollectiveName": false, + "name": "Fuminori Tokunaga", + "orcid": null + }, + { + "ForeName": "Shin-ichi", + "LastName": "Sakata", + "abbrevName": "Sakata S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichi Sakata", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Saeki", + "abbrevName": "Saeki Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Saeki", + "orcid": null + }, + { + "ForeName": "Yoshinori", + "LastName": "Satomi", + "abbrevName": "Satomi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshinori Satomi", + "orcid": null + }, + { + "ForeName": "Takayoshi", + "LastName": "Kirisako", + "abbrevName": "Kirisako T", + "email": null, + "isCollectiveName": false, + "name": "Takayoshi Kirisako", + "orcid": null + }, + { + "ForeName": "Kiyoko", + "LastName": "Kamei", + "abbrevName": "Kamei K", + "email": null, + "isCollectiveName": false, + "name": "Kiyoko Kamei", + "orcid": null + }, + { + "ForeName": "Tomoko", + "LastName": "Nakagawa", + "abbrevName": "Nakagawa T", + "email": null, + "isCollectiveName": false, + "name": "Tomoko Nakagawa", + "orcid": null + }, + { + "ForeName": "Michiko", + "LastName": "Kato", + "abbrevName": "Kato M", + "email": null, + "isCollectiveName": false, + "name": "Michiko Kato", + "orcid": null + }, + { + "ForeName": "Shigeo", + "LastName": "Murata", + "abbrevName": "Murata S", + "email": null, + "isCollectiveName": false, + "name": "Shigeo Murata", + "orcid": null + }, + { + "ForeName": "Shoji", + "LastName": "Yamaoka", + "abbrevName": "Yamaoka S", + "email": null, + "isCollectiveName": false, + "name": "Shoji Yamaoka", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Yamamoto", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Toshifumi", + "LastName": "Takao", + "abbrevName": "Takao T", + "email": null, + "isCollectiveName": false, + "name": "Toshifumi Takao", + "orcid": null + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka", + "orcid": null + }, + { + "ForeName": "Kazuhiro", + "LastName": "Iwai", + "abbrevName": "Iwai K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Iwai", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1821", + "pmid": "19136968", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation." + } + }, + { + "pmid": "18485876", + "pubmed": { + "ISODate": "2008-05-16T00:00:00.000Z", + "abstract": "The inflammatory response of mammalian cells to TNF-alpha can be switched to apoptosis either by cotreatment with a protein synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP.", + "authors": { + "abbreviation": "Lai Wang, Fenghe Du, Xiaodong Wang", + "authorList": [ + { + "ForeName": "Lai", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Lai Wang", + "orcid": null + }, + { + "ForeName": "Fenghe", + "LastName": "Du", + "abbrevName": "Du F", + "email": null, + "isCollectiveName": false, + "name": "Fenghe Du", + "orcid": null + }, + { + "ForeName": "Xiaodong", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaodong Wang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2008.03.036", + "pmid": "18485876", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Cell 133 2008", + "title": "TNF-alpha induces two distinct caspase-8 activation pathways." + } + }, + { + "pmid": "18408713", + "pubmed": { + "ISODate": "2008-05-01T00:00:00.000Z", + "abstract": "Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.", + "authors": { + "abbreviation": "Alexei Degterev, Junichi Hitomi, Megan Germscheid, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": "alexei.degterev@tufts.edu", + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Junichi", + "LastName": "Hitomi", + "abbrevName": "Hitomi J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Hitomi", + "orcid": null + }, + { + "ForeName": "Megan", + "LastName": "Germscheid", + "abbrevName": "Germscheid M", + "email": null, + "isCollectiveName": false, + "name": "Megan Germscheid", + "orcid": null + }, + { + "ForeName": "Irene", + "LastName": "Ch'en", + "abbrevName": "Ch'en IL", + "email": null, + "isCollectiveName": false, + "name": "Irene L Ch'en", + "orcid": null + }, + { + "ForeName": "Olga", + "LastName": "Korkina", + "abbrevName": "Korkina O", + "email": null, + "isCollectiveName": false, + "name": "Olga Korkina", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Teng", + "abbrevName": "Teng X", + "email": null, + "isCollectiveName": false, + "name": "Xin Teng", + "orcid": null + }, + { + "ForeName": "Derek", + "LastName": "Abbott", + "abbrevName": "Abbott D", + "email": null, + "isCollectiveName": false, + "name": "Derek Abbott", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Chengye", + "LastName": "Yuan", + "abbrevName": "Yuan C", + "email": null, + "isCollectiveName": false, + "name": "Chengye Yuan", + "orcid": null + }, + { + "ForeName": "Gerhard", + "LastName": "Wagner", + "abbrevName": "Wagner G", + "email": null, + "isCollectiveName": false, + "name": "Gerhard Wagner", + "orcid": null + }, + { + "ForeName": "Stephen", + "LastName": "Hedrick", + "abbrevName": "Hedrick SM", + "email": null, + "isCollectiveName": false, + "name": "Stephen M Hedrick", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Gerber", + "abbrevName": "Gerber SA", + "email": null, + "isCollectiveName": false, + "name": "Scott A Gerber", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Lugovskoy", + "abbrevName": "Lugovskoy A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Lugovskoy", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alexei", + "LastName": "Degterev", + "email": [ + "alexei.degterev@tufts.edu" + ], + "name": "Alexei Degterev" + } + ] + }, + "doi": "10.1038/nchembio.83", + "pmid": "18408713", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Chem Biol 4 2008", + "title": "Identification of RIP1 kinase as a specific cellular target of necrostatins." + } + }, + { + "pmid": "16603398", + "pubmed": { + "ISODate": "2006-04-21T00:00:00.000Z", + "abstract": "The receptor interacting protein kinase 1 (RIP1) is essential for the activation of nuclear factor kappaB (NF-kappaB) by tumor necrosis factor alpha (TNFalpha). Here, we present evidence that TNFalpha induces the polyubiquitination of RIP1 at Lys-377 and that this polyubiquitination is required for the activation of IkappaB kinase (IKK) and NF-kappaB. A point mutation of RIP1 at Lys-377 (K377R) abolishes its polyubiquitination as well as its ability to restore IKK activation in a RIP1-deficient cell line. The K377R mutation of RIP1 also prevents the recruitment of TAK1 and IKK complexes to TNF receptor. Interestingly, polyubiquitinated RIP1 recruits IKK through the binding between the polyubiquitin chains and NEMO, a regulatory subunit of the IKK complex. Mutations of NEMO that disrupt its polyubiquitin binding also abolish IKK activation. These results reveal the biochemical mechanism underlying the essential signaling function of NEMO and provide direct evidence that signal-induced site-specific ubiquitination of RIP1 is required for IKK activation.", + "authors": { + "abbreviation": "Chee-Kwee Ea, Li Deng, Zong-Ping Xia, ..., Zhijian J Chen", + "authorList": [ + { + "ForeName": "Chee-Kwee", + "LastName": "Ea", + "abbrevName": "Ea CK", + "email": null, + "isCollectiveName": false, + "name": "Chee-Kwee Ea", + "orcid": null + }, + { + "ForeName": "Li", + "LastName": "Deng", + "abbrevName": "Deng L", + "email": null, + "isCollectiveName": false, + "name": "Li Deng", + "orcid": null + }, + { + "ForeName": "Zong-Ping", + "LastName": "Xia", + "abbrevName": "Xia ZP", + "email": null, + "isCollectiveName": false, + "name": "Zong-Ping Xia", + "orcid": null + }, + { + "ForeName": "Gabriel", + "LastName": "Pineda", + "abbrevName": "Pineda G", + "email": null, + "isCollectiveName": false, + "name": "Gabriel Pineda", + "orcid": null + }, + { + "ForeName": "Zhijian", + "LastName": "Chen", + "abbrevName": "Chen ZJ", + "email": null, + "isCollectiveName": false, + "name": "Zhijian J Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2006.03.026", + "pmid": "16603398", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 22 2006", + "title": "Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO." + } + }, + { + "pmid": "15752363", + "pubmed": { + "ISODate": "2005-03-01T00:00:00.000Z", + "abstract": "Stimulation of glycogen-targeted protein phosphatase 1 (PP1) activity by insulin contributes to the dephosphorylation and activation of hepatic glycogen synthase (GS) leading to an increase in glycogen synthesis. The glycogen-targeting subunits of PP1, GL and R5/PTG, are downregulated in the livers of diabetic rodents and restored by insulin treatment. We show here that the mammalian gene PPP1R3E encodes a novel glycogen-targeting subunit of PP1 that is expressed in rodent liver. The phosphatase activity associated with R3E is slightly higher than that associated with R5/PTG and it is downregulated in streptozotocin-induced diabetes by 60-70% and restored by insulin treatment. Surprisingly, although mRNA for R3E is most highly expressed in rat liver and heart muscle, with only low levels in skeletal muscle, R3E mRNA is most abundant in human skeletal muscle and heart tissues with barely detectable levels in human liver. This species-specific difference in R3E mRNA expression has similarities to the high level of expression of GL mRNA in human but not rodent skeletal muscle. The observations imply that the mechanisms by which insulin regulates glycogen synthesis in liver and skeletal muscle are different in rodents and humans.", + "authors": { + "abbreviation": "Shonagh Munro, Hugo Ceulemans, Mathieu Bollen, ..., Patricia T W Cohen", + "authorList": [ + { + "ForeName": "Shonagh", + "LastName": "Munro", + "abbrevName": "Munro S", + "email": null, + "isCollectiveName": false, + "name": "Shonagh Munro", + "orcid": null + }, + { + "ForeName": "Hugo", + "LastName": "Ceulemans", + "abbrevName": "Ceulemans H", + "email": null, + "isCollectiveName": false, + "name": "Hugo Ceulemans", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bollen", + "abbrevName": "Bollen M", + "email": null, + "isCollectiveName": false, + "name": "Mathieu Bollen", + "orcid": null + }, + { + "ForeName": "Julie", + "LastName": "Diplexcito", + "abbrevName": "Diplexcito J", + "email": null, + "isCollectiveName": false, + "name": "Julie Diplexcito", + "orcid": null + }, + { + "ForeName": "Patricia", + "LastName": "Cohen", + "abbrevName": "Cohen PT", + "email": null, + "isCollectiveName": false, + "name": "Patricia T W Cohen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1742-4658.2005.04585.x", + "pmid": "15752363", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 272 2005", + "title": "A novel glycogen-targeting subunit of protein phosphatase 1 that is regulated by insulin and shows differential tissue distribution in humans and rodents." + } + }, + { + "pmid": "15327770", + "pubmed": { + "ISODate": "2004-08-27T00:00:00.000Z", + "abstract": "The activation of NF-kappaB and IKK requires an upstream kinase complex consisting of TAK1 and adaptor proteins such as TAB1, TAB2, or TAB3. TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains. Here we present evidence that TAB2 and TAB3 are receptors that bind preferentially to lysine 63-linked polyubiquitin chains through a highly conserved zinc finger (ZnF) domain. Mutations of the ZnF domain abolish the ability of TAB2 and TAB3 to bind polyubiquitin chains, as well as their ability to activate TAK1 and IKK. Significantly, replacement of the ZnF domain with a heterologous ubiquitin binding domain restored the ability of TAB2 and TAB3 to activate TAK1 and IKK. We also show that TAB2 binds to polyubiquitinated RIP following TNFalpha stimulation. These results indicate that polyubiquitin binding domains represent a new class of signaling domains that regulate protein kinase activity through a nonproteolytic mechanism.", + "authors": { + "abbreviation": "Atsuhiro Kanayama, Rashu B Seth, Lijun Sun, ..., Zhijian J Chen", + "authorList": [ + { + "ForeName": "Atsuhiro", + "LastName": "Kanayama", + "abbrevName": "Kanayama A", + "email": null, + "isCollectiveName": false, + "name": "Atsuhiro Kanayama", + "orcid": null + }, + { + "ForeName": "Rashu", + "LastName": "Seth", + "abbrevName": "Seth RB", + "email": null, + "isCollectiveName": false, + "name": "Rashu B Seth", + "orcid": null + }, + { + "ForeName": "Lijun", + "LastName": "Sun", + "abbrevName": "Sun L", + "email": null, + "isCollectiveName": false, + "name": "Lijun Sun", + "orcid": null + }, + { + "ForeName": "Chee-Kwee", + "LastName": "Ea", + "abbrevName": "Ea CK", + "email": null, + "isCollectiveName": false, + "name": "Chee-Kwee Ea", + "orcid": null + }, + { + "ForeName": "Mei", + "LastName": "Hong", + "abbrevName": "Hong M", + "email": null, + "isCollectiveName": false, + "name": "Mei Hong", + "orcid": null + }, + { + "ForeName": "Abdullah", + "LastName": "Shaito", + "abbrevName": "Shaito A", + "email": null, + "isCollectiveName": false, + "name": "Abdullah Shaito", + "orcid": null + }, + { + "ForeName": "Yu-Hsin", + "LastName": "Chiu", + "abbrevName": "Chiu YH", + "email": null, + "isCollectiveName": false, + "name": "Yu-Hsin Chiu", + "orcid": null + }, + { + "ForeName": "Li", + "LastName": "Deng", + "abbrevName": "Deng L", + "email": null, + "isCollectiveName": false, + "name": "Li Deng", + "orcid": null + }, + { + "ForeName": "Zhijian", + "LastName": "Chen", + "abbrevName": "Chen ZJ", + "email": null, + "isCollectiveName": false, + "name": "Zhijian J Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.molcel.2004.08.008", + "pmid": "15327770", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Cell 15 2004", + "title": "TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains." + } + }, + { + "pmid": "12887920", + "pubmed": { + "ISODate": "2003-07-25T00:00:00.000Z", + "abstract": "Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.", + "authors": { + "abbreviation": "Olivier Micheau, Jürg Tschopp", + "authorList": [ + { + "ForeName": "Olivier", + "LastName": "Micheau", + "abbrevName": "Micheau O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Micheau", + "orcid": null + }, + { + "ForeName": "Jürg", + "LastName": "Tschopp", + "abbrevName": "Tschopp J", + "email": null, + "isCollectiveName": false, + "name": "Jürg Tschopp", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/s0092-8674(03)00521-x", + "pmid": "12887920", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 114 2003", + "title": "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes." + } + }, + { + "pmid": "12040173", + "pubmed": { + "ISODate": "2002-05-31T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The interaction of TNF with TNF receptor-1 (TNF-R1) activates several signal transduction pathways. A common feature of each pathway is the TNF-induced formation of a multiprotein signaling complex at the cell membrane. Over the past decade, many of the components and mechanisms of these signaling pathways have been elucidated. We provide an overview of current knowledge of TNF signaling and introduce an STKE Connections Map that depicts a canonical view of this process.", + "authors": { + "abbreviation": "Guoqing Chen, David V Goeddel", + "authorList": [ + { + "ForeName": "Guoqing", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "goeddel@tularik.com", + "isCollectiveName": false, + "name": "Guoqing Chen", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Goeddel", + "abbrevName": "Goeddel DV", + "email": null, + "isCollectiveName": false, + "name": "David V Goeddel", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Guoqing", + "LastName": "Chen", + "email": [ + "goeddel@tularik.com" + ], + "name": "Guoqing Chen" + } + ] + }, + "doi": "10.1126/science.1071924", + "pmid": "12040173", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Science 296 2002", + "title": "TNF-R1 signaling: a beautiful pathway." + } + }, + { + "pmid": "11839776", + "pubmed": { + "ISODate": "2002-01-15T00:00:00.000Z", + "abstract": "Protein phosphatase 1 (PP1) is a major eukaryotic protein serine/threonine phosphatase that regulates an enormous variety of cellular functions through the interaction of its catalytic subunit (PP1c) with over fifty different established or putative regulatory subunits. Most of these target PP1c to specific subcellular locations and interact with a small hydrophobic groove on the surface of PP1c through a short conserved binding motif--the RVxF motif--which is often preceded by further basic residues. Weaker interactions may subsequently enhance binding and modulate PP1 activity/specificity in a variety of ways. Several putative targeting subunits do not possess an RVxF motif but nevertheless interact with the same region of PP1c. In addition, several 'modulator' proteins bind to PP1c but do not possess a domain targeting them to a specific location. Most are potent inhibitors of PP1c and possess at least two sites for interaction with PP1c, one of which is identical or similar to the RVxF motif. Regulation of PP1c in response to extracellular and intracellular signals occurs mostly through changes in the levels, conformation or phosphorylation status of targeting subunits. Understanding of the mode of action of PP1c complexes may facilitate development of drugs that target particular PP1c complexes and thereby modulate the phosphorylation state of a very limited subset of proteins.", + "authors": { + "abbreviation": "Patricia T W Cohen", + "authorList": [ + { + "ForeName": "Patricia", + "LastName": "Cohen", + "abbrevName": "Cohen PT", + "email": "p.t.w.cohen@dundee.ac.uk", + "isCollectiveName": false, + "name": "Patricia T W Cohen", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Patricia", + "LastName": "Cohen", + "email": [ + "p.t.w.cohen@dundee.ac.uk" + ], + "name": "Patricia T W Cohen" + } + ] + }, + "doi": "10.1242/jcs.115.2.241", + "pmid": "11839776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 115 2002", + "title": "Protein phosphatase 1--targeted in many directions." + } + }, + { + "pmid": "11460167", + "pubmed": { + "ISODate": "2001-07-19T00:00:00.000Z", + "abstract": "TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.", + "authors": { + "abbreviation": "C Wang, L Deng, M Hong, ..., Z J Chen", + "authorList": [ + { + "ForeName": "C", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "C Wang", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Deng", + "abbrevName": "Deng L", + "email": null, + "isCollectiveName": false, + "name": "L Deng", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hong", + "abbrevName": "Hong M", + "email": null, + "isCollectiveName": false, + "name": "M Hong", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Akkaraju", + "abbrevName": "Akkaraju GR", + "email": null, + "isCollectiveName": false, + "name": "G R Akkaraju", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Inoue", + "abbrevName": "Inoue J", + "email": null, + "isCollectiveName": false, + "name": "J Inoue", + "orcid": null + }, + { + "ForeName": "Z", + "LastName": "Chen", + "abbrevName": "Chen ZJ", + "email": null, + "isCollectiveName": false, + "name": "Z J Chen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/35085597", + "pmid": "11460167", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 412 2001", + "title": "TAK1 is a ubiquitin-dependent kinase of MKK and IKK." + } + }, + { + "pmid": "9721089", + "pubmed": { + "ISODate": "1998-08-28T00:00:00.000Z", + "abstract": "Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.", + "authors": { + "abbreviation": "A Ashkenazi, V M Dixit", + "authorList": [ + { + "ForeName": "A", + "LastName": "Ashkenazi", + "abbrevName": "Ashkenazi A", + "email": "aa@gene.com", + "isCollectiveName": false, + "name": "A Ashkenazi", + "orcid": null + }, + { + "ForeName": "V", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "V M Dixit", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "A", + "LastName": "Ashkenazi", + "email": [ + "aa@gene.com" + ], + "name": "A Ashkenazi" + } + ] + }, + "doi": "10.1126/science.281.5381.1305", + "pmid": "9721089", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Science 281 1998", + "title": "Death receptors: signaling and modulation." + } + }, + { + "pmid": "9155014", + "pubmed": { + "ISODate": "1997-04-15T00:00:00.000Z", + "abstract": "The diverse forms of protein phosphatase 1 in vivo result from the association of its catalytic subunit (PP1c) with different regulatory subunits, one of which is the G-subunit (G(M)) that targets PP1c to glycogen particles in muscle. Here we report the structure, at 3.0 A resolution, of PP1c in complex with a 13 residue peptide (G(M[63-75])) of G(M). The residues in G(M[63-75]) that interact with PP1c are those in the Arg/Lys-Val/Ile-Xaa-Phe motif that is present in almost every other identified mammalian PP1-binding subunit. Disrupting this motif in the G(M[63-75]) peptide and the M(110[1-38]) peptide (which mimics the myofibrillar targeting M110 subunit in stimulating the dephosphorylation of myosin) prevents these peptides from interacting with PP1. A short peptide from the PP1-binding protein p53BP2 that contains the RVXF motif also interacts with PP1c. These findings identify a recognition site on PP1c, invariant from yeast to humans, for a critical structural motif on regulatory subunits. This explains why the binding of PP1 to its regulatory subunits is mutually exclusive, and suggests a novel approach for identifying the functions of PP1-binding proteins whose roles are unknown.", + "authors": { + "abbreviation": "M P Egloff, D F Johnson, G Moorhead, ..., D Barford", + "authorList": [ + { + "ForeName": "M", + "LastName": "Egloff", + "abbrevName": "Egloff MP", + "email": null, + "isCollectiveName": false, + "name": "M P Egloff", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Johnson", + "abbrevName": "Johnson DF", + "email": null, + "isCollectiveName": false, + "name": "D F Johnson", + "orcid": null + }, + { + "ForeName": "G", + "LastName": "Moorhead", + "abbrevName": "Moorhead G", + "email": null, + "isCollectiveName": false, + "name": "G Moorhead", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Cohen", + "abbrevName": "Cohen PT", + "email": null, + "isCollectiveName": false, + "name": "P T Cohen", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Cohen", + "abbrevName": "Cohen P", + "email": null, + "isCollectiveName": false, + "name": "P Cohen", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Barford", + "abbrevName": "Barford D", + "email": null, + "isCollectiveName": false, + "name": "D Barford", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/16.8.1876", + "pmid": "9155014", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 16 1997", + "title": "Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1." + } + }, + { + "pmid": "3764421", + "pubmed": { + "ISODate": "1986-10-24T00:00:00.000Z", + "abstract": "Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.", + "authors": { + "abbreviation": "K J Tracey, B Beutler, S F Lowry, ..., J D Albert", + "authorList": [ + { + "ForeName": "K", + "LastName": "Tracey", + "abbrevName": "Tracey KJ", + "email": null, + "isCollectiveName": false, + "name": "K J Tracey", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Beutler", + "abbrevName": "Beutler B", + "email": null, + "isCollectiveName": false, + "name": "B Beutler", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Lowry", + "abbrevName": "Lowry SF", + "email": null, + "isCollectiveName": false, + "name": "S F Lowry", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Merryweather", + "abbrevName": "Merryweather J", + "email": null, + "isCollectiveName": false, + "name": "J Merryweather", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Wolpe", + "abbrevName": "Wolpe S", + "email": null, + "isCollectiveName": false, + "name": "S Wolpe", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Milsark", + "abbrevName": "Milsark IW", + "email": null, + "isCollectiveName": false, + "name": "I W Milsark", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Hariri", + "abbrevName": "Hariri RJ", + "email": null, + "isCollectiveName": false, + "name": "R J Hariri", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Fahey", + "abbrevName": "Fahey TJ", + "email": null, + "isCollectiveName": false, + "name": "T J Fahey", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Zentella", + "abbrevName": "Zentella A", + "email": null, + "isCollectiveName": false, + "name": "A Zentella", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Albert", + "abbrevName": "Albert JD", + "email": null, + "isCollectiveName": false, + "name": "J D Albert", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.3764421", + "pmid": "3764421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Science 234 1986", + "title": "Shock and tissue injury induced by recombinant human cachectin." + } + } + ], + "relatedPapers": [ + { + "pmid": "27819681", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.", + "authors": { + "abbreviation": "Juan Lin, Snehlata Kumari, Chun Kim, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20558", + "pmid": "27819681", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation." + } + }, + { + "pmid": "27258786", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.", + "authors": { + "abbreviation": "B Shutinoski, N A Alturki, D Rijal, ..., S Sad", + "authorList": [ + { + "ForeName": "B", + "LastName": "Shutinoski", + "abbrevName": "Shutinoski B", + "email": null, + "isCollectiveName": false, + "name": "B Shutinoski", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Alturki", + "abbrevName": "Alturki NA", + "email": null, + "isCollectiveName": false, + "name": "N A Alturki", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rijal", + "abbrevName": "Rijal D", + "email": null, + "isCollectiveName": false, + "name": "D Rijal", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "J Bertin", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Gough", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Schlossmacher", + "abbrevName": "Schlossmacher MG", + "email": null, + "isCollectiveName": false, + "name": "M G Schlossmacher", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sad", + "abbrevName": "Sad S", + "email": null, + "isCollectiveName": false, + "name": "S Sad", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.51", + "pmid": "27258786", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo." + } + }, + { + "pmid": "25132550", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.", + "authors": { + "abbreviation": "Marius Dannappel, Katerina Vlantis, Snehlata Kumari, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Marius", + "LastName": "Dannappel", + "abbrevName": "Dannappel M", + "email": null, + "isCollectiveName": false, + "name": "Marius Dannappel", + "orcid": null + }, + { + "ForeName": "Katerina", + "LastName": "Vlantis", + "abbrevName": "Vlantis K", + "email": null, + "isCollectiveName": false, + "name": "Katerina Vlantis", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Eftychi", + "abbrevName": "Eftychi C", + "email": null, + "isCollectiveName": false, + "name": "Christina Eftychi", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Hermance", + "abbrevName": "Hermance N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Hermance", + "orcid": null + }, + { + "ForeName": "Matija", + "LastName": "Zelic", + "abbrevName": "Zelic M", + "email": null, + "isCollectiveName": false, + "name": "Matija Zelic", + "orcid": null + }, + { + "ForeName": "Petra", + "LastName": "Kirsch", + "abbrevName": "Kirsch P", + "email": null, + "isCollectiveName": false, + "name": "Petra Kirsch", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "Andre", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "Andre Bleich", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Kelliher", + "abbrevName": "Kelliher M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Kelliher", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13608", + "pmid": "25132550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis." + } + }, + { + "pmid": "33311474", + "pubmed": { + "ISODate": "2020-12-11T00:00:00.000Z", + "abstract": "RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.", + "authors": { + "abbreviation": "Xingyan Li, Mengmeng Zhang, Xinyue Huang, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Mengmeng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mengmeng Zhang", + "orcid": null + }, + { + "ForeName": "Xinyue", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xinyue Huang", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Liang", + "abbrevName": "Liang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liang", + "orcid": null + }, + { + "ForeName": "Ganquan", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Ganquan Li", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": "shanbing@sioc.ac.cn", + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "email": [ + "shanbing@sioc.ac.cn" + ], + "name": "Bing Shan" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-020-19935-y", + "pmid": "33311474", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + }, + { + "pmid": "30867408", + "pubmed": { + "ISODate": "2019-03-13T00:00:00.000Z", + "abstract": "RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.", + "authors": { + "abbreviation": "Xuhua Zhang, John P Dowling, Jianke Zhang", + "authorList": [ + { + "ForeName": "Xuhua", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xuhua Zhang", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Dowling", + "abbrevName": "Dowling JP", + "email": null, + "isCollectiveName": false, + "name": "John P Dowling", + "orcid": null + }, + { + "ForeName": "Jianke", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "jianke.zhang@jefferson.edu", + "isCollectiveName": false, + "name": "Jianke Zhang", + "orcid": "0000-0001-9880-8435" + } + ], + "contacts": [ + { + "ForeName": "Jianke", + "LastName": "Zhang", + "email": [ + "jianke.zhang@jefferson.edu" + ], + "name": "Jianke Zhang" + } + ] + }, + "doi": "10.1038/s41419-019-1490-8", + "pmid": "30867408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + }, + { + "pmid": "31235688", + "pubmed": { + "ISODate": "2019-06-24T00:00:00.000Z", + "abstract": "Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.", + "authors": { + "abbreviation": "Jue Hou, Jie Ju, Zili Zhang, ..., Sudan He", + "authorList": [ + { + "ForeName": "Jue", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jue Hou", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Ju", + "abbrevName": "Ju J", + "email": null, + "isCollectiveName": false, + "name": "Jie Ju", + "orcid": null + }, + { + "ForeName": "Zili", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zili Zhang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhao", + "abbrevName": "Zhao C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhao", + "orcid": null + }, + { + "ForeName": "Zhanhui", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhanhui Li", + "orcid": null + }, + { + "ForeName": "Jiyue", + "LastName": "Zheng", + "abbrevName": "Zheng J", + "email": null, + "isCollectiveName": false, + "name": "Jiyue Zheng", + "orcid": null + }, + { + "ForeName": "Tian", + "LastName": "Sheng", + "abbrevName": "Sheng T", + "email": null, + "isCollectiveName": false, + "name": "Tian Sheng", + "orcid": null + }, + { + "ForeName": "Hongjian", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hongjian Zhang", + "orcid": null + }, + { + "ForeName": "Linkun", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Linkun Hu", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Yu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhang", + "orcid": null + }, + { + "ForeName": "Yangxin", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yangxin Li", + "orcid": null + }, + { + "ForeName": "Meng", + "LastName": "Wu", + "abbrevName": "Wu M", + "email": null, + "isCollectiveName": false, + "name": "Meng Wu", + "orcid": null + }, + { + "ForeName": "Haikuo", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": "mahaikuo123@163.com", + "isCollectiveName": false, + "name": "Haikuo Ma", + "orcid": null + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": "xiaohuzhang@suda.edu.cn", + "isCollectiveName": false, + "name": "Xiaohu Zhang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan2018@163.com", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Haikuo", + "LastName": "Ma", + "email": [ + "mahaikuo123@163.com" + ], + "name": "Haikuo Ma" + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "email": [ + "xiaohuzhang@suda.edu.cn" + ], + "name": "Xiaohu Zhang" + }, + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan2018@163.com" + ], + "name": "Sudan He" + } + ] + }, + "doi": "10.1038/s41419-019-1735-6", + "pmid": "31235688", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis." + } + }, + { + "pmid": "34990405", + "pubmed": { + "ISODate": "2022-02-15T00:00:00.000Z", + "abstract": "Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.", + "authors": { + "abbreviation": "Haifeng Yin, Xiaoyun Guo, Yi Chen, ..., Qinghang Liu", + "authorList": [ + { + "ForeName": "Haifeng", + "LastName": "Yin", + "abbrevName": "Yin H", + "email": null, + "isCollectiveName": false, + "name": "Haifeng Yin", + "orcid": null + }, + { + "ForeName": "Xiaoyun", + "LastName": "Guo", + "abbrevName": "Guo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyun Guo", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Chen", + "orcid": null + }, + { + "ForeName": "Yachang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yachang Zeng", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Mo", + "abbrevName": "Mo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Mo", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Hong", + "abbrevName": "Hong S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Hong", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Hui He", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jing Li", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Steinmetz", + "orcid": null + }, + { + "ForeName": "Qinghang", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI152297", + "pmid": "34990405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 132 2022", + "title": "TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis." + } + }, + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "23727581", + "pubmed": { + "ISODate": "2013-06-28T00:00:00.000Z", + "abstract": "While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.", + "authors": { + "abbreviation": "Ryodai Shindo, Hidenao Kakehashi, Ko Okumura, ..., Hiroyasu Nakano", + "authorList": [ + { + "ForeName": "Ryodai", + "LastName": "Shindo", + "abbrevName": "Shindo R", + "email": null, + "isCollectiveName": false, + "name": "Ryodai Shindo", + "orcid": null + }, + { + "ForeName": "Hidenao", + "LastName": "Kakehashi", + "abbrevName": "Kakehashi H", + "email": null, + "isCollectiveName": false, + "name": "Hidenao Kakehashi", + "orcid": null + }, + { + "ForeName": "Ko", + "LastName": "Okumura", + "abbrevName": "Okumura K", + "email": null, + "isCollectiveName": false, + "name": "Ko Okumura", + "orcid": null + }, + { + "ForeName": "Yoshito", + "LastName": "Kumagai", + "abbrevName": "Kumagai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshito Kumagai", + "orcid": null + }, + { + "ForeName": "Hiroyasu", + "LastName": "Nakano", + "abbrevName": "Nakano H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyasu Nakano", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2013.05.075", + "pmid": "23727581", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 436 2013", + "title": "Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation." + } + }, + { + "pmid": "29440439", + "pubmed": { + "ISODate": "2018-02-27T00:00:00.000Z", + "abstract": "RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFα-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.", + "authors": { + "abbreviation": "Huyan Meng, Zhen Liu, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Liu", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Guowei", + "LastName": "Wu", + "abbrevName": "Wu G", + "email": null, + "isCollectiveName": false, + "name": "Guowei Wu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Christofferson", + "abbrevName": "Christofferson DE", + "email": null, + "isCollectiveName": false, + "name": "Dana E Christofferson", + "orcid": null + }, + { + "ForeName": "Chunting", + "LastName": "Qi", + "abbrevName": "Qi C", + "email": null, + "isCollectiveName": false, + "name": "Chunting Qi", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Yu", + "abbrevName": "Yu Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Yu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Ying", + "LastName": "Li", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Ying Li" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1722013115", + "pmid": "29440439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis." + } + }, + { + "pmid": "25195660", + "pubmed": { + "ISODate": "2014-11-01T00:00:00.000Z", + "abstract": "Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.", + "authors": { + "abbreviation": "Conor J Kearney, Sean P Cullen, Danielle Clancy, Seamus J Martin", + "authorList": [ + { + "ForeName": "Conor", + "LastName": "Kearney", + "abbrevName": "Kearney CJ", + "email": null, + "isCollectiveName": false, + "name": "Conor J Kearney", + "orcid": null + }, + { + "ForeName": "Sean", + "LastName": "Cullen", + "abbrevName": "Cullen SP", + "email": null, + "isCollectiveName": false, + "name": "Sean P Cullen", + "orcid": null + }, + { + "ForeName": "Danielle", + "LastName": "Clancy", + "abbrevName": "Clancy D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Clancy", + "orcid": null + }, + { + "ForeName": "Seamus", + "LastName": "Martin", + "abbrevName": "Martin SJ", + "email": null, + "isCollectiveName": false, + "name": "Seamus J Martin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/febs.13034", + "pmid": "25195660", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 281 2014", + "title": "RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "33858959", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.", + "authors": { + "abbreviation": "Snehlata Kumari, Trieu-My Van, Daniela Preukschat, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": "s.kumari@uq.edu.au", + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Preukschat", + "abbrevName": "Preukschat D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Preukschat", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schuenke", + "abbrevName": "Schuenke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schuenke", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "André", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "André Bleich", + "orcid": null + }, + { + "ForeName": "Ulf", + "LastName": "Klein", + "abbrevName": "Klein U", + "email": null, + "isCollectiveName": false, + "name": "Ulf Klein", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "email": [ + "s.kumari@uq.edu.au" + ], + "name": "Snehlata Kumari" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.26508/lsa.202000956", + "pmid": "33858959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Life Sci Alliance 4 2021", + "title": "NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation." + } + }, + { + "pmid": "34262020", + "pubmed": { + "ISODate": "2021-07-14T00:00:00.000Z", + "abstract": "Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.", + "authors": { + "abbreviation": "Tom Delanghe, Jon Huyghe, Seungheon Lee, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Huyghe", + "abbrevName": "Huyghe J", + "email": null, + "isCollectiveName": false, + "name": "Jon Huyghe", + "orcid": null + }, + { + "ForeName": "Seungheon", + "LastName": "Lee", + "abbrevName": "Lee S", + "email": null, + "isCollectiveName": false, + "name": "Seungheon Lee", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": "0000-0002-2527-1101" + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41419-021-03994-0", + "pmid": "34262020", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor." + } + }, + { + "pmid": "31028177", + "pubmed": { + "ISODate": "2019-05-20T00:00:00.000Z", + "abstract": "Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.", + "authors": { + "abbreviation": "Zicheng Wang, Jiannan Feng, Jiyun Yu, Guozhu Chen", + "authorList": [ + { + "ForeName": "Zicheng", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zicheng Wang", + "orcid": "0000-0003-2648-8289" + }, + { + "ForeName": "Jiannan", + "LastName": "Feng", + "abbrevName": "Feng J", + "email": null, + "isCollectiveName": false, + "name": "Jiannan Feng", + "orcid": null + }, + { + "ForeName": "Jiyun", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jiyun Yu", + "orcid": "0000-0003-3475-1956" + }, + { + "ForeName": "Guozhu", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "chenguozhu2002@126.com", + "isCollectiveName": false, + "name": "Guozhu Chen", + "orcid": "0000-0002-6067-8150" + } + ], + "contacts": [ + { + "ForeName": "Guozhu", + "LastName": "Chen", + "email": [ + "chenguozhu2002@126.com" + ], + "name": "Guozhu Chen" + } + ] + }, + "doi": "10.1242/jcs.227777", + "pmid": "31028177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation." + } + }, + { + "pmid": "27605011", + "pubmed": { + "ISODate": "2016-10-15T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-κB activation in terms of IκBα phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1D138N) mice did not exacerbate αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.", + "authors": { + "abbreviation": "Jo Suda, Lily Dara, Luoluo Yang, ..., Zhang-Xu Liu", + "authorList": [ + { + "ForeName": "Jo", + "LastName": "Suda", + "abbrevName": "Suda J", + "email": null, + "isCollectiveName": false, + "name": "Jo Suda", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Dara", + "abbrevName": "Dara L", + "email": null, + "isCollectiveName": false, + "name": "Lily Dara", + "orcid": "0000-0002-0121-7186" + }, + { + "ForeName": "Luoluo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Luoluo Yang", + "orcid": "0000-0001-8099-9982" + }, + { + "ForeName": "Mariam", + "LastName": "Aghajan", + "abbrevName": "Aghajan M", + "email": null, + "isCollectiveName": false, + "name": "Mariam Aghajan", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Song", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Kaplowitz", + "abbrevName": "Kaplowitz N", + "email": null, + "isCollectiveName": false, + "name": "Neil Kaplowitz", + "orcid": "0000-0002-9424-393X" + }, + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "abbrevName": "Liu ZX", + "email": "zxliu@usc.edu", + "isCollectiveName": false, + "name": "Zhang-Xu Liu", + "orcid": "0000-0001-7290-3506" + } + ], + "contacts": [ + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "email": [ + "zxliu@usc.edu" + ], + "name": "Zhang-Xu Liu" + } + ] + }, + "doi": "10.4049/jimmunol.1600690", + "pmid": "27605011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Immunol 197 2016", + "title": "Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB." + } + }, + { + "pmid": "36329033", + "pubmed": { + "ISODate": "2022-11-03T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.", + "authors": { + "abbreviation": "Hailin Tu, Weihang Xiong, Jie Zhang, ..., Xin Lin", + "authorList": [ + { + "ForeName": "Hailin", + "LastName": "Tu", + "abbrevName": "Tu H", + "email": null, + "isCollectiveName": false, + "name": "Hailin Tu", + "orcid": null + }, + { + "ForeName": "Weihang", + "LastName": "Xiong", + "abbrevName": "Xiong W", + "email": null, + "isCollectiveName": false, + "name": "Weihang Xiong", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Xueqiang", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xueqiang Zhao", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": "linxin307@tsinghua.edu.cn", + "isCollectiveName": false, + "name": "Xin Lin", + "orcid": "0000-0003-0956-3654" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Lin", + "email": [ + "linxin307@tsinghua.edu.cn" + ], + "name": "Xin Lin" + } + ] + }, + "doi": "10.1038/s41467-022-34080-4", + "pmid": "36329033", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Commun 13 2022", + "title": "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation." + } + }, + { + "pmid": "22362767", + "pubmed": { + "ISODate": "2012-04-27T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).", + "authors": { + "abbreviation": "Linde Duprez, Mathieu J M Bertrand, Tom Vanden Berghe, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Nele", + "LastName": "Festjens", + "abbrevName": "Festjens N", + "email": null, + "isCollectiveName": false, + "name": "Nele Festjens", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.288670", + "pmid": "22362767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "29078411", + "pubmed": { + "ISODate": "2017-11-07T00:00:00.000Z", + "abstract": "Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.", + "authors": { + "abbreviation": "Huibing Wang, Huyan Meng, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Kezhou", + "LastName": "Zhu", + "abbrevName": "Zhu K", + "email": null, + "isCollectiveName": false, + "name": "Kezhou Zhu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan K Mookhtiar", + "orcid": null + }, + { + "ForeName": "Huiting", + "LastName": "Wei", + "abbrevName": "Wei H", + "email": null, + "isCollectiveName": false, + "name": "Huiting Wei", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Shao-Cong", + "LastName": "Sun", + "abbrevName": "Sun SC", + "email": null, + "isCollectiveName": false, + "name": "Shao-Cong Sun", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1715742114", + "pmid": "29078411", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP." + } + }, + { + "pmid": "28701375", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.", + "authors": { + "abbreviation": "Ran Wei, Lily Wen Xu, Jianping Liu, ..., Heling Pan", + "authorList": [ + { + "ForeName": "Ran", + "LastName": "Wei", + "abbrevName": "Wei R", + "email": null, + "isCollectiveName": false, + "name": "Ran Wei", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Xu", + "abbrevName": "Xu LW", + "email": null, + "isCollectiveName": false, + "name": "Lily Wen Xu", + "orcid": null + }, + { + "ForeName": "Jianping", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Liu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Pei", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Zhang", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.299776.117", + "pmid": "28701375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genes Dev 31 2017", + "title": "SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "34813352", + "pubmed": { + "ISODate": "2021-11-23T00:00:00.000Z", + "abstract": "The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.", + "authors": { + "abbreviation": "Daichao Xu, Chengyu Zou, Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Daichao Xu" + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Chengyu Zou" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1146/annurev-genet-071719-022748", + "pmid": "34813352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Genet 55 2021", + "title": "Genetic Regulation of RIPK1 and Necroptosis." + } + }, + { + "pmid": "25186904", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.", + "authors": { + "abbreviation": "Nozomi Takahashi, Lars Vereecke, Mathieu J M Bertrand, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Lars", + "LastName": "Vereecke", + "abbrevName": "Vereecke L", + "email": null, + "isCollectiveName": false, + "name": "Lars Vereecke", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Berger", + "abbrevName": "Berger SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Berger", + "orcid": null + }, + { + "ForeName": "Tatyana", + "LastName": "Divert", + "abbrevName": "Divert T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Divert", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Gonçalves", + "orcid": null + }, + { + "ForeName": "Mozes", + "LastName": "Sze", + "abbrevName": "Sze M", + "email": null, + "isCollectiveName": false, + "name": "Mozes Sze", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Stephanie", + "LastName": "Kourula", + "abbrevName": "Kourula S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kourula", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Lefebvre", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Günther", + "abbrevName": "Günther C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Günther", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Becker", + "abbrevName": "Becker C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Becker", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Geert", + "LastName": "van Loo", + "abbrevName": "van Loo G", + "email": null, + "isCollectiveName": false, + "name": "Geert van Loo", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13706", + "pmid": "25186904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." + } + }, + { + "pmid": "29452637", + "pubmed": { + "ISODate": "2018-02-15T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.", + "authors": { + "abbreviation": "Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": "alessandro.annibaldi@icr.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Kirby", + "LastName": "Swatek", + "abbrevName": "Swatek KN", + "email": null, + "isCollectiveName": false, + "name": "Kirby N Swatek", + "orcid": null + }, + { + "ForeName": "Jianbin", + "LastName": "Ruan", + "abbrevName": "Ruan J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Ruan", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Katiuscia", + "LastName": "Bianchi", + "abbrevName": "Bianchi K", + "email": null, + "isCollectiveName": false, + "name": "Katiuscia Bianchi", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Wu", + "abbrevName": "Wu H", + "email": null, + "isCollectiveName": false, + "name": "Hao Wu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "email": [ + "alessandro.annibaldi@icr.ac.uk" + ], + "name": "Alessandro Annibaldi" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2018.01.027", + "pmid": "29452637", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 69 2018", + "title": "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." + } + }, + { + "pmid": "27819682", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.", + "authors": { + "abbreviation": "Kim Newton, Katherine E Wickliffe, Allie Maltzman, ..., Vishva M Dixit", + "authorList": [ + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe KE", + "email": null, + "isCollectiveName": false, + "name": "Katherine E Wickliffe", + "orcid": null + }, + { + "ForeName": "Allie", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "Allie Maltzman", + "orcid": null + }, + { + "ForeName": "Debra", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "Debra L Dugger", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Strasser", + "abbrevName": "Strasser A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Strasser", + "orcid": null + }, + { + "ForeName": "Victoria", + "LastName": "Pham", + "abbrevName": "Pham VC", + "email": null, + "isCollectiveName": false, + "name": "Victoria C Pham", + "orcid": null + }, + { + "ForeName": "Jennie", + "LastName": "Lill", + "abbrevName": "Lill JR", + "email": null, + "isCollectiveName": false, + "name": "Jennie R Lill", + "orcid": null + }, + { + "ForeName": "Merone", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "Merone Roose-Girma", + "orcid": null + }, + { + "ForeName": "Søren", + "LastName": "Warming", + "abbrevName": "Warming S", + "email": null, + "isCollectiveName": false, + "name": "Søren Warming", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Solon", + "abbrevName": "Solon M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Solon", + "orcid": null + }, + { + "ForeName": "Hai", + "LastName": "Ngu", + "abbrevName": "Ngu H", + "email": null, + "isCollectiveName": false, + "name": "Hai Ngu", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "Joshua D Webster", + "orcid": null + }, + { + "ForeName": "Vishva", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "Vishva M Dixit", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20559", + "pmid": "27819682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 inhibits ZBP1-driven necroptosis during development." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": true + } + ], + "element": [ + { + "_creationTimestamp": "2022-12-06T20:14:01.166Z", + "_newestOpId": "4a8b3e7c-d319-4938-8792-900c0403dfe3", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "604477" + }, + { + "db": "HGNC", + "id": "HGNC:1553" + }, + { + "db": "Ensembl", + "id": "ENSG00000122565" + } + ], + "defaultOrganismIndex": 2, + "distance": 0.1428571428571429, + "esScore": 9.066786, + "id": "11335", + "name": "CBX3", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 1400000100, + "shortSynonyms": [ + "CBX3", + "HECH", + "HP1-GAMMA", + "HP1Hs-gamma", + "chromobox protein homolog 3", + "HP1 gamma homolog", + "heterochromatin protein HP1 gamma", + "heterochromatin protein 1 homolog gamma", + "chromobox homolog 3 (HP1 gamma homolog, Drosophila)", + "heterochromatin-like protein 1", + "chromobox 3" + ], + "synonyms": [ + "HECH", + "HP1-GAMMA", + "HP1Hs-gamma", + "chromobox protein homolog 3", + "HP1 gamma homolog", + "chromobox homolog 3 (HP1 gamma homolog, Drosophila)", + "heterochromatin protein 1 homolog gamma", + "heterochromatin protein HP1 gamma", + "heterochromatin-like protein 1", + "modifier 2 protein", + "chromobox 3" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "e4355ec8-9c2f-43c4-bbc4-f54ea7b6318d", + "liveId": "82459508-5c2c-4967-a0c8-dc7f91e72f2e", + "lock": null, + "locked": false, + "name": "PP1gamma", + "parentId": "b2483833-8ca2-4246-8125-7cff29dec7ae", + "position": { + "x": 152.40506329113924, + "y": 101.26582278481014 + }, + "relatedPapers": [ + { + "pmid": "22362767", + "pubmed": { + "ISODate": "2012-04-27T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).", + "authors": { + "abbreviation": "Linde Duprez, Mathieu J M Bertrand, Tom Vanden Berghe, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Nele", + "LastName": "Festjens", + "abbrevName": "Festjens N", + "email": null, + "isCollectiveName": false, + "name": "Nele Festjens", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.288670", + "pmid": "22362767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis." + } + }, + { + "pmid": "29440439", + "pubmed": { + "ISODate": "2018-02-27T00:00:00.000Z", + "abstract": "RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFα-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.", + "authors": { + "abbreviation": "Huyan Meng, Zhen Liu, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Liu", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Guowei", + "LastName": "Wu", + "abbrevName": "Wu G", + "email": null, + "isCollectiveName": false, + "name": "Guowei Wu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Christofferson", + "abbrevName": "Christofferson DE", + "email": null, + "isCollectiveName": false, + "name": "Dana E Christofferson", + "orcid": null + }, + { + "ForeName": "Chunting", + "LastName": "Qi", + "abbrevName": "Qi C", + "email": null, + "isCollectiveName": false, + "name": "Chunting Qi", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Yu", + "abbrevName": "Yu Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Yu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Ying", + "LastName": "Li", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Ying Li" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1722013115", + "pmid": "29440439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis." + } + }, + { + "pmid": "31235688", + "pubmed": { + "ISODate": "2019-06-24T00:00:00.000Z", + "abstract": "Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.", + "authors": { + "abbreviation": "Jue Hou, Jie Ju, Zili Zhang, ..., Sudan He", + "authorList": [ + { + "ForeName": "Jue", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jue Hou", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Ju", + "abbrevName": "Ju J", + "email": null, + "isCollectiveName": false, + "name": "Jie Ju", + "orcid": null + }, + { + "ForeName": "Zili", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zili Zhang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhao", + "abbrevName": "Zhao C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhao", + "orcid": null + }, + { + "ForeName": "Zhanhui", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhanhui Li", + "orcid": null + }, + { + "ForeName": "Jiyue", + "LastName": "Zheng", + "abbrevName": "Zheng J", + "email": null, + "isCollectiveName": false, + "name": "Jiyue Zheng", + "orcid": null + }, + { + "ForeName": "Tian", + "LastName": "Sheng", + "abbrevName": "Sheng T", + "email": null, + "isCollectiveName": false, + "name": "Tian Sheng", + "orcid": null + }, + { + "ForeName": "Hongjian", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hongjian Zhang", + "orcid": null + }, + { + "ForeName": "Linkun", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Linkun Hu", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Yu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhang", + "orcid": null + }, + { + "ForeName": "Yangxin", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yangxin Li", + "orcid": null + }, + { + "ForeName": "Meng", + "LastName": "Wu", + "abbrevName": "Wu M", + "email": null, + "isCollectiveName": false, + "name": "Meng Wu", + "orcid": null + }, + { + "ForeName": "Haikuo", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": "mahaikuo123@163.com", + "isCollectiveName": false, + "name": "Haikuo Ma", + "orcid": null + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": "xiaohuzhang@suda.edu.cn", + "isCollectiveName": false, + "name": "Xiaohu Zhang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan2018@163.com", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Haikuo", + "LastName": "Ma", + "email": [ + "mahaikuo123@163.com" + ], + "name": "Haikuo Ma" + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "email": [ + "xiaohuzhang@suda.edu.cn" + ], + "name": "Xiaohu Zhang" + }, + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan2018@163.com" + ], + "name": "Sudan He" + } + ] + }, + "doi": "10.1038/s41419-019-1735-6", + "pmid": "31235688", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis." + } + }, + { + "pmid": "34990405", + "pubmed": { + "ISODate": "2022-02-15T00:00:00.000Z", + "abstract": "Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.", + "authors": { + "abbreviation": "Haifeng Yin, Xiaoyun Guo, Yi Chen, ..., Qinghang Liu", + "authorList": [ + { + "ForeName": "Haifeng", + "LastName": "Yin", + "abbrevName": "Yin H", + "email": null, + "isCollectiveName": false, + "name": "Haifeng Yin", + "orcid": null + }, + { + "ForeName": "Xiaoyun", + "LastName": "Guo", + "abbrevName": "Guo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyun Guo", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Chen", + "orcid": null + }, + { + "ForeName": "Yachang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yachang Zeng", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Mo", + "abbrevName": "Mo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Mo", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Hong", + "abbrevName": "Hong S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Hong", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Hui He", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jing Li", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Steinmetz", + "orcid": null + }, + { + "ForeName": "Qinghang", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI152297", + "pmid": "34990405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 132 2022", + "title": "TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis." + } + }, + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "34813352", + "pubmed": { + "ISODate": "2021-11-23T00:00:00.000Z", + "abstract": "The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.", + "authors": { + "abbreviation": "Daichao Xu, Chengyu Zou, Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Daichao Xu" + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Chengyu Zou" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1146/annurev-genet-071719-022748", + "pmid": "34813352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Genet 55 2021", + "title": "Genetic Regulation of RIPK1 and Necroptosis." + } + }, + { + "pmid": "33311474", + "pubmed": { + "ISODate": "2020-12-11T00:00:00.000Z", + "abstract": "RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.", + "authors": { + "abbreviation": "Xingyan Li, Mengmeng Zhang, Xinyue Huang, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Mengmeng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mengmeng Zhang", + "orcid": null + }, + { + "ForeName": "Xinyue", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xinyue Huang", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Liang", + "abbrevName": "Liang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liang", + "orcid": null + }, + { + "ForeName": "Ganquan", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Ganquan Li", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": "shanbing@sioc.ac.cn", + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "email": [ + "shanbing@sioc.ac.cn" + ], + "name": "Bing Shan" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-020-19935-y", + "pmid": "33311474", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "25195660", + "pubmed": { + "ISODate": "2014-11-01T00:00:00.000Z", + "abstract": "Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.", + "authors": { + "abbreviation": "Conor J Kearney, Sean P Cullen, Danielle Clancy, Seamus J Martin", + "authorList": [ + { + "ForeName": "Conor", + "LastName": "Kearney", + "abbrevName": "Kearney CJ", + "email": null, + "isCollectiveName": false, + "name": "Conor J Kearney", + "orcid": null + }, + { + "ForeName": "Sean", + "LastName": "Cullen", + "abbrevName": "Cullen SP", + "email": null, + "isCollectiveName": false, + "name": "Sean P Cullen", + "orcid": null + }, + { + "ForeName": "Danielle", + "LastName": "Clancy", + "abbrevName": "Clancy D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Clancy", + "orcid": null + }, + { + "ForeName": "Seamus", + "LastName": "Martin", + "abbrevName": "Martin SJ", + "email": null, + "isCollectiveName": false, + "name": "Seamus J Martin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/febs.13034", + "pmid": "25195660", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 281 2014", + "title": "RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis." + } + }, + { + "pmid": "33858959", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.", + "authors": { + "abbreviation": "Snehlata Kumari, Trieu-My Van, Daniela Preukschat, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": "s.kumari@uq.edu.au", + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Preukschat", + "abbrevName": "Preukschat D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Preukschat", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schuenke", + "abbrevName": "Schuenke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schuenke", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "André", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "André Bleich", + "orcid": null + }, + { + "ForeName": "Ulf", + "LastName": "Klein", + "abbrevName": "Klein U", + "email": null, + "isCollectiveName": false, + "name": "Ulf Klein", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "email": [ + "s.kumari@uq.edu.au" + ], + "name": "Snehlata Kumari" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.26508/lsa.202000956", + "pmid": "33858959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Life Sci Alliance 4 2021", + "title": "NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation." + } + }, + { + "pmid": "31028177", + "pubmed": { + "ISODate": "2019-05-20T00:00:00.000Z", + "abstract": "Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.", + "authors": { + "abbreviation": "Zicheng Wang, Jiannan Feng, Jiyun Yu, Guozhu Chen", + "authorList": [ + { + "ForeName": "Zicheng", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zicheng Wang", + "orcid": "0000-0003-2648-8289" + }, + { + "ForeName": "Jiannan", + "LastName": "Feng", + "abbrevName": "Feng J", + "email": null, + "isCollectiveName": false, + "name": "Jiannan Feng", + "orcid": null + }, + { + "ForeName": "Jiyun", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jiyun Yu", + "orcid": "0000-0003-3475-1956" + }, + { + "ForeName": "Guozhu", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "chenguozhu2002@126.com", + "isCollectiveName": false, + "name": "Guozhu Chen", + "orcid": "0000-0002-6067-8150" + } + ], + "contacts": [ + { + "ForeName": "Guozhu", + "LastName": "Chen", + "email": [ + "chenguozhu2002@126.com" + ], + "name": "Guozhu Chen" + } + ] + }, + "doi": "10.1242/jcs.227777", + "pmid": "31028177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + }, + { + "pmid": "28701375", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.", + "authors": { + "abbreviation": "Ran Wei, Lily Wen Xu, Jianping Liu, ..., Heling Pan", + "authorList": [ + { + "ForeName": "Ran", + "LastName": "Wei", + "abbrevName": "Wei R", + "email": null, + "isCollectiveName": false, + "name": "Ran Wei", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Xu", + "abbrevName": "Xu LW", + "email": null, + "isCollectiveName": false, + "name": "Lily Wen Xu", + "orcid": null + }, + { + "ForeName": "Jianping", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Liu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Pei", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Zhang", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.299776.117", + "pmid": "28701375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genes Dev 31 2017", + "title": "SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination." + } + }, + { + "pmid": "27819682", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.", + "authors": { + "abbreviation": "Kim Newton, Katherine E Wickliffe, Allie Maltzman, ..., Vishva M Dixit", + "authorList": [ + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe KE", + "email": null, + "isCollectiveName": false, + "name": "Katherine E Wickliffe", + "orcid": null + }, + { + "ForeName": "Allie", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "Allie Maltzman", + "orcid": null + }, + { + "ForeName": "Debra", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "Debra L Dugger", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Strasser", + "abbrevName": "Strasser A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Strasser", + "orcid": null + }, + { + "ForeName": "Victoria", + "LastName": "Pham", + "abbrevName": "Pham VC", + "email": null, + "isCollectiveName": false, + "name": "Victoria C Pham", + "orcid": null + }, + { + "ForeName": "Jennie", + "LastName": "Lill", + "abbrevName": "Lill JR", + "email": null, + "isCollectiveName": false, + "name": "Jennie R Lill", + "orcid": null + }, + { + "ForeName": "Merone", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "Merone Roose-Girma", + "orcid": null + }, + { + "ForeName": "Søren", + "LastName": "Warming", + "abbrevName": "Warming S", + "email": null, + "isCollectiveName": false, + "name": "Søren Warming", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Solon", + "abbrevName": "Solon M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Solon", + "orcid": null + }, + { + "ForeName": "Hai", + "LastName": "Ngu", + "abbrevName": "Ngu H", + "email": null, + "isCollectiveName": false, + "name": "Hai Ngu", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "Joshua D Webster", + "orcid": null + }, + { + "ForeName": "Vishva", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "Vishva M Dixit", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20559", + "pmid": "27819682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 inhibits ZBP1-driven necroptosis during development." + } + }, + { + "pmid": "23727581", + "pubmed": { + "ISODate": "2013-06-28T00:00:00.000Z", + "abstract": "While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.", + "authors": { + "abbreviation": "Ryodai Shindo, Hidenao Kakehashi, Ko Okumura, ..., Hiroyasu Nakano", + "authorList": [ + { + "ForeName": "Ryodai", + "LastName": "Shindo", + "abbrevName": "Shindo R", + "email": null, + "isCollectiveName": false, + "name": "Ryodai Shindo", + "orcid": null + }, + { + "ForeName": "Hidenao", + "LastName": "Kakehashi", + "abbrevName": "Kakehashi H", + "email": null, + "isCollectiveName": false, + "name": "Hidenao Kakehashi", + "orcid": null + }, + { + "ForeName": "Ko", + "LastName": "Okumura", + "abbrevName": "Okumura K", + "email": null, + "isCollectiveName": false, + "name": "Ko Okumura", + "orcid": null + }, + { + "ForeName": "Yoshito", + "LastName": "Kumagai", + "abbrevName": "Kumagai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshito Kumagai", + "orcid": null + }, + { + "ForeName": "Hiroyasu", + "LastName": "Nakano", + "abbrevName": "Nakano H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyasu Nakano", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2013.05.075", + "pmid": "23727581", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 436 2013", + "title": "Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation." + } + }, + { + "pmid": "25132550", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.", + "authors": { + "abbreviation": "Marius Dannappel, Katerina Vlantis, Snehlata Kumari, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Marius", + "LastName": "Dannappel", + "abbrevName": "Dannappel M", + "email": null, + "isCollectiveName": false, + "name": "Marius Dannappel", + "orcid": null + }, + { + "ForeName": "Katerina", + "LastName": "Vlantis", + "abbrevName": "Vlantis K", + "email": null, + "isCollectiveName": false, + "name": "Katerina Vlantis", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Eftychi", + "abbrevName": "Eftychi C", + "email": null, + "isCollectiveName": false, + "name": "Christina Eftychi", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Hermance", + "abbrevName": "Hermance N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Hermance", + "orcid": null + }, + { + "ForeName": "Matija", + "LastName": "Zelic", + "abbrevName": "Zelic M", + "email": null, + "isCollectiveName": false, + "name": "Matija Zelic", + "orcid": null + }, + { + "ForeName": "Petra", + "LastName": "Kirsch", + "abbrevName": "Kirsch P", + "email": null, + "isCollectiveName": false, + "name": "Petra Kirsch", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "Andre", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "Andre Bleich", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Kelliher", + "abbrevName": "Kelliher M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Kelliher", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13608", + "pmid": "25132550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + }, + { + "pmid": "29078411", + "pubmed": { + "ISODate": "2017-11-07T00:00:00.000Z", + "abstract": "Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.", + "authors": { + "abbreviation": "Huibing Wang, Huyan Meng, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Kezhou", + "LastName": "Zhu", + "abbrevName": "Zhu K", + "email": null, + "isCollectiveName": false, + "name": "Kezhou Zhu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan K Mookhtiar", + "orcid": null + }, + { + "ForeName": "Huiting", + "LastName": "Wei", + "abbrevName": "Wei H", + "email": null, + "isCollectiveName": false, + "name": "Huiting Wei", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Shao-Cong", + "LastName": "Sun", + "abbrevName": "Sun SC", + "email": null, + "isCollectiveName": false, + "name": "Shao-Cong Sun", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1715742114", + "pmid": "29078411", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP." + } + }, + { + "pmid": "34262020", + "pubmed": { + "ISODate": "2021-07-14T00:00:00.000Z", + "abstract": "Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.", + "authors": { + "abbreviation": "Tom Delanghe, Jon Huyghe, Seungheon Lee, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Huyghe", + "abbrevName": "Huyghe J", + "email": null, + "isCollectiveName": false, + "name": "Jon Huyghe", + "orcid": null + }, + { + "ForeName": "Seungheon", + "LastName": "Lee", + "abbrevName": "Lee S", + "email": null, + "isCollectiveName": false, + "name": "Seungheon Lee", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": "0000-0002-2527-1101" + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41419-021-03994-0", + "pmid": "34262020", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor." + } + }, + { + "pmid": "27605011", + "pubmed": { + "ISODate": "2016-10-15T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-κB activation in terms of IκBα phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1D138N) mice did not exacerbate αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.", + "authors": { + "abbreviation": "Jo Suda, Lily Dara, Luoluo Yang, ..., Zhang-Xu Liu", + "authorList": [ + { + "ForeName": "Jo", + "LastName": "Suda", + "abbrevName": "Suda J", + "email": null, + "isCollectiveName": false, + "name": "Jo Suda", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Dara", + "abbrevName": "Dara L", + "email": null, + "isCollectiveName": false, + "name": "Lily Dara", + "orcid": "0000-0002-0121-7186" + }, + { + "ForeName": "Luoluo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Luoluo Yang", + "orcid": "0000-0001-8099-9982" + }, + { + "ForeName": "Mariam", + "LastName": "Aghajan", + "abbrevName": "Aghajan M", + "email": null, + "isCollectiveName": false, + "name": "Mariam Aghajan", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Song", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Kaplowitz", + "abbrevName": "Kaplowitz N", + "email": null, + "isCollectiveName": false, + "name": "Neil Kaplowitz", + "orcid": "0000-0002-9424-393X" + }, + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "abbrevName": "Liu ZX", + "email": "zxliu@usc.edu", + "isCollectiveName": false, + "name": "Zhang-Xu Liu", + "orcid": "0000-0001-7290-3506" + } + ], + "contacts": [ + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "email": [ + "zxliu@usc.edu" + ], + "name": "Zhang-Xu Liu" + } + ] + }, + "doi": "10.4049/jimmunol.1600690", + "pmid": "27605011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Immunol 197 2016", + "title": "Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "27258786", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.", + "authors": { + "abbreviation": "B Shutinoski, N A Alturki, D Rijal, ..., S Sad", + "authorList": [ + { + "ForeName": "B", + "LastName": "Shutinoski", + "abbrevName": "Shutinoski B", + "email": null, + "isCollectiveName": false, + "name": "B Shutinoski", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Alturki", + "abbrevName": "Alturki NA", + "email": null, + "isCollectiveName": false, + "name": "N A Alturki", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rijal", + "abbrevName": "Rijal D", + "email": null, + "isCollectiveName": false, + "name": "D Rijal", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "J Bertin", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Gough", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Schlossmacher", + "abbrevName": "Schlossmacher MG", + "email": null, + "isCollectiveName": false, + "name": "M G Schlossmacher", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sad", + "abbrevName": "Sad S", + "email": null, + "isCollectiveName": false, + "name": "S Sad", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.51", + "pmid": "27258786", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo." + } + }, + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "36329033", + "pubmed": { + "ISODate": "2022-11-03T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.", + "authors": { + "abbreviation": "Hailin Tu, Weihang Xiong, Jie Zhang, ..., Xin Lin", + "authorList": [ + { + "ForeName": "Hailin", + "LastName": "Tu", + "abbrevName": "Tu H", + "email": null, + "isCollectiveName": false, + "name": "Hailin Tu", + "orcid": null + }, + { + "ForeName": "Weihang", + "LastName": "Xiong", + "abbrevName": "Xiong W", + "email": null, + "isCollectiveName": false, + "name": "Weihang Xiong", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Xueqiang", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xueqiang Zhao", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": "linxin307@tsinghua.edu.cn", + "isCollectiveName": false, + "name": "Xin Lin", + "orcid": "0000-0003-0956-3654" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Lin", + "email": [ + "linxin307@tsinghua.edu.cn" + ], + "name": "Xin Lin" + } + ] + }, + "doi": "10.1038/s41467-022-34080-4", + "pmid": "36329033", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Commun 13 2022", + "title": "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation." + } + }, + { + "pmid": "27819681", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.", + "authors": { + "abbreviation": "Juan Lin, Snehlata Kumari, Chun Kim, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20558", + "pmid": "27819681", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation." + } + }, + { + "pmid": "30867408", + "pubmed": { + "ISODate": "2019-03-13T00:00:00.000Z", + "abstract": "RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.", + "authors": { + "abbreviation": "Xuhua Zhang, John P Dowling, Jianke Zhang", + "authorList": [ + { + "ForeName": "Xuhua", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xuhua Zhang", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Dowling", + "abbrevName": "Dowling JP", + "email": null, + "isCollectiveName": false, + "name": "John P Dowling", + "orcid": null + }, + { + "ForeName": "Jianke", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "jianke.zhang@jefferson.edu", + "isCollectiveName": false, + "name": "Jianke Zhang", + "orcid": "0000-0001-9880-8435" + } + ], + "contacts": [ + { + "ForeName": "Jianke", + "LastName": "Zhang", + "email": [ + "jianke.zhang@jefferson.edu" + ], + "name": "Jianke Zhang" + } + ] + }, + "doi": "10.1038/s41419-019-1490-8", + "pmid": "30867408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development." + } + }, + { + "pmid": "29452637", + "pubmed": { + "ISODate": "2018-02-15T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.", + "authors": { + "abbreviation": "Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": "alessandro.annibaldi@icr.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Kirby", + "LastName": "Swatek", + "abbrevName": "Swatek KN", + "email": null, + "isCollectiveName": false, + "name": "Kirby N Swatek", + "orcid": null + }, + { + "ForeName": "Jianbin", + "LastName": "Ruan", + "abbrevName": "Ruan J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Ruan", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Katiuscia", + "LastName": "Bianchi", + "abbrevName": "Bianchi K", + "email": null, + "isCollectiveName": false, + "name": "Katiuscia Bianchi", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Wu", + "abbrevName": "Wu H", + "email": null, + "isCollectiveName": false, + "name": "Hao Wu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "email": [ + "alessandro.annibaldi@icr.ac.uk" + ], + "name": "Alessandro Annibaldi" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2018.01.027", + "pmid": "29452637", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 69 2018", + "title": "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + }, + { + "pmid": "25186904", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.", + "authors": { + "abbreviation": "Nozomi Takahashi, Lars Vereecke, Mathieu J M Bertrand, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Lars", + "LastName": "Vereecke", + "abbrevName": "Vereecke L", + "email": null, + "isCollectiveName": false, + "name": "Lars Vereecke", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Berger", + "abbrevName": "Berger SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Berger", + "orcid": null + }, + { + "ForeName": "Tatyana", + "LastName": "Divert", + "abbrevName": "Divert T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Divert", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Gonçalves", + "orcid": null + }, + { + "ForeName": "Mozes", + "LastName": "Sze", + "abbrevName": "Sze M", + "email": null, + "isCollectiveName": false, + "name": "Mozes Sze", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Stephanie", + "LastName": "Kourula", + "abbrevName": "Kourula S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kourula", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Lefebvre", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Günther", + "abbrevName": "Günther C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Günther", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Becker", + "abbrevName": "Becker C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Becker", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Geert", + "LastName": "van Loo", + "abbrevName": "van Loo G", + "email": null, + "isCollectiveName": false, + "name": "Geert van Loo", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13706", + "pmid": "25186904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-12-06T20:14:08.242Z", + "_newestOpId": "205db106-6b4d-4950-9236-0f2e8a425a22", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "e4355ec8-9c2f-43c4-bbc4-f54ea7b6318d" + }, + { + "id": "3e669fd7-8018-4098-b305-f050f090099e" + } + ], + "id": "b2483833-8ca2-4246-8125-7cff29dec7ae", + "liveId": "75fa6f9a-dddd-4319-a956-0ccfe41b571e", + "lock": null, + "locked": false, + "name": "", + "position": { + "x": 146.31012658227849, + "y": 113.67088607594937 + }, + "relatedPapers": [ + { + "pmid": "29452637", + "pubmed": { + "ISODate": "2018-02-15T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.", + "authors": { + "abbreviation": "Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": "alessandro.annibaldi@icr.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Kirby", + "LastName": "Swatek", + "abbrevName": "Swatek KN", + "email": null, + "isCollectiveName": false, + "name": "Kirby N Swatek", + "orcid": null + }, + { + "ForeName": "Jianbin", + "LastName": "Ruan", + "abbrevName": "Ruan J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Ruan", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Katiuscia", + "LastName": "Bianchi", + "abbrevName": "Bianchi K", + "email": null, + "isCollectiveName": false, + "name": "Katiuscia Bianchi", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Wu", + "abbrevName": "Wu H", + "email": null, + "isCollectiveName": false, + "name": "Hao Wu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "email": [ + "alessandro.annibaldi@icr.ac.uk" + ], + "name": "Alessandro Annibaldi" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2018.01.027", + "pmid": "29452637", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 69 2018", + "title": "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." + } + }, + { + "pmid": "34990405", + "pubmed": { + "ISODate": "2022-02-15T00:00:00.000Z", + "abstract": "Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.", + "authors": { + "abbreviation": "Haifeng Yin, Xiaoyun Guo, Yi Chen, ..., Qinghang Liu", + "authorList": [ + { + "ForeName": "Haifeng", + "LastName": "Yin", + "abbrevName": "Yin H", + "email": null, + "isCollectiveName": false, + "name": "Haifeng Yin", + "orcid": null + }, + { + "ForeName": "Xiaoyun", + "LastName": "Guo", + "abbrevName": "Guo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyun Guo", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Chen", + "orcid": null + }, + { + "ForeName": "Yachang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yachang Zeng", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Mo", + "abbrevName": "Mo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Mo", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Hong", + "abbrevName": "Hong S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Hong", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Hui He", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jing Li", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Steinmetz", + "orcid": null + }, + { + "ForeName": "Qinghang", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI152297", + "pmid": "34990405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 132 2022", + "title": "TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + }, + { + "pmid": "22362767", + "pubmed": { + "ISODate": "2012-04-27T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).", + "authors": { + "abbreviation": "Linde Duprez, Mathieu J M Bertrand, Tom Vanden Berghe, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Nele", + "LastName": "Festjens", + "abbrevName": "Festjens N", + "email": null, + "isCollectiveName": false, + "name": "Nele Festjens", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.288670", + "pmid": "22362767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis." + } + }, + { + "pmid": "25195660", + "pubmed": { + "ISODate": "2014-11-01T00:00:00.000Z", + "abstract": "Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.", + "authors": { + "abbreviation": "Conor J Kearney, Sean P Cullen, Danielle Clancy, Seamus J Martin", + "authorList": [ + { + "ForeName": "Conor", + "LastName": "Kearney", + "abbrevName": "Kearney CJ", + "email": null, + "isCollectiveName": false, + "name": "Conor J Kearney", + "orcid": null + }, + { + "ForeName": "Sean", + "LastName": "Cullen", + "abbrevName": "Cullen SP", + "email": null, + "isCollectiveName": false, + "name": "Sean P Cullen", + "orcid": null + }, + { + "ForeName": "Danielle", + "LastName": "Clancy", + "abbrevName": "Clancy D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Clancy", + "orcid": null + }, + { + "ForeName": "Seamus", + "LastName": "Martin", + "abbrevName": "Martin SJ", + "email": null, + "isCollectiveName": false, + "name": "Seamus J Martin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/febs.13034", + "pmid": "25195660", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 281 2014", + "title": "RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis." + } + }, + { + "pmid": "23727581", + "pubmed": { + "ISODate": "2013-06-28T00:00:00.000Z", + "abstract": "While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.", + "authors": { + "abbreviation": "Ryodai Shindo, Hidenao Kakehashi, Ko Okumura, ..., Hiroyasu Nakano", + "authorList": [ + { + "ForeName": "Ryodai", + "LastName": "Shindo", + "abbrevName": "Shindo R", + "email": null, + "isCollectiveName": false, + "name": "Ryodai Shindo", + "orcid": null + }, + { + "ForeName": "Hidenao", + "LastName": "Kakehashi", + "abbrevName": "Kakehashi H", + "email": null, + "isCollectiveName": false, + "name": "Hidenao Kakehashi", + "orcid": null + }, + { + "ForeName": "Ko", + "LastName": "Okumura", + "abbrevName": "Okumura K", + "email": null, + "isCollectiveName": false, + "name": "Ko Okumura", + "orcid": null + }, + { + "ForeName": "Yoshito", + "LastName": "Kumagai", + "abbrevName": "Kumagai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshito Kumagai", + "orcid": null + }, + { + "ForeName": "Hiroyasu", + "LastName": "Nakano", + "abbrevName": "Nakano H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyasu Nakano", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2013.05.075", + "pmid": "23727581", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 436 2013", + "title": "Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation." + } + }, + { + "pmid": "34262020", + "pubmed": { + "ISODate": "2021-07-14T00:00:00.000Z", + "abstract": "Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.", + "authors": { + "abbreviation": "Tom Delanghe, Jon Huyghe, Seungheon Lee, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Huyghe", + "abbrevName": "Huyghe J", + "email": null, + "isCollectiveName": false, + "name": "Jon Huyghe", + "orcid": null + }, + { + "ForeName": "Seungheon", + "LastName": "Lee", + "abbrevName": "Lee S", + "email": null, + "isCollectiveName": false, + "name": "Seungheon Lee", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": "0000-0002-2527-1101" + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41419-021-03994-0", + "pmid": "34262020", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor." + } + }, + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "27819682", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.", + "authors": { + "abbreviation": "Kim Newton, Katherine E Wickliffe, Allie Maltzman, ..., Vishva M Dixit", + "authorList": [ + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe KE", + "email": null, + "isCollectiveName": false, + "name": "Katherine E Wickliffe", + "orcid": null + }, + { + "ForeName": "Allie", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "Allie Maltzman", + "orcid": null + }, + { + "ForeName": "Debra", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "Debra L Dugger", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Strasser", + "abbrevName": "Strasser A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Strasser", + "orcid": null + }, + { + "ForeName": "Victoria", + "LastName": "Pham", + "abbrevName": "Pham VC", + "email": null, + "isCollectiveName": false, + "name": "Victoria C Pham", + "orcid": null + }, + { + "ForeName": "Jennie", + "LastName": "Lill", + "abbrevName": "Lill JR", + "email": null, + "isCollectiveName": false, + "name": "Jennie R Lill", + "orcid": null + }, + { + "ForeName": "Merone", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "Merone Roose-Girma", + "orcid": null + }, + { + "ForeName": "Søren", + "LastName": "Warming", + "abbrevName": "Warming S", + "email": null, + "isCollectiveName": false, + "name": "Søren Warming", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Solon", + "abbrevName": "Solon M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Solon", + "orcid": null + }, + { + "ForeName": "Hai", + "LastName": "Ngu", + "abbrevName": "Ngu H", + "email": null, + "isCollectiveName": false, + "name": "Hai Ngu", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "Joshua D Webster", + "orcid": null + }, + { + "ForeName": "Vishva", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "Vishva M Dixit", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20559", + "pmid": "27819682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 inhibits ZBP1-driven necroptosis during development." + } + }, + { + "pmid": "31235688", + "pubmed": { + "ISODate": "2019-06-24T00:00:00.000Z", + "abstract": "Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.", + "authors": { + "abbreviation": "Jue Hou, Jie Ju, Zili Zhang, ..., Sudan He", + "authorList": [ + { + "ForeName": "Jue", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jue Hou", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Ju", + "abbrevName": "Ju J", + "email": null, + "isCollectiveName": false, + "name": "Jie Ju", + "orcid": null + }, + { + "ForeName": "Zili", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zili Zhang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhao", + "abbrevName": "Zhao C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhao", + "orcid": null + }, + { + "ForeName": "Zhanhui", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhanhui Li", + "orcid": null + }, + { + "ForeName": "Jiyue", + "LastName": "Zheng", + "abbrevName": "Zheng J", + "email": null, + "isCollectiveName": false, + "name": "Jiyue Zheng", + "orcid": null + }, + { + "ForeName": "Tian", + "LastName": "Sheng", + "abbrevName": "Sheng T", + "email": null, + "isCollectiveName": false, + "name": "Tian Sheng", + "orcid": null + }, + { + "ForeName": "Hongjian", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hongjian Zhang", + "orcid": null + }, + { + "ForeName": "Linkun", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Linkun Hu", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Yu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhang", + "orcid": null + }, + { + "ForeName": "Yangxin", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yangxin Li", + "orcid": null + }, + { + "ForeName": "Meng", + "LastName": "Wu", + "abbrevName": "Wu M", + "email": null, + "isCollectiveName": false, + "name": "Meng Wu", + "orcid": null + }, + { + "ForeName": "Haikuo", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": "mahaikuo123@163.com", + "isCollectiveName": false, + "name": "Haikuo Ma", + "orcid": null + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": "xiaohuzhang@suda.edu.cn", + "isCollectiveName": false, + "name": "Xiaohu Zhang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan2018@163.com", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Haikuo", + "LastName": "Ma", + "email": [ + "mahaikuo123@163.com" + ], + "name": "Haikuo Ma" + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "email": [ + "xiaohuzhang@suda.edu.cn" + ], + "name": "Xiaohu Zhang" + }, + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan2018@163.com" + ], + "name": "Sudan He" + } + ] + }, + "doi": "10.1038/s41419-019-1735-6", + "pmid": "31235688", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis." + } + }, + { + "pmid": "30867408", + "pubmed": { + "ISODate": "2019-03-13T00:00:00.000Z", + "abstract": "RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.", + "authors": { + "abbreviation": "Xuhua Zhang, John P Dowling, Jianke Zhang", + "authorList": [ + { + "ForeName": "Xuhua", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xuhua Zhang", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Dowling", + "abbrevName": "Dowling JP", + "email": null, + "isCollectiveName": false, + "name": "John P Dowling", + "orcid": null + }, + { + "ForeName": "Jianke", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "jianke.zhang@jefferson.edu", + "isCollectiveName": false, + "name": "Jianke Zhang", + "orcid": "0000-0001-9880-8435" + } + ], + "contacts": [ + { + "ForeName": "Jianke", + "LastName": "Zhang", + "email": [ + "jianke.zhang@jefferson.edu" + ], + "name": "Jianke Zhang" + } + ] + }, + "doi": "10.1038/s41419-019-1490-8", + "pmid": "30867408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development." + } + }, + { + "pmid": "34813352", + "pubmed": { + "ISODate": "2021-11-23T00:00:00.000Z", + "abstract": "The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.", + "authors": { + "abbreviation": "Daichao Xu, Chengyu Zou, Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Daichao Xu" + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Chengyu Zou" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1146/annurev-genet-071719-022748", + "pmid": "34813352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Genet 55 2021", + "title": "Genetic Regulation of RIPK1 and Necroptosis." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "33858959", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.", + "authors": { + "abbreviation": "Snehlata Kumari, Trieu-My Van, Daniela Preukschat, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": "s.kumari@uq.edu.au", + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Preukschat", + "abbrevName": "Preukschat D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Preukschat", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schuenke", + "abbrevName": "Schuenke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schuenke", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "André", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "André Bleich", + "orcid": null + }, + { + "ForeName": "Ulf", + "LastName": "Klein", + "abbrevName": "Klein U", + "email": null, + "isCollectiveName": false, + "name": "Ulf Klein", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "email": [ + "s.kumari@uq.edu.au" + ], + "name": "Snehlata Kumari" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.26508/lsa.202000956", + "pmid": "33858959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Life Sci Alliance 4 2021", + "title": "NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "33311474", + "pubmed": { + "ISODate": "2020-12-11T00:00:00.000Z", + "abstract": "RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.", + "authors": { + "abbreviation": "Xingyan Li, Mengmeng Zhang, Xinyue Huang, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Mengmeng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mengmeng Zhang", + "orcid": null + }, + { + "ForeName": "Xinyue", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xinyue Huang", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Liang", + "abbrevName": "Liang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liang", + "orcid": null + }, + { + "ForeName": "Ganquan", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Ganquan Li", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": "shanbing@sioc.ac.cn", + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "email": [ + "shanbing@sioc.ac.cn" + ], + "name": "Bing Shan" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-020-19935-y", + "pmid": "33311474", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners." + } + }, + { + "pmid": "27819681", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.", + "authors": { + "abbreviation": "Juan Lin, Snehlata Kumari, Chun Kim, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20558", + "pmid": "27819681", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation." + } + }, + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "27258786", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.", + "authors": { + "abbreviation": "B Shutinoski, N A Alturki, D Rijal, ..., S Sad", + "authorList": [ + { + "ForeName": "B", + "LastName": "Shutinoski", + "abbrevName": "Shutinoski B", + "email": null, + "isCollectiveName": false, + "name": "B Shutinoski", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Alturki", + "abbrevName": "Alturki NA", + "email": null, + "isCollectiveName": false, + "name": "N A Alturki", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rijal", + "abbrevName": "Rijal D", + "email": null, + "isCollectiveName": false, + "name": "D Rijal", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "J Bertin", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Gough", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Schlossmacher", + "abbrevName": "Schlossmacher MG", + "email": null, + "isCollectiveName": false, + "name": "M G Schlossmacher", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sad", + "abbrevName": "Sad S", + "email": null, + "isCollectiveName": false, + "name": "S Sad", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.51", + "pmid": "27258786", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo." + } + }, + { + "pmid": "25186904", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.", + "authors": { + "abbreviation": "Nozomi Takahashi, Lars Vereecke, Mathieu J M Bertrand, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Lars", + "LastName": "Vereecke", + "abbrevName": "Vereecke L", + "email": null, + "isCollectiveName": false, + "name": "Lars Vereecke", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Berger", + "abbrevName": "Berger SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Berger", + "orcid": null + }, + { + "ForeName": "Tatyana", + "LastName": "Divert", + "abbrevName": "Divert T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Divert", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Gonçalves", + "orcid": null + }, + { + "ForeName": "Mozes", + "LastName": "Sze", + "abbrevName": "Sze M", + "email": null, + "isCollectiveName": false, + "name": "Mozes Sze", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Stephanie", + "LastName": "Kourula", + "abbrevName": "Kourula S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kourula", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Lefebvre", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Günther", + "abbrevName": "Günther C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Günther", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Becker", + "abbrevName": "Becker C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Becker", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Geert", + "LastName": "van Loo", + "abbrevName": "van Loo G", + "email": null, + "isCollectiveName": false, + "name": "Geert van Loo", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13706", + "pmid": "25186904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." + } + }, + { + "pmid": "28701375", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.", + "authors": { + "abbreviation": "Ran Wei, Lily Wen Xu, Jianping Liu, ..., Heling Pan", + "authorList": [ + { + "ForeName": "Ran", + "LastName": "Wei", + "abbrevName": "Wei R", + "email": null, + "isCollectiveName": false, + "name": "Ran Wei", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Xu", + "abbrevName": "Xu LW", + "email": null, + "isCollectiveName": false, + "name": "Lily Wen Xu", + "orcid": null + }, + { + "ForeName": "Jianping", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Liu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Pei", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Zhang", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.299776.117", + "pmid": "28701375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genes Dev 31 2017", + "title": "SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination." + } + }, + { + "pmid": "29078411", + "pubmed": { + "ISODate": "2017-11-07T00:00:00.000Z", + "abstract": "Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.", + "authors": { + "abbreviation": "Huibing Wang, Huyan Meng, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Kezhou", + "LastName": "Zhu", + "abbrevName": "Zhu K", + "email": null, + "isCollectiveName": false, + "name": "Kezhou Zhu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan K Mookhtiar", + "orcid": null + }, + { + "ForeName": "Huiting", + "LastName": "Wei", + "abbrevName": "Wei H", + "email": null, + "isCollectiveName": false, + "name": "Huiting Wei", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Shao-Cong", + "LastName": "Sun", + "abbrevName": "Sun SC", + "email": null, + "isCollectiveName": false, + "name": "Shao-Cong Sun", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1715742114", + "pmid": "29078411", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP." + } + }, + { + "pmid": "27605011", + "pubmed": { + "ISODate": "2016-10-15T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-κB activation in terms of IκBα phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1D138N) mice did not exacerbate αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.", + "authors": { + "abbreviation": "Jo Suda, Lily Dara, Luoluo Yang, ..., Zhang-Xu Liu", + "authorList": [ + { + "ForeName": "Jo", + "LastName": "Suda", + "abbrevName": "Suda J", + "email": null, + "isCollectiveName": false, + "name": "Jo Suda", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Dara", + "abbrevName": "Dara L", + "email": null, + "isCollectiveName": false, + "name": "Lily Dara", + "orcid": "0000-0002-0121-7186" + }, + { + "ForeName": "Luoluo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Luoluo Yang", + "orcid": "0000-0001-8099-9982" + }, + { + "ForeName": "Mariam", + "LastName": "Aghajan", + "abbrevName": "Aghajan M", + "email": null, + "isCollectiveName": false, + "name": "Mariam Aghajan", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Song", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Kaplowitz", + "abbrevName": "Kaplowitz N", + "email": null, + "isCollectiveName": false, + "name": "Neil Kaplowitz", + "orcid": "0000-0002-9424-393X" + }, + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "abbrevName": "Liu ZX", + "email": "zxliu@usc.edu", + "isCollectiveName": false, + "name": "Zhang-Xu Liu", + "orcid": "0000-0001-7290-3506" + } + ], + "contacts": [ + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "email": [ + "zxliu@usc.edu" + ], + "name": "Zhang-Xu Liu" + } + ] + }, + "doi": "10.4049/jimmunol.1600690", + "pmid": "27605011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Immunol 197 2016", + "title": "Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB." + } + }, + { + "pmid": "31028177", + "pubmed": { + "ISODate": "2019-05-20T00:00:00.000Z", + "abstract": "Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.", + "authors": { + "abbreviation": "Zicheng Wang, Jiannan Feng, Jiyun Yu, Guozhu Chen", + "authorList": [ + { + "ForeName": "Zicheng", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zicheng Wang", + "orcid": "0000-0003-2648-8289" + }, + { + "ForeName": "Jiannan", + "LastName": "Feng", + "abbrevName": "Feng J", + "email": null, + "isCollectiveName": false, + "name": "Jiannan Feng", + "orcid": null + }, + { + "ForeName": "Jiyun", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jiyun Yu", + "orcid": "0000-0003-3475-1956" + }, + { + "ForeName": "Guozhu", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "chenguozhu2002@126.com", + "isCollectiveName": false, + "name": "Guozhu Chen", + "orcid": "0000-0002-6067-8150" + } + ], + "contacts": [ + { + "ForeName": "Guozhu", + "LastName": "Chen", + "email": [ + "chenguozhu2002@126.com" + ], + "name": "Guozhu Chen" + } + ] + }, + "doi": "10.1242/jcs.227777", + "pmid": "31028177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation." + } + }, + { + "pmid": "25132550", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.", + "authors": { + "abbreviation": "Marius Dannappel, Katerina Vlantis, Snehlata Kumari, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Marius", + "LastName": "Dannappel", + "abbrevName": "Dannappel M", + "email": null, + "isCollectiveName": false, + "name": "Marius Dannappel", + "orcid": null + }, + { + "ForeName": "Katerina", + "LastName": "Vlantis", + "abbrevName": "Vlantis K", + "email": null, + "isCollectiveName": false, + "name": "Katerina Vlantis", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Eftychi", + "abbrevName": "Eftychi C", + "email": null, + "isCollectiveName": false, + "name": "Christina Eftychi", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Hermance", + "abbrevName": "Hermance N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Hermance", + "orcid": null + }, + { + "ForeName": "Matija", + "LastName": "Zelic", + "abbrevName": "Zelic M", + "email": null, + "isCollectiveName": false, + "name": "Matija Zelic", + "orcid": null + }, + { + "ForeName": "Petra", + "LastName": "Kirsch", + "abbrevName": "Kirsch P", + "email": null, + "isCollectiveName": false, + "name": "Petra Kirsch", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "Andre", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "Andre Bleich", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Kelliher", + "abbrevName": "Kelliher M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Kelliher", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13608", + "pmid": "25132550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis." + } + }, + { + "pmid": "29440439", + "pubmed": { + "ISODate": "2018-02-27T00:00:00.000Z", + "abstract": "RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFα-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.", + "authors": { + "abbreviation": "Huyan Meng, Zhen Liu, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Liu", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Guowei", + "LastName": "Wu", + "abbrevName": "Wu G", + "email": null, + "isCollectiveName": false, + "name": "Guowei Wu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Christofferson", + "abbrevName": "Christofferson DE", + "email": null, + "isCollectiveName": false, + "name": "Dana E Christofferson", + "orcid": null + }, + { + "ForeName": "Chunting", + "LastName": "Qi", + "abbrevName": "Qi C", + "email": null, + "isCollectiveName": false, + "name": "Chunting Qi", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Yu", + "abbrevName": "Yu Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Yu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Ying", + "LastName": "Li", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Ying Li" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1722013115", + "pmid": "29440439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "36329033", + "pubmed": { + "ISODate": "2022-11-03T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.", + "authors": { + "abbreviation": "Hailin Tu, Weihang Xiong, Jie Zhang, ..., Xin Lin", + "authorList": [ + { + "ForeName": "Hailin", + "LastName": "Tu", + "abbrevName": "Tu H", + "email": null, + "isCollectiveName": false, + "name": "Hailin Tu", + "orcid": null + }, + { + "ForeName": "Weihang", + "LastName": "Xiong", + "abbrevName": "Xiong W", + "email": null, + "isCollectiveName": false, + "name": "Weihang Xiong", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Xueqiang", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xueqiang Zhao", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": "linxin307@tsinghua.edu.cn", + "isCollectiveName": false, + "name": "Xin Lin", + "orcid": "0000-0003-0956-3654" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Lin", + "email": [ + "linxin307@tsinghua.edu.cn" + ], + "name": "Xin Lin" + } + ] + }, + "doi": "10.1038/s41467-022-34080-4", + "pmid": "36329033", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Commun 13 2022", + "title": "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + } + ], + "secret": "read-only", + "type": "complex" + }, + { + "_creationTimestamp": "2022-12-06T20:12:50.624Z", + "_newestOpId": "f7c27d9b-8617-4014-ad06-e8f2191929e4", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "619541" + }, + { + "db": "HGNC", + "id": "HGNC:14945" + }, + { + "db": "Ensembl", + "id": "ENSG00000219607" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.344946, + "id": "648791", + "name": "PPP1R3G", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "protein phosphatase 1 regulatory subunit 3G", + "protein phosphatase 1, regulatory (inhibitor) subunit 3G", + "putative protein phosphatase 1 regulatory inhibitor subunit 3G" + ], + "synonyms": [ + "protein phosphatase 1 regulatory subunit 3G", + "protein phosphatase 1, regulatory (inhibitor) subunit 3G", + "putative protein phosphatase 1 regulatory inhibitor subunit 3G" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "3e669fd7-8018-4098-b305-f050f090099e", + "liveId": "f526e826-ad78-4d59-b2af-b2ebeea04047", + "lock": null, + "locked": false, + "name": "PPP1R3G", + "parentId": "b2483833-8ca2-4246-8125-7cff29dec7ae", + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "31235688", + "pubmed": { + "ISODate": "2019-06-24T00:00:00.000Z", + "abstract": "Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.", + "authors": { + "abbreviation": "Jue Hou, Jie Ju, Zili Zhang, ..., Sudan He", + "authorList": [ + { + "ForeName": "Jue", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jue Hou", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Ju", + "abbrevName": "Ju J", + "email": null, + "isCollectiveName": false, + "name": "Jie Ju", + "orcid": null + }, + { + "ForeName": "Zili", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zili Zhang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhao", + "abbrevName": "Zhao C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhao", + "orcid": null + }, + { + "ForeName": "Zhanhui", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhanhui Li", + "orcid": null + }, + { + "ForeName": "Jiyue", + "LastName": "Zheng", + "abbrevName": "Zheng J", + "email": null, + "isCollectiveName": false, + "name": "Jiyue Zheng", + "orcid": null + }, + { + "ForeName": "Tian", + "LastName": "Sheng", + "abbrevName": "Sheng T", + "email": null, + "isCollectiveName": false, + "name": "Tian Sheng", + "orcid": null + }, + { + "ForeName": "Hongjian", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hongjian Zhang", + "orcid": null + }, + { + "ForeName": "Linkun", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Linkun Hu", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Yu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhang", + "orcid": null + }, + { + "ForeName": "Yangxin", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yangxin Li", + "orcid": null + }, + { + "ForeName": "Meng", + "LastName": "Wu", + "abbrevName": "Wu M", + "email": null, + "isCollectiveName": false, + "name": "Meng Wu", + "orcid": null + }, + { + "ForeName": "Haikuo", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": "mahaikuo123@163.com", + "isCollectiveName": false, + "name": "Haikuo Ma", + "orcid": null + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": "xiaohuzhang@suda.edu.cn", + "isCollectiveName": false, + "name": "Xiaohu Zhang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan2018@163.com", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Haikuo", + "LastName": "Ma", + "email": [ + "mahaikuo123@163.com" + ], + "name": "Haikuo Ma" + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "email": [ + "xiaohuzhang@suda.edu.cn" + ], + "name": "Xiaohu Zhang" + }, + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan2018@163.com" + ], + "name": "Sudan He" + } + ] + }, + "doi": "10.1038/s41419-019-1735-6", + "pmid": "31235688", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + }, + { + "pmid": "29078411", + "pubmed": { + "ISODate": "2017-11-07T00:00:00.000Z", + "abstract": "Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.", + "authors": { + "abbreviation": "Huibing Wang, Huyan Meng, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Kezhou", + "LastName": "Zhu", + "abbrevName": "Zhu K", + "email": null, + "isCollectiveName": false, + "name": "Kezhou Zhu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan K Mookhtiar", + "orcid": null + }, + { + "ForeName": "Huiting", + "LastName": "Wei", + "abbrevName": "Wei H", + "email": null, + "isCollectiveName": false, + "name": "Huiting Wei", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Shao-Cong", + "LastName": "Sun", + "abbrevName": "Sun SC", + "email": null, + "isCollectiveName": false, + "name": "Shao-Cong Sun", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1715742114", + "pmid": "29078411", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP." + } + }, + { + "pmid": "34262020", + "pubmed": { + "ISODate": "2021-07-14T00:00:00.000Z", + "abstract": "Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.", + "authors": { + "abbreviation": "Tom Delanghe, Jon Huyghe, Seungheon Lee, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Huyghe", + "abbrevName": "Huyghe J", + "email": null, + "isCollectiveName": false, + "name": "Jon Huyghe", + "orcid": null + }, + { + "ForeName": "Seungheon", + "LastName": "Lee", + "abbrevName": "Lee S", + "email": null, + "isCollectiveName": false, + "name": "Seungheon Lee", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": "0000-0002-2527-1101" + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41419-021-03994-0", + "pmid": "34262020", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor." + } + }, + { + "pmid": "27819682", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.", + "authors": { + "abbreviation": "Kim Newton, Katherine E Wickliffe, Allie Maltzman, ..., Vishva M Dixit", + "authorList": [ + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe KE", + "email": null, + "isCollectiveName": false, + "name": "Katherine E Wickliffe", + "orcid": null + }, + { + "ForeName": "Allie", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "Allie Maltzman", + "orcid": null + }, + { + "ForeName": "Debra", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "Debra L Dugger", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Strasser", + "abbrevName": "Strasser A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Strasser", + "orcid": null + }, + { + "ForeName": "Victoria", + "LastName": "Pham", + "abbrevName": "Pham VC", + "email": null, + "isCollectiveName": false, + "name": "Victoria C Pham", + "orcid": null + }, + { + "ForeName": "Jennie", + "LastName": "Lill", + "abbrevName": "Lill JR", + "email": null, + "isCollectiveName": false, + "name": "Jennie R Lill", + "orcid": null + }, + { + "ForeName": "Merone", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "Merone Roose-Girma", + "orcid": null + }, + { + "ForeName": "Søren", + "LastName": "Warming", + "abbrevName": "Warming S", + "email": null, + "isCollectiveName": false, + "name": "Søren Warming", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Solon", + "abbrevName": "Solon M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Solon", + "orcid": null + }, + { + "ForeName": "Hai", + "LastName": "Ngu", + "abbrevName": "Ngu H", + "email": null, + "isCollectiveName": false, + "name": "Hai Ngu", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "Joshua D Webster", + "orcid": null + }, + { + "ForeName": "Vishva", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "Vishva M Dixit", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20559", + "pmid": "27819682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 inhibits ZBP1-driven necroptosis during development." + } + }, + { + "pmid": "31028177", + "pubmed": { + "ISODate": "2019-05-20T00:00:00.000Z", + "abstract": "Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.", + "authors": { + "abbreviation": "Zicheng Wang, Jiannan Feng, Jiyun Yu, Guozhu Chen", + "authorList": [ + { + "ForeName": "Zicheng", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zicheng Wang", + "orcid": "0000-0003-2648-8289" + }, + { + "ForeName": "Jiannan", + "LastName": "Feng", + "abbrevName": "Feng J", + "email": null, + "isCollectiveName": false, + "name": "Jiannan Feng", + "orcid": null + }, + { + "ForeName": "Jiyun", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jiyun Yu", + "orcid": "0000-0003-3475-1956" + }, + { + "ForeName": "Guozhu", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "chenguozhu2002@126.com", + "isCollectiveName": false, + "name": "Guozhu Chen", + "orcid": "0000-0002-6067-8150" + } + ], + "contacts": [ + { + "ForeName": "Guozhu", + "LastName": "Chen", + "email": [ + "chenguozhu2002@126.com" + ], + "name": "Guozhu Chen" + } + ] + }, + "doi": "10.1242/jcs.227777", + "pmid": "31028177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation." + } + }, + { + "pmid": "34813352", + "pubmed": { + "ISODate": "2021-11-23T00:00:00.000Z", + "abstract": "The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.", + "authors": { + "abbreviation": "Daichao Xu, Chengyu Zou, Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Daichao Xu" + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Chengyu Zou" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1146/annurev-genet-071719-022748", + "pmid": "34813352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Genet 55 2021", + "title": "Genetic Regulation of RIPK1 and Necroptosis." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + }, + { + "pmid": "36329033", + "pubmed": { + "ISODate": "2022-11-03T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.", + "authors": { + "abbreviation": "Hailin Tu, Weihang Xiong, Jie Zhang, ..., Xin Lin", + "authorList": [ + { + "ForeName": "Hailin", + "LastName": "Tu", + "abbrevName": "Tu H", + "email": null, + "isCollectiveName": false, + "name": "Hailin Tu", + "orcid": null + }, + { + "ForeName": "Weihang", + "LastName": "Xiong", + "abbrevName": "Xiong W", + "email": null, + "isCollectiveName": false, + "name": "Weihang Xiong", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Xueqiang", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xueqiang Zhao", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": "linxin307@tsinghua.edu.cn", + "isCollectiveName": false, + "name": "Xin Lin", + "orcid": "0000-0003-0956-3654" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Lin", + "email": [ + "linxin307@tsinghua.edu.cn" + ], + "name": "Xin Lin" + } + ] + }, + "doi": "10.1038/s41467-022-34080-4", + "pmid": "36329033", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Commun 13 2022", + "title": "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation." + } + }, + { + "pmid": "25132550", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.", + "authors": { + "abbreviation": "Marius Dannappel, Katerina Vlantis, Snehlata Kumari, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Marius", + "LastName": "Dannappel", + "abbrevName": "Dannappel M", + "email": null, + "isCollectiveName": false, + "name": "Marius Dannappel", + "orcid": null + }, + { + "ForeName": "Katerina", + "LastName": "Vlantis", + "abbrevName": "Vlantis K", + "email": null, + "isCollectiveName": false, + "name": "Katerina Vlantis", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Eftychi", + "abbrevName": "Eftychi C", + "email": null, + "isCollectiveName": false, + "name": "Christina Eftychi", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Hermance", + "abbrevName": "Hermance N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Hermance", + "orcid": null + }, + { + "ForeName": "Matija", + "LastName": "Zelic", + "abbrevName": "Zelic M", + "email": null, + "isCollectiveName": false, + "name": "Matija Zelic", + "orcid": null + }, + { + "ForeName": "Petra", + "LastName": "Kirsch", + "abbrevName": "Kirsch P", + "email": null, + "isCollectiveName": false, + "name": "Petra Kirsch", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "Andre", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "Andre Bleich", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Kelliher", + "abbrevName": "Kelliher M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Kelliher", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13608", + "pmid": "25132550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis." + } + }, + { + "pmid": "23727581", + "pubmed": { + "ISODate": "2013-06-28T00:00:00.000Z", + "abstract": "While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.", + "authors": { + "abbreviation": "Ryodai Shindo, Hidenao Kakehashi, Ko Okumura, ..., Hiroyasu Nakano", + "authorList": [ + { + "ForeName": "Ryodai", + "LastName": "Shindo", + "abbrevName": "Shindo R", + "email": null, + "isCollectiveName": false, + "name": "Ryodai Shindo", + "orcid": null + }, + { + "ForeName": "Hidenao", + "LastName": "Kakehashi", + "abbrevName": "Kakehashi H", + "email": null, + "isCollectiveName": false, + "name": "Hidenao Kakehashi", + "orcid": null + }, + { + "ForeName": "Ko", + "LastName": "Okumura", + "abbrevName": "Okumura K", + "email": null, + "isCollectiveName": false, + "name": "Ko Okumura", + "orcid": null + }, + { + "ForeName": "Yoshito", + "LastName": "Kumagai", + "abbrevName": "Kumagai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshito Kumagai", + "orcid": null + }, + { + "ForeName": "Hiroyasu", + "LastName": "Nakano", + "abbrevName": "Nakano H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyasu Nakano", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2013.05.075", + "pmid": "23727581", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 436 2013", + "title": "Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation." + } + }, + { + "pmid": "30867408", + "pubmed": { + "ISODate": "2019-03-13T00:00:00.000Z", + "abstract": "RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.", + "authors": { + "abbreviation": "Xuhua Zhang, John P Dowling, Jianke Zhang", + "authorList": [ + { + "ForeName": "Xuhua", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xuhua Zhang", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Dowling", + "abbrevName": "Dowling JP", + "email": null, + "isCollectiveName": false, + "name": "John P Dowling", + "orcid": null + }, + { + "ForeName": "Jianke", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "jianke.zhang@jefferson.edu", + "isCollectiveName": false, + "name": "Jianke Zhang", + "orcid": "0000-0001-9880-8435" + } + ], + "contacts": [ + { + "ForeName": "Jianke", + "LastName": "Zhang", + "email": [ + "jianke.zhang@jefferson.edu" + ], + "name": "Jianke Zhang" + } + ] + }, + "doi": "10.1038/s41419-019-1490-8", + "pmid": "30867408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development." + } + }, + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "25186904", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.", + "authors": { + "abbreviation": "Nozomi Takahashi, Lars Vereecke, Mathieu J M Bertrand, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Lars", + "LastName": "Vereecke", + "abbrevName": "Vereecke L", + "email": null, + "isCollectiveName": false, + "name": "Lars Vereecke", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Berger", + "abbrevName": "Berger SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Berger", + "orcid": null + }, + { + "ForeName": "Tatyana", + "LastName": "Divert", + "abbrevName": "Divert T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Divert", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Gonçalves", + "orcid": null + }, + { + "ForeName": "Mozes", + "LastName": "Sze", + "abbrevName": "Sze M", + "email": null, + "isCollectiveName": false, + "name": "Mozes Sze", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Stephanie", + "LastName": "Kourula", + "abbrevName": "Kourula S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kourula", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Lefebvre", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Günther", + "abbrevName": "Günther C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Günther", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Becker", + "abbrevName": "Becker C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Becker", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Geert", + "LastName": "van Loo", + "abbrevName": "van Loo G", + "email": null, + "isCollectiveName": false, + "name": "Geert van Loo", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13706", + "pmid": "25186904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." + } + }, + { + "pmid": "33311474", + "pubmed": { + "ISODate": "2020-12-11T00:00:00.000Z", + "abstract": "RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.", + "authors": { + "abbreviation": "Xingyan Li, Mengmeng Zhang, Xinyue Huang, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Mengmeng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mengmeng Zhang", + "orcid": null + }, + { + "ForeName": "Xinyue", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xinyue Huang", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Liang", + "abbrevName": "Liang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liang", + "orcid": null + }, + { + "ForeName": "Ganquan", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Ganquan Li", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": "shanbing@sioc.ac.cn", + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "email": [ + "shanbing@sioc.ac.cn" + ], + "name": "Bing Shan" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-020-19935-y", + "pmid": "33311474", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners." + } + }, + { + "pmid": "27258786", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.", + "authors": { + "abbreviation": "B Shutinoski, N A Alturki, D Rijal, ..., S Sad", + "authorList": [ + { + "ForeName": "B", + "LastName": "Shutinoski", + "abbrevName": "Shutinoski B", + "email": null, + "isCollectiveName": false, + "name": "B Shutinoski", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Alturki", + "abbrevName": "Alturki NA", + "email": null, + "isCollectiveName": false, + "name": "N A Alturki", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rijal", + "abbrevName": "Rijal D", + "email": null, + "isCollectiveName": false, + "name": "D Rijal", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "J Bertin", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Gough", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Schlossmacher", + "abbrevName": "Schlossmacher MG", + "email": null, + "isCollectiveName": false, + "name": "M G Schlossmacher", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sad", + "abbrevName": "Sad S", + "email": null, + "isCollectiveName": false, + "name": "S Sad", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.51", + "pmid": "27258786", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo." + } + }, + { + "pmid": "27819681", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.", + "authors": { + "abbreviation": "Juan Lin, Snehlata Kumari, Chun Kim, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20558", + "pmid": "27819681", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation." + } + }, + { + "pmid": "28701375", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.", + "authors": { + "abbreviation": "Ran Wei, Lily Wen Xu, Jianping Liu, ..., Heling Pan", + "authorList": [ + { + "ForeName": "Ran", + "LastName": "Wei", + "abbrevName": "Wei R", + "email": null, + "isCollectiveName": false, + "name": "Ran Wei", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Xu", + "abbrevName": "Xu LW", + "email": null, + "isCollectiveName": false, + "name": "Lily Wen Xu", + "orcid": null + }, + { + "ForeName": "Jianping", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Liu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Pei", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Zhang", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.299776.117", + "pmid": "28701375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genes Dev 31 2017", + "title": "SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination." + } + }, + { + "pmid": "29440439", + "pubmed": { + "ISODate": "2018-02-27T00:00:00.000Z", + "abstract": "RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFα-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.", + "authors": { + "abbreviation": "Huyan Meng, Zhen Liu, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Liu", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Guowei", + "LastName": "Wu", + "abbrevName": "Wu G", + "email": null, + "isCollectiveName": false, + "name": "Guowei Wu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Christofferson", + "abbrevName": "Christofferson DE", + "email": null, + "isCollectiveName": false, + "name": "Dana E Christofferson", + "orcid": null + }, + { + "ForeName": "Chunting", + "LastName": "Qi", + "abbrevName": "Qi C", + "email": null, + "isCollectiveName": false, + "name": "Chunting Qi", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Yu", + "abbrevName": "Yu Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Yu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Ying", + "LastName": "Li", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Ying Li" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1722013115", + "pmid": "29440439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis." + } + }, + { + "pmid": "33858959", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.", + "authors": { + "abbreviation": "Snehlata Kumari, Trieu-My Van, Daniela Preukschat, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": "s.kumari@uq.edu.au", + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Preukschat", + "abbrevName": "Preukschat D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Preukschat", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schuenke", + "abbrevName": "Schuenke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schuenke", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "André", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "André Bleich", + "orcid": null + }, + { + "ForeName": "Ulf", + "LastName": "Klein", + "abbrevName": "Klein U", + "email": null, + "isCollectiveName": false, + "name": "Ulf Klein", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "email": [ + "s.kumari@uq.edu.au" + ], + "name": "Snehlata Kumari" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.26508/lsa.202000956", + "pmid": "33858959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Life Sci Alliance 4 2021", + "title": "NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + }, + { + "pmid": "34990405", + "pubmed": { + "ISODate": "2022-02-15T00:00:00.000Z", + "abstract": "Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.", + "authors": { + "abbreviation": "Haifeng Yin, Xiaoyun Guo, Yi Chen, ..., Qinghang Liu", + "authorList": [ + { + "ForeName": "Haifeng", + "LastName": "Yin", + "abbrevName": "Yin H", + "email": null, + "isCollectiveName": false, + "name": "Haifeng Yin", + "orcid": null + }, + { + "ForeName": "Xiaoyun", + "LastName": "Guo", + "abbrevName": "Guo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyun Guo", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Chen", + "orcid": null + }, + { + "ForeName": "Yachang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yachang Zeng", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Mo", + "abbrevName": "Mo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Mo", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Hong", + "abbrevName": "Hong S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Hong", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Hui He", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jing Li", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Steinmetz", + "orcid": null + }, + { + "ForeName": "Qinghang", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI152297", + "pmid": "34990405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 132 2022", + "title": "TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis." + } + }, + { + "pmid": "25195660", + "pubmed": { + "ISODate": "2014-11-01T00:00:00.000Z", + "abstract": "Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.", + "authors": { + "abbreviation": "Conor J Kearney, Sean P Cullen, Danielle Clancy, Seamus J Martin", + "authorList": [ + { + "ForeName": "Conor", + "LastName": "Kearney", + "abbrevName": "Kearney CJ", + "email": null, + "isCollectiveName": false, + "name": "Conor J Kearney", + "orcid": null + }, + { + "ForeName": "Sean", + "LastName": "Cullen", + "abbrevName": "Cullen SP", + "email": null, + "isCollectiveName": false, + "name": "Sean P Cullen", + "orcid": null + }, + { + "ForeName": "Danielle", + "LastName": "Clancy", + "abbrevName": "Clancy D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Clancy", + "orcid": null + }, + { + "ForeName": "Seamus", + "LastName": "Martin", + "abbrevName": "Martin SJ", + "email": null, + "isCollectiveName": false, + "name": "Seamus J Martin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/febs.13034", + "pmid": "25195660", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 281 2014", + "title": "RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis." + } + }, + { + "pmid": "29452637", + "pubmed": { + "ISODate": "2018-02-15T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.", + "authors": { + "abbreviation": "Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": "alessandro.annibaldi@icr.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Kirby", + "LastName": "Swatek", + "abbrevName": "Swatek KN", + "email": null, + "isCollectiveName": false, + "name": "Kirby N Swatek", + "orcid": null + }, + { + "ForeName": "Jianbin", + "LastName": "Ruan", + "abbrevName": "Ruan J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Ruan", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Katiuscia", + "LastName": "Bianchi", + "abbrevName": "Bianchi K", + "email": null, + "isCollectiveName": false, + "name": "Katiuscia Bianchi", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Wu", + "abbrevName": "Wu H", + "email": null, + "isCollectiveName": false, + "name": "Hao Wu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "email": [ + "alessandro.annibaldi@icr.ac.uk" + ], + "name": "Alessandro Annibaldi" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2018.01.027", + "pmid": "29452637", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 69 2018", + "title": "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." + } + }, + { + "pmid": "27605011", + "pubmed": { + "ISODate": "2016-10-15T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-κB activation in terms of IκBα phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1D138N) mice did not exacerbate αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.", + "authors": { + "abbreviation": "Jo Suda, Lily Dara, Luoluo Yang, ..., Zhang-Xu Liu", + "authorList": [ + { + "ForeName": "Jo", + "LastName": "Suda", + "abbrevName": "Suda J", + "email": null, + "isCollectiveName": false, + "name": "Jo Suda", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Dara", + "abbrevName": "Dara L", + "email": null, + "isCollectiveName": false, + "name": "Lily Dara", + "orcid": "0000-0002-0121-7186" + }, + { + "ForeName": "Luoluo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Luoluo Yang", + "orcid": "0000-0001-8099-9982" + }, + { + "ForeName": "Mariam", + "LastName": "Aghajan", + "abbrevName": "Aghajan M", + "email": null, + "isCollectiveName": false, + "name": "Mariam Aghajan", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Song", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Kaplowitz", + "abbrevName": "Kaplowitz N", + "email": null, + "isCollectiveName": false, + "name": "Neil Kaplowitz", + "orcid": "0000-0002-9424-393X" + }, + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "abbrevName": "Liu ZX", + "email": "zxliu@usc.edu", + "isCollectiveName": false, + "name": "Zhang-Xu Liu", + "orcid": "0000-0001-7290-3506" + } + ], + "contacts": [ + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "email": [ + "zxliu@usc.edu" + ], + "name": "Zhang-Xu Liu" + } + ] + }, + "doi": "10.4049/jimmunol.1600690", + "pmid": "27605011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Immunol 197 2016", + "title": "Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "22362767", + "pubmed": { + "ISODate": "2012-04-27T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).", + "authors": { + "abbreviation": "Linde Duprez, Mathieu J M Bertrand, Tom Vanden Berghe, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Nele", + "LastName": "Festjens", + "abbrevName": "Festjens N", + "email": null, + "isCollectiveName": false, + "name": "Nele Festjens", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.288670", + "pmid": "22362767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-12-06T20:15:56.710Z", + "_newestOpId": "8243b6e8-984c-4e0a-bc44-92b75c398b2a", + "_ops": [], + "association": "dephosphorylation", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "b2483833-8ca2-4246-8125-7cff29dec7ae" + }, + { + "group": "positive", + "id": "f9673773-0fa4-4c6c-bae3-8dc7373bc9d7" + } + ], + "id": "80f93da0-91c1-41f4-b549-6e99a2eb870c", + "liveId": "76026645-8827-4cec-8de2-518ca7a081dc", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "25132550", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.", + "authors": { + "abbreviation": "Marius Dannappel, Katerina Vlantis, Snehlata Kumari, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Marius", + "LastName": "Dannappel", + "abbrevName": "Dannappel M", + "email": null, + "isCollectiveName": false, + "name": "Marius Dannappel", + "orcid": null + }, + { + "ForeName": "Katerina", + "LastName": "Vlantis", + "abbrevName": "Vlantis K", + "email": null, + "isCollectiveName": false, + "name": "Katerina Vlantis", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Eftychi", + "abbrevName": "Eftychi C", + "email": null, + "isCollectiveName": false, + "name": "Christina Eftychi", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Hermance", + "abbrevName": "Hermance N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Hermance", + "orcid": null + }, + { + "ForeName": "Matija", + "LastName": "Zelic", + "abbrevName": "Zelic M", + "email": null, + "isCollectiveName": false, + "name": "Matija Zelic", + "orcid": null + }, + { + "ForeName": "Petra", + "LastName": "Kirsch", + "abbrevName": "Kirsch P", + "email": null, + "isCollectiveName": false, + "name": "Petra Kirsch", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "Andre", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "Andre Bleich", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Kelliher", + "abbrevName": "Kelliher M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Kelliher", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13608", + "pmid": "25132550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis." + } + }, + { + "pmid": "27819681", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.", + "authors": { + "abbreviation": "Juan Lin, Snehlata Kumari, Chun Kim, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20558", + "pmid": "27819681", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "27605011", + "pubmed": { + "ISODate": "2016-10-15T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-κB activation in terms of IκBα phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1D138N) mice did not exacerbate αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.", + "authors": { + "abbreviation": "Jo Suda, Lily Dara, Luoluo Yang, ..., Zhang-Xu Liu", + "authorList": [ + { + "ForeName": "Jo", + "LastName": "Suda", + "abbrevName": "Suda J", + "email": null, + "isCollectiveName": false, + "name": "Jo Suda", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Dara", + "abbrevName": "Dara L", + "email": null, + "isCollectiveName": false, + "name": "Lily Dara", + "orcid": "0000-0002-0121-7186" + }, + { + "ForeName": "Luoluo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Luoluo Yang", + "orcid": "0000-0001-8099-9982" + }, + { + "ForeName": "Mariam", + "LastName": "Aghajan", + "abbrevName": "Aghajan M", + "email": null, + "isCollectiveName": false, + "name": "Mariam Aghajan", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Song", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Kaplowitz", + "abbrevName": "Kaplowitz N", + "email": null, + "isCollectiveName": false, + "name": "Neil Kaplowitz", + "orcid": "0000-0002-9424-393X" + }, + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "abbrevName": "Liu ZX", + "email": "zxliu@usc.edu", + "isCollectiveName": false, + "name": "Zhang-Xu Liu", + "orcid": "0000-0001-7290-3506" + } + ], + "contacts": [ + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "email": [ + "zxliu@usc.edu" + ], + "name": "Zhang-Xu Liu" + } + ] + }, + "doi": "10.4049/jimmunol.1600690", + "pmid": "27605011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Immunol 197 2016", + "title": "Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB." + } + }, + { + "pmid": "27258786", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.", + "authors": { + "abbreviation": "B Shutinoski, N A Alturki, D Rijal, ..., S Sad", + "authorList": [ + { + "ForeName": "B", + "LastName": "Shutinoski", + "abbrevName": "Shutinoski B", + "email": null, + "isCollectiveName": false, + "name": "B Shutinoski", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Alturki", + "abbrevName": "Alturki NA", + "email": null, + "isCollectiveName": false, + "name": "N A Alturki", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rijal", + "abbrevName": "Rijal D", + "email": null, + "isCollectiveName": false, + "name": "D Rijal", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "J Bertin", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Gough", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Schlossmacher", + "abbrevName": "Schlossmacher MG", + "email": null, + "isCollectiveName": false, + "name": "M G Schlossmacher", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sad", + "abbrevName": "Sad S", + "email": null, + "isCollectiveName": false, + "name": "S Sad", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.51", + "pmid": "27258786", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo." + } + }, + { + "pmid": "34813352", + "pubmed": { + "ISODate": "2021-11-23T00:00:00.000Z", + "abstract": "The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.", + "authors": { + "abbreviation": "Daichao Xu, Chengyu Zou, Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Daichao Xu" + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Chengyu Zou" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1146/annurev-genet-071719-022748", + "pmid": "34813352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Genet 55 2021", + "title": "Genetic Regulation of RIPK1 and Necroptosis." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + }, + { + "pmid": "22362767", + "pubmed": { + "ISODate": "2012-04-27T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).", + "authors": { + "abbreviation": "Linde Duprez, Mathieu J M Bertrand, Tom Vanden Berghe, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Nele", + "LastName": "Festjens", + "abbrevName": "Festjens N", + "email": null, + "isCollectiveName": false, + "name": "Nele Festjens", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.288670", + "pmid": "22362767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis." + } + }, + { + "pmid": "33311474", + "pubmed": { + "ISODate": "2020-12-11T00:00:00.000Z", + "abstract": "RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.", + "authors": { + "abbreviation": "Xingyan Li, Mengmeng Zhang, Xinyue Huang, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Mengmeng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mengmeng Zhang", + "orcid": null + }, + { + "ForeName": "Xinyue", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xinyue Huang", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Liang", + "abbrevName": "Liang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liang", + "orcid": null + }, + { + "ForeName": "Ganquan", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Ganquan Li", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": "shanbing@sioc.ac.cn", + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "email": [ + "shanbing@sioc.ac.cn" + ], + "name": "Bing Shan" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-020-19935-y", + "pmid": "33311474", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners." + } + }, + { + "pmid": "23727581", + "pubmed": { + "ISODate": "2013-06-28T00:00:00.000Z", + "abstract": "While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.", + "authors": { + "abbreviation": "Ryodai Shindo, Hidenao Kakehashi, Ko Okumura, ..., Hiroyasu Nakano", + "authorList": [ + { + "ForeName": "Ryodai", + "LastName": "Shindo", + "abbrevName": "Shindo R", + "email": null, + "isCollectiveName": false, + "name": "Ryodai Shindo", + "orcid": null + }, + { + "ForeName": "Hidenao", + "LastName": "Kakehashi", + "abbrevName": "Kakehashi H", + "email": null, + "isCollectiveName": false, + "name": "Hidenao Kakehashi", + "orcid": null + }, + { + "ForeName": "Ko", + "LastName": "Okumura", + "abbrevName": "Okumura K", + "email": null, + "isCollectiveName": false, + "name": "Ko Okumura", + "orcid": null + }, + { + "ForeName": "Yoshito", + "LastName": "Kumagai", + "abbrevName": "Kumagai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshito Kumagai", + "orcid": null + }, + { + "ForeName": "Hiroyasu", + "LastName": "Nakano", + "abbrevName": "Nakano H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyasu Nakano", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2013.05.075", + "pmid": "23727581", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 436 2013", + "title": "Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "34262020", + "pubmed": { + "ISODate": "2021-07-14T00:00:00.000Z", + "abstract": "Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.", + "authors": { + "abbreviation": "Tom Delanghe, Jon Huyghe, Seungheon Lee, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Huyghe", + "abbrevName": "Huyghe J", + "email": null, + "isCollectiveName": false, + "name": "Jon Huyghe", + "orcid": null + }, + { + "ForeName": "Seungheon", + "LastName": "Lee", + "abbrevName": "Lee S", + "email": null, + "isCollectiveName": false, + "name": "Seungheon Lee", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": "0000-0002-2527-1101" + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41419-021-03994-0", + "pmid": "34262020", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor." + } + }, + { + "pmid": "34990405", + "pubmed": { + "ISODate": "2022-02-15T00:00:00.000Z", + "abstract": "Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.", + "authors": { + "abbreviation": "Haifeng Yin, Xiaoyun Guo, Yi Chen, ..., Qinghang Liu", + "authorList": [ + { + "ForeName": "Haifeng", + "LastName": "Yin", + "abbrevName": "Yin H", + "email": null, + "isCollectiveName": false, + "name": "Haifeng Yin", + "orcid": null + }, + { + "ForeName": "Xiaoyun", + "LastName": "Guo", + "abbrevName": "Guo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyun Guo", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Chen", + "orcid": null + }, + { + "ForeName": "Yachang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yachang Zeng", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Mo", + "abbrevName": "Mo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Mo", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Hong", + "abbrevName": "Hong S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Hong", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Hui He", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jing Li", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Steinmetz", + "orcid": null + }, + { + "ForeName": "Qinghang", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI152297", + "pmid": "34990405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 132 2022", + "title": "TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis." + } + }, + { + "pmid": "36329033", + "pubmed": { + "ISODate": "2022-11-03T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.", + "authors": { + "abbreviation": "Hailin Tu, Weihang Xiong, Jie Zhang, ..., Xin Lin", + "authorList": [ + { + "ForeName": "Hailin", + "LastName": "Tu", + "abbrevName": "Tu H", + "email": null, + "isCollectiveName": false, + "name": "Hailin Tu", + "orcid": null + }, + { + "ForeName": "Weihang", + "LastName": "Xiong", + "abbrevName": "Xiong W", + "email": null, + "isCollectiveName": false, + "name": "Weihang Xiong", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Xueqiang", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xueqiang Zhao", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": "linxin307@tsinghua.edu.cn", + "isCollectiveName": false, + "name": "Xin Lin", + "orcid": "0000-0003-0956-3654" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Lin", + "email": [ + "linxin307@tsinghua.edu.cn" + ], + "name": "Xin Lin" + } + ] + }, + "doi": "10.1038/s41467-022-34080-4", + "pmid": "36329033", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Commun 13 2022", + "title": "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation." + } + }, + { + "pmid": "29440439", + "pubmed": { + "ISODate": "2018-02-27T00:00:00.000Z", + "abstract": "RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFα-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.", + "authors": { + "abbreviation": "Huyan Meng, Zhen Liu, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Liu", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Guowei", + "LastName": "Wu", + "abbrevName": "Wu G", + "email": null, + "isCollectiveName": false, + "name": "Guowei Wu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Christofferson", + "abbrevName": "Christofferson DE", + "email": null, + "isCollectiveName": false, + "name": "Dana E Christofferson", + "orcid": null + }, + { + "ForeName": "Chunting", + "LastName": "Qi", + "abbrevName": "Qi C", + "email": null, + "isCollectiveName": false, + "name": "Chunting Qi", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Yu", + "abbrevName": "Yu Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Yu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Ying", + "LastName": "Li", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Ying Li" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1722013115", + "pmid": "29440439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis." + } + }, + { + "pmid": "25195660", + "pubmed": { + "ISODate": "2014-11-01T00:00:00.000Z", + "abstract": "Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.", + "authors": { + "abbreviation": "Conor J Kearney, Sean P Cullen, Danielle Clancy, Seamus J Martin", + "authorList": [ + { + "ForeName": "Conor", + "LastName": "Kearney", + "abbrevName": "Kearney CJ", + "email": null, + "isCollectiveName": false, + "name": "Conor J Kearney", + "orcid": null + }, + { + "ForeName": "Sean", + "LastName": "Cullen", + "abbrevName": "Cullen SP", + "email": null, + "isCollectiveName": false, + "name": "Sean P Cullen", + "orcid": null + }, + { + "ForeName": "Danielle", + "LastName": "Clancy", + "abbrevName": "Clancy D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Clancy", + "orcid": null + }, + { + "ForeName": "Seamus", + "LastName": "Martin", + "abbrevName": "Martin SJ", + "email": null, + "isCollectiveName": false, + "name": "Seamus J Martin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/febs.13034", + "pmid": "25195660", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 281 2014", + "title": "RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis." + } + }, + { + "pmid": "25186904", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.", + "authors": { + "abbreviation": "Nozomi Takahashi, Lars Vereecke, Mathieu J M Bertrand, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Lars", + "LastName": "Vereecke", + "abbrevName": "Vereecke L", + "email": null, + "isCollectiveName": false, + "name": "Lars Vereecke", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Berger", + "abbrevName": "Berger SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Berger", + "orcid": null + }, + { + "ForeName": "Tatyana", + "LastName": "Divert", + "abbrevName": "Divert T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Divert", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Gonçalves", + "orcid": null + }, + { + "ForeName": "Mozes", + "LastName": "Sze", + "abbrevName": "Sze M", + "email": null, + "isCollectiveName": false, + "name": "Mozes Sze", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Stephanie", + "LastName": "Kourula", + "abbrevName": "Kourula S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kourula", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Lefebvre", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Günther", + "abbrevName": "Günther C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Günther", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Becker", + "abbrevName": "Becker C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Becker", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Geert", + "LastName": "van Loo", + "abbrevName": "van Loo G", + "email": null, + "isCollectiveName": false, + "name": "Geert van Loo", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13706", + "pmid": "25186904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." + } + }, + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "28701375", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.", + "authors": { + "abbreviation": "Ran Wei, Lily Wen Xu, Jianping Liu, ..., Heling Pan", + "authorList": [ + { + "ForeName": "Ran", + "LastName": "Wei", + "abbrevName": "Wei R", + "email": null, + "isCollectiveName": false, + "name": "Ran Wei", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Xu", + "abbrevName": "Xu LW", + "email": null, + "isCollectiveName": false, + "name": "Lily Wen Xu", + "orcid": null + }, + { + "ForeName": "Jianping", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Liu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Pei", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Zhang", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.299776.117", + "pmid": "28701375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genes Dev 31 2017", + "title": "SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "31028177", + "pubmed": { + "ISODate": "2019-05-20T00:00:00.000Z", + "abstract": "Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.", + "authors": { + "abbreviation": "Zicheng Wang, Jiannan Feng, Jiyun Yu, Guozhu Chen", + "authorList": [ + { + "ForeName": "Zicheng", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zicheng Wang", + "orcid": "0000-0003-2648-8289" + }, + { + "ForeName": "Jiannan", + "LastName": "Feng", + "abbrevName": "Feng J", + "email": null, + "isCollectiveName": false, + "name": "Jiannan Feng", + "orcid": null + }, + { + "ForeName": "Jiyun", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jiyun Yu", + "orcid": "0000-0003-3475-1956" + }, + { + "ForeName": "Guozhu", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "chenguozhu2002@126.com", + "isCollectiveName": false, + "name": "Guozhu Chen", + "orcid": "0000-0002-6067-8150" + } + ], + "contacts": [ + { + "ForeName": "Guozhu", + "LastName": "Chen", + "email": [ + "chenguozhu2002@126.com" + ], + "name": "Guozhu Chen" + } + ] + }, + "doi": "10.1242/jcs.227777", + "pmid": "31028177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + }, + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "31235688", + "pubmed": { + "ISODate": "2019-06-24T00:00:00.000Z", + "abstract": "Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.", + "authors": { + "abbreviation": "Jue Hou, Jie Ju, Zili Zhang, ..., Sudan He", + "authorList": [ + { + "ForeName": "Jue", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jue Hou", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Ju", + "abbrevName": "Ju J", + "email": null, + "isCollectiveName": false, + "name": "Jie Ju", + "orcid": null + }, + { + "ForeName": "Zili", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zili Zhang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhao", + "abbrevName": "Zhao C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhao", + "orcid": null + }, + { + "ForeName": "Zhanhui", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhanhui Li", + "orcid": null + }, + { + "ForeName": "Jiyue", + "LastName": "Zheng", + "abbrevName": "Zheng J", + "email": null, + "isCollectiveName": false, + "name": "Jiyue Zheng", + "orcid": null + }, + { + "ForeName": "Tian", + "LastName": "Sheng", + "abbrevName": "Sheng T", + "email": null, + "isCollectiveName": false, + "name": "Tian Sheng", + "orcid": null + }, + { + "ForeName": "Hongjian", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hongjian Zhang", + "orcid": null + }, + { + "ForeName": "Linkun", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Linkun Hu", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Yu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhang", + "orcid": null + }, + { + "ForeName": "Yangxin", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yangxin Li", + "orcid": null + }, + { + "ForeName": "Meng", + "LastName": "Wu", + "abbrevName": "Wu M", + "email": null, + "isCollectiveName": false, + "name": "Meng Wu", + "orcid": null + }, + { + "ForeName": "Haikuo", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": "mahaikuo123@163.com", + "isCollectiveName": false, + "name": "Haikuo Ma", + "orcid": null + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": "xiaohuzhang@suda.edu.cn", + "isCollectiveName": false, + "name": "Xiaohu Zhang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan2018@163.com", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Haikuo", + "LastName": "Ma", + "email": [ + "mahaikuo123@163.com" + ], + "name": "Haikuo Ma" + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "email": [ + "xiaohuzhang@suda.edu.cn" + ], + "name": "Xiaohu Zhang" + }, + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan2018@163.com" + ], + "name": "Sudan He" + } + ] + }, + "doi": "10.1038/s41419-019-1735-6", + "pmid": "31235688", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis." + } + }, + { + "pmid": "33858959", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.", + "authors": { + "abbreviation": "Snehlata Kumari, Trieu-My Van, Daniela Preukschat, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": "s.kumari@uq.edu.au", + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Preukschat", + "abbrevName": "Preukschat D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Preukschat", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schuenke", + "abbrevName": "Schuenke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schuenke", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "André", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "André Bleich", + "orcid": null + }, + { + "ForeName": "Ulf", + "LastName": "Klein", + "abbrevName": "Klein U", + "email": null, + "isCollectiveName": false, + "name": "Ulf Klein", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "email": [ + "s.kumari@uq.edu.au" + ], + "name": "Snehlata Kumari" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.26508/lsa.202000956", + "pmid": "33858959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Life Sci Alliance 4 2021", + "title": "NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation." + } + }, + { + "pmid": "27819682", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.", + "authors": { + "abbreviation": "Kim Newton, Katherine E Wickliffe, Allie Maltzman, ..., Vishva M Dixit", + "authorList": [ + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe KE", + "email": null, + "isCollectiveName": false, + "name": "Katherine E Wickliffe", + "orcid": null + }, + { + "ForeName": "Allie", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "Allie Maltzman", + "orcid": null + }, + { + "ForeName": "Debra", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "Debra L Dugger", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Strasser", + "abbrevName": "Strasser A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Strasser", + "orcid": null + }, + { + "ForeName": "Victoria", + "LastName": "Pham", + "abbrevName": "Pham VC", + "email": null, + "isCollectiveName": false, + "name": "Victoria C Pham", + "orcid": null + }, + { + "ForeName": "Jennie", + "LastName": "Lill", + "abbrevName": "Lill JR", + "email": null, + "isCollectiveName": false, + "name": "Jennie R Lill", + "orcid": null + }, + { + "ForeName": "Merone", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "Merone Roose-Girma", + "orcid": null + }, + { + "ForeName": "Søren", + "LastName": "Warming", + "abbrevName": "Warming S", + "email": null, + "isCollectiveName": false, + "name": "Søren Warming", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Solon", + "abbrevName": "Solon M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Solon", + "orcid": null + }, + { + "ForeName": "Hai", + "LastName": "Ngu", + "abbrevName": "Ngu H", + "email": null, + "isCollectiveName": false, + "name": "Hai Ngu", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "Joshua D Webster", + "orcid": null + }, + { + "ForeName": "Vishva", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "Vishva M Dixit", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20559", + "pmid": "27819682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 inhibits ZBP1-driven necroptosis during development." + } + }, + { + "pmid": "29078411", + "pubmed": { + "ISODate": "2017-11-07T00:00:00.000Z", + "abstract": "Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.", + "authors": { + "abbreviation": "Huibing Wang, Huyan Meng, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Kezhou", + "LastName": "Zhu", + "abbrevName": "Zhu K", + "email": null, + "isCollectiveName": false, + "name": "Kezhou Zhu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan K Mookhtiar", + "orcid": null + }, + { + "ForeName": "Huiting", + "LastName": "Wei", + "abbrevName": "Wei H", + "email": null, + "isCollectiveName": false, + "name": "Huiting Wei", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Shao-Cong", + "LastName": "Sun", + "abbrevName": "Sun SC", + "email": null, + "isCollectiveName": false, + "name": "Shao-Cong Sun", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1715742114", + "pmid": "29078411", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP." + } + }, + { + "pmid": "30867408", + "pubmed": { + "ISODate": "2019-03-13T00:00:00.000Z", + "abstract": "RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.", + "authors": { + "abbreviation": "Xuhua Zhang, John P Dowling, Jianke Zhang", + "authorList": [ + { + "ForeName": "Xuhua", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xuhua Zhang", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Dowling", + "abbrevName": "Dowling JP", + "email": null, + "isCollectiveName": false, + "name": "John P Dowling", + "orcid": null + }, + { + "ForeName": "Jianke", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "jianke.zhang@jefferson.edu", + "isCollectiveName": false, + "name": "Jianke Zhang", + "orcid": "0000-0001-9880-8435" + } + ], + "contacts": [ + { + "ForeName": "Jianke", + "LastName": "Zhang", + "email": [ + "jianke.zhang@jefferson.edu" + ], + "name": "Jianke Zhang" + } + ] + }, + "doi": "10.1038/s41419-019-1490-8", + "pmid": "30867408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development." + } + }, + { + "pmid": "29452637", + "pubmed": { + "ISODate": "2018-02-15T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.", + "authors": { + "abbreviation": "Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": "alessandro.annibaldi@icr.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Kirby", + "LastName": "Swatek", + "abbrevName": "Swatek KN", + "email": null, + "isCollectiveName": false, + "name": "Kirby N Swatek", + "orcid": null + }, + { + "ForeName": "Jianbin", + "LastName": "Ruan", + "abbrevName": "Ruan J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Ruan", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Katiuscia", + "LastName": "Bianchi", + "abbrevName": "Bianchi K", + "email": null, + "isCollectiveName": false, + "name": "Katiuscia Bianchi", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Wu", + "abbrevName": "Wu H", + "email": null, + "isCollectiveName": false, + "name": "Hao Wu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "email": [ + "alessandro.annibaldi@icr.ac.uk" + ], + "name": "Alessandro Annibaldi" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2018.01.027", + "pmid": "29452637", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 69 2018", + "title": "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." + } + } + ], + "secret": "read-only", + "type": "dephosphorylation" + }, + { + "_creationTimestamp": "2022-12-06T20:15:33.183Z", + "_newestOpId": 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kinase 1", + "cell death protein RIP", + "receptor (TNFRSF)-interacting serine-threonine kinase 1", + "receptor-interacting protein 1", + "receptor-interacting protein kinase 1", + "serine/threonine-protein kinase RIP", + "receptor interacting serine/threonine kinase 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "f9673773-0fa4-4c6c-bae3-8dc7373bc9d7", + "liveId": "da0aed22-4fa8-48be-bd17-33375f7c36c9", + "lock": null, + "locked": false, + "name": "RIPK1", + "position": { + "x": 275.9493670886076, + "y": 111.89873417721518 + }, + "relatedPapers": [ + { + "pmid": "34990405", + "pubmed": { + "ISODate": "2022-02-15T00:00:00.000Z", + "abstract": "Mutations in TGF-β-activated kinase 1 binding protein 2 (TAB2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here, we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing receptor-interacting protein kinase 1 (RIPK1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling after pathological stress. In cardiomyocytes, deletion of TAB2 but not its close homolog TAB3 promoted TNF-α-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knockin effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrated that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.", + "authors": { + "abbreviation": "Haifeng Yin, Xiaoyun Guo, Yi Chen, ..., Qinghang Liu", + "authorList": [ + { + "ForeName": "Haifeng", + "LastName": "Yin", + "abbrevName": "Yin H", + "email": null, + "isCollectiveName": false, + "name": "Haifeng Yin", + "orcid": null + }, + { + "ForeName": "Xiaoyun", + "LastName": "Guo", + "abbrevName": "Guo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoyun Guo", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Chen", + "orcid": null + }, + { + "ForeName": "Yachang", + "LastName": "Zeng", + "abbrevName": "Zeng Y", + "email": null, + "isCollectiveName": false, + "name": "Yachang Zeng", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Mo", + "abbrevName": "Mo X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Mo", + "orcid": null + }, + { + "ForeName": "Siqi", + "LastName": "Hong", + "abbrevName": "Hong S", + "email": null, + "isCollectiveName": false, + "name": "Siqi Hong", + "orcid": null + }, + { + "ForeName": "Hui", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Hui He", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jing Li", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Steinmetz", + "orcid": null + }, + { + "ForeName": "Qinghang", + "LastName": "Liu", + "abbrevName": "Liu Q", + "email": null, + "isCollectiveName": false, + "name": "Qinghang Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI152297", + "pmid": "34990405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 132 2022", + "title": "TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis." + } + }, + { + "pmid": "27819681", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.", + "authors": { + "abbreviation": "Juan Lin, Snehlata Kumari, Chun Kim, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20558", + "pmid": "27819681", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation." + } + }, + { + "pmid": "25186904", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.", + "authors": { + "abbreviation": "Nozomi Takahashi, Lars Vereecke, Mathieu J M Bertrand, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Nozomi", + "LastName": "Takahashi", + "abbrevName": "Takahashi N", + "email": null, + "isCollectiveName": false, + "name": "Nozomi Takahashi", + "orcid": null + }, + { + "ForeName": "Lars", + "LastName": "Vereecke", + "abbrevName": "Vereecke L", + "email": null, + "isCollectiveName": false, + "name": "Lars Vereecke", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Scott", + "LastName": "Berger", + "abbrevName": "Berger SB", + "email": null, + "isCollectiveName": false, + "name": "Scott B Berger", + "orcid": null + }, + { + "ForeName": "Tatyana", + "LastName": "Divert", + "abbrevName": "Divert T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Divert", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Gonçalves", + "abbrevName": "Gonçalves A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Gonçalves", + "orcid": null + }, + { + "ForeName": "Mozes", + "LastName": "Sze", + "abbrevName": "Sze M", + "email": null, + "isCollectiveName": false, + "name": "Mozes Sze", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Stephanie", + "LastName": "Kourula", + "abbrevName": "Kourula S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kourula", + "orcid": null + }, + { + "ForeName": "Vera", + "LastName": "Goossens", + "abbrevName": "Goossens V", + "email": null, + "isCollectiveName": false, + "name": "Vera Goossens", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Lefebvre", + "orcid": null + }, + { + "ForeName": "Claudia", + "LastName": "Günther", + "abbrevName": "Günther C", + "email": null, + "isCollectiveName": false, + "name": "Claudia Günther", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Becker", + "abbrevName": "Becker C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Becker", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Gough", + "orcid": null + }, + { + "ForeName": "Wim", + "LastName": "Declercq", + "abbrevName": "Declercq W", + "email": null, + "isCollectiveName": false, + "name": "Wim Declercq", + "orcid": null + }, + { + "ForeName": "Geert", + "LastName": "van Loo", + "abbrevName": "van Loo G", + "email": null, + "isCollectiveName": false, + "name": "Geert van Loo", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13706", + "pmid": "25186904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." + } + }, + { + "pmid": "29891719", + "pubmed": { + "ISODate": "2018-06-26T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed \"iuRIPK1.\" iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.", + "authors": { + "abbreviation": "Palak Amin, Marcus Florez, Ayaz Najafov, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Florez", + "abbrevName": "Florez M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Florez", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Dimitry", + "LastName": "Ofengeim", + "abbrevName": "Ofengeim D", + "email": null, + "isCollectiveName": false, + "name": "Dimitry Ofengeim", + "orcid": null + }, + { + "ForeName": "Slawomir", + "LastName": "Dziedzic", + "abbrevName": "Dziedzic SA", + "email": null, + "isCollectiveName": false, + "name": "Slawomir A Dziedzic", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Vica", + "LastName": "Barrett", + "abbrevName": "Barrett VJ", + "email": null, + "isCollectiveName": false, + "name": "Vica Jean Barrett", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "LaVoie", + "abbrevName": "LaVoie MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J LaVoie", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1806973115", + "pmid": "29891719", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis." + } + }, + { + "pmid": "29440439", + "pubmed": { + "ISODate": "2018-02-27T00:00:00.000Z", + "abstract": "RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNFα, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNFα-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.", + "authors": { + "abbreviation": "Huyan Meng, Zhen Liu, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Zhen", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Liu", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Taijie", + "LastName": "Jin", + "abbrevName": "Jin T", + "email": null, + "isCollectiveName": false, + "name": "Taijie Jin", + "orcid": null + }, + { + "ForeName": "Guowei", + "LastName": "Wu", + "abbrevName": "Wu G", + "email": null, + "isCollectiveName": false, + "name": "Guowei Wu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Christofferson", + "abbrevName": "Christofferson DE", + "email": null, + "isCollectiveName": false, + "name": "Dana E Christofferson", + "orcid": null + }, + { + "ForeName": "Chunting", + "LastName": "Qi", + "abbrevName": "Qi C", + "email": null, + "isCollectiveName": false, + "name": "Chunting Qi", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Yu", + "abbrevName": "Yu Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Yu", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "liying@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Ying", + "LastName": "Li", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Ying Li" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "liying@sioc.ac.cn", + "junying_yuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1722013115", + "pmid": "29440439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis." + } + }, + { + "pmid": "25195660", + "pubmed": { + "ISODate": "2014-11-01T00:00:00.000Z", + "abstract": "Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor-interacting serine/threonine kinase (RIPK)3. Because inhibitors of RIPK1 kinase activity such as necrostatin-1 block necroptosis in many settings, RIPK1 is thought to be required for activation of RIPK3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor-induced, lipopolysaccharide-induced and polyIC-induced necroptosis, RIPK1 knockdown unexpectedly potentiated this process. In contrast, RIPK3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK1, indicating that its ability to suppress necroptosis was indeed RIPK1-dependent. These data argue that RIPK1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK1 on necroptosis, as opposed to blocking its participation in this process.", + "authors": { + "abbreviation": "Conor J Kearney, Sean P Cullen, Danielle Clancy, Seamus J Martin", + "authorList": [ + { + "ForeName": "Conor", + "LastName": "Kearney", + "abbrevName": "Kearney CJ", + "email": null, + "isCollectiveName": false, + "name": "Conor J Kearney", + "orcid": null + }, + { + "ForeName": "Sean", + "LastName": "Cullen", + "abbrevName": "Cullen SP", + "email": null, + "isCollectiveName": false, + "name": "Sean P Cullen", + "orcid": null + }, + { + "ForeName": "Danielle", + "LastName": "Clancy", + "abbrevName": "Clancy D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Clancy", + "orcid": null + }, + { + "ForeName": "Seamus", + "LastName": "Martin", + "abbrevName": "Martin SJ", + "email": null, + "isCollectiveName": false, + "name": "Seamus J Martin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1111/febs.13034", + "pmid": "25195660", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS J 281 2014", + "title": "RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis." + } + }, + { + "pmid": "25132550", + "pubmed": { + "ISODate": "2014-09-04T00:00:00.000Z", + "abstract": "Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.", + "authors": { + "abbreviation": "Marius Dannappel, Katerina Vlantis, Snehlata Kumari, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Marius", + "LastName": "Dannappel", + "abbrevName": "Dannappel M", + "email": null, + "isCollectiveName": false, + "name": "Marius Dannappel", + "orcid": null + }, + { + "ForeName": "Katerina", + "LastName": "Vlantis", + "abbrevName": "Vlantis K", + "email": null, + "isCollectiveName": false, + "name": "Katerina Vlantis", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": null + }, + { + "ForeName": "Apostolos", + "LastName": "Polykratis", + "abbrevName": "Polykratis A", + "email": null, + "isCollectiveName": false, + "name": "Apostolos Polykratis", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Laurens", + "LastName": "Wachsmuth", + "abbrevName": "Wachsmuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurens Wachsmuth", + "orcid": null + }, + { + "ForeName": "Christina", + "LastName": "Eftychi", + "abbrevName": "Eftychi C", + "email": null, + "isCollectiveName": false, + "name": "Christina Eftychi", + "orcid": null + }, + { + "ForeName": "Juan", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Juan Lin", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Hermance", + "abbrevName": "Hermance N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Hermance", + "orcid": null + }, + { + "ForeName": "Matija", + "LastName": "Zelic", + "abbrevName": "Zelic M", + "email": null, + "isCollectiveName": false, + "name": "Matija Zelic", + "orcid": null + }, + { + "ForeName": "Petra", + "LastName": "Kirsch", + "abbrevName": "Kirsch P", + "email": null, + "isCollectiveName": false, + "name": "Petra Kirsch", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "Andre", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "Andre Bleich", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Kelliher", + "abbrevName": "Kelliher M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Kelliher", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": null, + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature13608", + "pmid": "25132550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 513 2014", + "title": "RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis." + } + }, + { + "pmid": "32269263", + "pubmed": { + "ISODate": "2020-04-08T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.", + "authors": { + "abbreviation": "Lucie Laurien, Masahiro Nagata, Hannah Schünke, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Masahiro", + "LastName": "Nagata", + "abbrevName": "Nagata M", + "email": null, + "isCollectiveName": false, + "name": "Masahiro Nagata", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schünke", + "abbrevName": "Schünke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schünke", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Janica", + "LastName": "Wiederstein", + "abbrevName": "Wiederstein JL", + "email": null, + "isCollectiveName": false, + "name": "Janica L Wiederstein", + "orcid": null + }, + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": null, + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Robin", + "LastName": "Schwarzer", + "abbrevName": "Schwarzer R", + "email": null, + "isCollectiveName": false, + "name": "Robin Schwarzer", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Corona", + "abbrevName": "Corona T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Corona", + "orcid": null + }, + { + "ForeName": "Marcus", + "LastName": "Krüger", + "abbrevName": "Krüger M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Krüger", + "orcid": "0000-0002-5846-6941" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + }, + { + "ForeName": "Vangelis", + "LastName": "Kondylis", + "abbrevName": "Kondylis V", + "email": null, + "isCollectiveName": false, + "name": "Vangelis Kondylis", + "orcid": "0000-0002-6970-8731" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.1038/s41467-020-15466-8", + "pmid": "32269263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation." + } + }, + { + "pmid": "27819682", + "pubmed": { + "ISODate": "2016-12-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.", + "authors": { + "abbreviation": "Kim Newton, Katherine E Wickliffe, Allie Maltzman, ..., Vishva M Dixit", + "authorList": [ + { + "ForeName": "Kim", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "Kim Newton", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Wickliffe", + "abbrevName": "Wickliffe KE", + "email": null, + "isCollectiveName": false, + "name": "Katherine E Wickliffe", + "orcid": null + }, + { + "ForeName": "Allie", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "Allie Maltzman", + "orcid": null + }, + { + "ForeName": "Debra", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "Debra L Dugger", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Strasser", + "abbrevName": "Strasser A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Strasser", + "orcid": null + }, + { + "ForeName": "Victoria", + "LastName": "Pham", + "abbrevName": "Pham VC", + "email": null, + "isCollectiveName": false, + "name": "Victoria C Pham", + "orcid": null + }, + { + "ForeName": "Jennie", + "LastName": "Lill", + "abbrevName": "Lill JR", + "email": null, + "isCollectiveName": false, + "name": "Jennie R Lill", + "orcid": null + }, + { + "ForeName": "Merone", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "Merone Roose-Girma", + "orcid": null + }, + { + "ForeName": "Søren", + "LastName": "Warming", + "abbrevName": "Warming S", + "email": null, + "isCollectiveName": false, + "name": "Søren Warming", + "orcid": null + }, + { + "ForeName": "Margaret", + "LastName": "Solon", + "abbrevName": "Solon M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Solon", + "orcid": null + }, + { + "ForeName": "Hai", + "LastName": "Ngu", + "abbrevName": "Ngu H", + "email": null, + "isCollectiveName": false, + "name": "Hai Ngu", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "Joshua D Webster", + "orcid": null + }, + { + "ForeName": "Vishva", + "LastName": "Dixit", + "abbrevName": "Dixit VM", + "email": null, + "isCollectiveName": false, + "name": "Vishva M Dixit", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature20559", + "pmid": "27819682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 540 2016", + "title": "RIPK1 inhibits ZBP1-driven necroptosis during development." + } + }, + { + "pmid": "27177019", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.", + "authors": { + "abbreviation": "K Newton, D L Dugger, A Maltzman, ..., D Vucic", + "authorList": [ + { + "ForeName": "K", + "LastName": "Newton", + "abbrevName": "Newton K", + "email": null, + "isCollectiveName": false, + "name": "K Newton", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Dugger", + "abbrevName": "Dugger DL", + "email": null, + "isCollectiveName": false, + "name": "D L Dugger", + "orcid": null + }, + { + "ForeName": "A", + "LastName": "Maltzman", + "abbrevName": "Maltzman A", + "email": null, + "isCollectiveName": false, + "name": "A Maltzman", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Greve", + "abbrevName": "Greve JM", + "email": null, + "isCollectiveName": false, + "name": "J M Greve", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Hedehus", + "abbrevName": "Hedehus M", + "email": null, + "isCollectiveName": false, + "name": "M Hedehus", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "Martin-McNulty", + "abbrevName": "Martin-McNulty B", + "email": null, + "isCollectiveName": false, + "name": "B Martin-McNulty", + "orcid": null + }, + { + "ForeName": "R", + "LastName": "Carano", + "abbrevName": "Carano RA", + "email": null, + "isCollectiveName": false, + "name": "R A D Carano", + "orcid": null + }, + { + "ForeName": "T", + "LastName": "Cao", + "abbrevName": "Cao TC", + "email": null, + "isCollectiveName": false, + "name": "T C Cao", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "van Bruggen", + "abbrevName": "van Bruggen N", + "email": null, + "isCollectiveName": false, + "name": "N van Bruggen", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Bernstein", + "abbrevName": "Bernstein L", + "email": null, + "isCollectiveName": false, + "name": "L Bernstein", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Lee", + "abbrevName": "Lee WP", + "email": null, + "isCollectiveName": false, + "name": "W P Lee", + "orcid": null + }, + { + "ForeName": "X", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "X Wu", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "DeVoss", + "abbrevName": "DeVoss J", + "email": null, + "isCollectiveName": false, + "name": "J DeVoss", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "J Zhang", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Jeet", + "abbrevName": "Jeet S", + "email": null, + "isCollectiveName": false, + "name": "S Jeet", + "orcid": null + }, + { + "ForeName": "I", + "LastName": "Peng", + "abbrevName": "Peng I", + "email": null, + "isCollectiveName": false, + "name": "I Peng", + "orcid": null + }, + { + "ForeName": "B", + "LastName": "McKenzie", + "abbrevName": "McKenzie BS", + "email": null, + "isCollectiveName": false, + "name": "B S McKenzie", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Roose-Girma", + "abbrevName": "Roose-Girma M", + "email": null, + "isCollectiveName": false, + "name": "M Roose-Girma", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Caplazi", + "abbrevName": "Caplazi P", + "email": null, + "isCollectiveName": false, + "name": "P Caplazi", + "orcid": null + }, + { + "ForeName": "L", + "LastName": "Diehl", + "abbrevName": "Diehl L", + "email": null, + "isCollectiveName": false, + "name": "L Diehl", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Webster", + "abbrevName": "Webster JD", + "email": null, + "isCollectiveName": false, + "name": "J D Webster", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Vucic", + "abbrevName": "Vucic D", + "email": null, + "isCollectiveName": false, + "name": "D Vucic", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.46", + "pmid": "27177019", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury." + } + }, + { + "pmid": "27258786", + "pubmed": { + "ISODate": "2016-10-01T00:00:00.000Z", + "abstract": "Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.", + "authors": { + "abbreviation": "B Shutinoski, N A Alturki, D Rijal, ..., S Sad", + "authorList": [ + { + "ForeName": "B", + "LastName": "Shutinoski", + "abbrevName": "Shutinoski B", + "email": null, + "isCollectiveName": false, + "name": "B Shutinoski", + "orcid": null + }, + { + "ForeName": "N", + "LastName": "Alturki", + "abbrevName": "Alturki NA", + "email": null, + "isCollectiveName": false, + "name": "N A Alturki", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rijal", + "abbrevName": "Rijal D", + "email": null, + "isCollectiveName": false, + "name": "D Rijal", + "orcid": null + }, + { + "ForeName": "J", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "J Bertin", + "orcid": null + }, + { + "ForeName": "P", + "LastName": "Gough", + "abbrevName": "Gough PJ", + "email": null, + "isCollectiveName": false, + "name": "P J Gough", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Schlossmacher", + "abbrevName": "Schlossmacher MG", + "email": null, + "isCollectiveName": false, + "name": "M G Schlossmacher", + "orcid": null + }, + { + "ForeName": "S", + "LastName": "Sad", + "abbrevName": "Sad S", + "email": null, + "isCollectiveName": false, + "name": "S Sad", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2016.51", + "pmid": "27258786", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Differ 23 2016", + "title": "K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo." + } + }, + { + "pmid": "34262020", + "pubmed": { + "ISODate": "2021-07-14T00:00:00.000Z", + "abstract": "Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.", + "authors": { + "abbreviation": "Tom Delanghe, Jon Huyghe, Seungheon Lee, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Jon", + "LastName": "Huyghe", + "abbrevName": "Huyghe J", + "email": null, + "isCollectiveName": false, + "name": "Jon Huyghe", + "orcid": null + }, + { + "ForeName": "Seungheon", + "LastName": "Lee", + "abbrevName": "Lee S", + "email": null, + "isCollectiveName": false, + "name": "Seungheon Lee", + "orcid": null + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": "0000-0002-2527-1101" + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "Barbara", + "LastName": "Gilbert", + "abbrevName": "Gilbert B", + "email": null, + "isCollectiveName": false, + "name": "Barbara Gilbert", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Alexei", + "LastName": "Degterev", + "abbrevName": "Degterev A", + "email": null, + "isCollectiveName": false, + "name": "Alexei Degterev", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Cuny", + "abbrevName": "Cuny GD", + "email": null, + "isCollectiveName": false, + "name": "Gregory D Cuny", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": "mathieu.bertrand@irc.vib-ugent.be", + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [ + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "email": [ + "mathieu.bertrand@irc.vib-ugent.be" + ], + "name": "Mathieu J M Bertrand" + } + ] + }, + "doi": "10.1038/s41419-021-03994-0", + "pmid": "34262020", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 12 2021", + "title": "Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor." + } + }, + { + "pmid": "31235688", + "pubmed": { + "ISODate": "2019-06-24T00:00:00.000Z", + "abstract": "Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.", + "authors": { + "abbreviation": "Jue Hou, Jie Ju, Zili Zhang, ..., Sudan He", + "authorList": [ + { + "ForeName": "Jue", + "LastName": "Hou", + "abbrevName": "Hou J", + "email": null, + "isCollectiveName": false, + "name": "Jue Hou", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Ju", + "abbrevName": "Ju J", + "email": null, + "isCollectiveName": false, + "name": "Jie Ju", + "orcid": null + }, + { + "ForeName": "Zili", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zili Zhang", + "orcid": null + }, + { + "ForeName": "Cong", + "LastName": "Zhao", + "abbrevName": "Zhao C", + "email": null, + "isCollectiveName": false, + "name": "Cong Zhao", + "orcid": null + }, + { + "ForeName": "Zhanhui", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhanhui Li", + "orcid": null + }, + { + "ForeName": "Jiyue", + "LastName": "Zheng", + "abbrevName": "Zheng J", + "email": null, + "isCollectiveName": false, + "name": "Jiyue Zheng", + "orcid": null + }, + { + "ForeName": "Tian", + "LastName": "Sheng", + "abbrevName": "Sheng T", + "email": null, + "isCollectiveName": false, + "name": "Tian Sheng", + "orcid": null + }, + { + "ForeName": "Hongjian", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hongjian Zhang", + "orcid": null + }, + { + "ForeName": "Linkun", + "LastName": "Hu", + "abbrevName": "Hu L", + "email": null, + "isCollectiveName": false, + "name": "Linkun Hu", + "orcid": null + }, + { + "ForeName": "Xiaoliang", + "LastName": "Yu", + "abbrevName": "Yu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoliang Yu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhang", + "orcid": null + }, + { + "ForeName": "Yangxin", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yangxin Li", + "orcid": null + }, + { + "ForeName": "Meng", + "LastName": "Wu", + "abbrevName": "Wu M", + "email": null, + "isCollectiveName": false, + "name": "Meng Wu", + "orcid": null + }, + { + "ForeName": "Haikuo", + "LastName": "Ma", + "abbrevName": "Ma H", + "email": "mahaikuo123@163.com", + "isCollectiveName": false, + "name": "Haikuo Ma", + "orcid": null + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": "xiaohuzhang@suda.edu.cn", + "isCollectiveName": false, + "name": "Xiaohu Zhang", + "orcid": null + }, + { + "ForeName": "Sudan", + "LastName": "He", + "abbrevName": "He S", + "email": "hesudan2018@163.com", + "isCollectiveName": false, + "name": "Sudan He", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Haikuo", + "LastName": "Ma", + "email": [ + "mahaikuo123@163.com" + ], + "name": "Haikuo Ma" + }, + { + "ForeName": "Xiaohu", + "LastName": "Zhang", + "email": [ + "xiaohuzhang@suda.edu.cn" + ], + "name": "Xiaohu Zhang" + }, + { + "ForeName": "Sudan", + "LastName": "He", + "email": [ + "hesudan2018@163.com" + ], + "name": "Sudan He" + } + ] + }, + "doi": "10.1038/s41419-019-1735-6", + "pmid": "31235688", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis." + } + }, + { + "pmid": "28506461", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.", + "authors": { + "abbreviation": "Isabel Jaco, Alessandro Annibaldi, Najoua Lalaoui, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Isabel", + "LastName": "Jaco", + "abbrevName": "Jaco I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Jaco", + "orcid": null + }, + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Najoua", + "LastName": "Lalaoui", + "abbrevName": "Lalaoui N", + "email": null, + "isCollectiveName": false, + "name": "Najoua Lalaoui", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Wilson", + "abbrevName": "Wilson R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Wilson", + "orcid": null + }, + { + "ForeName": "Tencho", + "LastName": "Tenev", + "abbrevName": "Tenev T", + "email": null, + "isCollectiveName": false, + "name": "Tencho Tenev", + "orcid": null + }, + { + "ForeName": "Lucie", + "LastName": "Laurien", + "abbrevName": "Laurien L", + "email": null, + "isCollectiveName": false, + "name": "Lucie Laurien", + "orcid": null + }, + { + "ForeName": "Chun", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chun Kim", + "orcid": null + }, + { + "ForeName": "Kunzah", + "LastName": "Jamal", + "abbrevName": "Jamal K", + "email": null, + "isCollectiveName": false, + "name": "Kunzah Jamal", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Diep", + "LastName": "Chau", + "abbrevName": "Chau D", + "email": null, + "isCollectiveName": false, + "name": "Diep Chau", + "orcid": null + }, + { + "ForeName": "James", + "LastName": "Murphy", + "abbrevName": "Murphy JM", + "email": null, + "isCollectiveName": false, + "name": "James M Murphy", + "orcid": null + }, + { + "ForeName": "Gabriela", + "LastName": "Brumatti", + "abbrevName": "Brumatti G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Brumatti", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Feltham", + "abbrevName": "Feltham R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Feltham", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": "silke@wehi.edu.au", + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + }, + { + "ForeName": "John", + "LastName": "Silke", + "email": [ + "silke@wehi.edu.au" + ], + "name": "John Silke" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2017.05.003", + "pmid": "28506461", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 66 2017", + "title": "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." + } + }, + { + "pmid": "36329033", + "pubmed": { + "ISODate": "2022-11-03T00:00:00.000Z", + "abstract": "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.", + "authors": { + "abbreviation": "Hailin Tu, Weihang Xiong, Jie Zhang, ..., Xin Lin", + "authorList": [ + { + "ForeName": "Hailin", + "LastName": "Tu", + "abbrevName": "Tu H", + "email": null, + "isCollectiveName": false, + "name": "Hailin Tu", + "orcid": null + }, + { + "ForeName": "Weihang", + "LastName": "Xiong", + "abbrevName": "Xiong W", + "email": null, + "isCollectiveName": false, + "name": "Weihang Xiong", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhang", + "orcid": null + }, + { + "ForeName": "Xueqiang", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xueqiang Zhao", + "orcid": null + }, + { + "ForeName": "Xin", + "LastName": "Lin", + "abbrevName": "Lin X", + "email": "linxin307@tsinghua.edu.cn", + "isCollectiveName": false, + "name": "Xin Lin", + "orcid": "0000-0003-0956-3654" + } + ], + "contacts": [ + { + "ForeName": "Xin", + "LastName": "Lin", + "email": [ + "linxin307@tsinghua.edu.cn" + ], + "name": "Xin Lin" + } + ] + }, + "doi": "10.1038/s41467-022-34080-4", + "pmid": "36329033", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Commun 13 2022", + "title": "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation." + } + }, + { + "pmid": "29452637", + "pubmed": { + "ISODate": "2018-02-15T00:00:00.000Z", + "abstract": "Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP)1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.", + "authors": { + "abbreviation": "Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe, ..., Pascal Meier", + "authorList": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "abbrevName": "Annibaldi A", + "email": "alessandro.annibaldi@icr.ac.uk", + "isCollectiveName": false, + "name": "Alessandro Annibaldi", + "orcid": null + }, + { + "ForeName": "Sidonie", + "LastName": "Wicky John", + "abbrevName": "Wicky John S", + "email": null, + "isCollectiveName": false, + "name": "Sidonie Wicky John", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Kirby", + "LastName": "Swatek", + "abbrevName": "Swatek KN", + "email": null, + "isCollectiveName": false, + "name": "Kirby N Swatek", + "orcid": null + }, + { + "ForeName": "Jianbin", + "LastName": "Ruan", + "abbrevName": "Ruan J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Ruan", + "orcid": null + }, + { + "ForeName": "Gianmaria", + "LastName": "Liccardi", + "abbrevName": "Liccardi G", + "email": null, + "isCollectiveName": false, + "name": "Gianmaria Liccardi", + "orcid": null + }, + { + "ForeName": "Katiuscia", + "LastName": "Bianchi", + "abbrevName": "Bianchi K", + "email": null, + "isCollectiveName": false, + "name": "Katiuscia Bianchi", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott", + "orcid": null + }, + { + "ForeName": "Sze", + "LastName": "Choi", + "abbrevName": "Choi SM", + "email": null, + "isCollectiveName": false, + "name": "Sze Men Choi", + "orcid": null + }, + { + "ForeName": "Samya", + "LastName": "Van Coillie", + "abbrevName": "Van Coillie S", + "email": null, + "isCollectiveName": false, + "name": "Samya Van Coillie", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Bertin", + "abbrevName": "Bertin J", + "email": null, + "isCollectiveName": false, + "name": "John Bertin", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Wu", + "abbrevName": "Wu H", + "email": null, + "isCollectiveName": false, + "name": "Hao Wu", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Komander", + "abbrevName": "Komander D", + "email": null, + "isCollectiveName": false, + "name": "David Komander", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Silke", + "abbrevName": "Silke J", + "email": null, + "isCollectiveName": false, + "name": "John Silke", + "orcid": null + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "abbrevName": "Meier P", + "email": "pmeier@icr.ac.uk", + "isCollectiveName": false, + "name": "Pascal Meier", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alessandro", + "LastName": "Annibaldi", + "email": [ + "alessandro.annibaldi@icr.ac.uk" + ], + "name": "Alessandro Annibaldi" + }, + { + "ForeName": "Pascal", + "LastName": "Meier", + "email": [ + "pmeier@icr.ac.uk" + ], + "name": "Pascal Meier" + } + ] + }, + "doi": "10.1016/j.molcel.2018.01.027", + "pmid": "29452637", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 69 2018", + "title": "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." + } + }, + { + "pmid": "27605011", + "pubmed": { + "ISODate": "2016-10-15T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-κB activation in terms of IκBα phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1D138N) mice did not exacerbate αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.", + "authors": { + "abbreviation": "Jo Suda, Lily Dara, Luoluo Yang, ..., Zhang-Xu Liu", + "authorList": [ + { + "ForeName": "Jo", + "LastName": "Suda", + "abbrevName": "Suda J", + "email": null, + "isCollectiveName": false, + "name": "Jo Suda", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Dara", + "abbrevName": "Dara L", + "email": null, + "isCollectiveName": false, + "name": "Lily Dara", + "orcid": "0000-0002-0121-7186" + }, + { + "ForeName": "Luoluo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Luoluo Yang", + "orcid": "0000-0001-8099-9982" + }, + { + "ForeName": "Mariam", + "LastName": "Aghajan", + "abbrevName": "Aghajan M", + "email": null, + "isCollectiveName": false, + "name": "Mariam Aghajan", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Song", + "abbrevName": "Song Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Song", + "orcid": null + }, + { + "ForeName": "Neil", + "LastName": "Kaplowitz", + "abbrevName": "Kaplowitz N", + "email": null, + "isCollectiveName": false, + "name": "Neil Kaplowitz", + "orcid": "0000-0002-9424-393X" + }, + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "abbrevName": "Liu ZX", + "email": "zxliu@usc.edu", + "isCollectiveName": false, + "name": "Zhang-Xu Liu", + "orcid": "0000-0001-7290-3506" + } + ], + "contacts": [ + { + "ForeName": "Zhang-Xu", + "LastName": "Liu", + "email": [ + "zxliu@usc.edu" + ], + "name": "Zhang-Xu Liu" + } + ] + }, + "doi": "10.4049/jimmunol.1600690", + "pmid": "27605011", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Immunol 197 2016", + "title": "Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB." + } + }, + { + "pmid": "28701375", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.", + "authors": { + "abbreviation": "Ran Wei, Lily Wen Xu, Jianping Liu, ..., Heling Pan", + "authorList": [ + { + "ForeName": "Ran", + "LastName": "Wei", + "abbrevName": "Wei R", + "email": null, + "isCollectiveName": false, + "name": "Ran Wei", + "orcid": null + }, + { + "ForeName": "Lily", + "LastName": "Xu", + "abbrevName": "Xu LW", + "email": null, + "isCollectiveName": false, + "name": "Lily Wen Xu", + "orcid": null + }, + { + "ForeName": "Jianping", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianping Liu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Pei", + "LastName": "Zhang", + "abbrevName": "Zhang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Zhang", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Zheming", + "LastName": "Wu", + "abbrevName": "Wu Z", + "email": null, + "isCollectiveName": false, + "name": "Zheming Wu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lifeng", + "LastName": "Pan", + "abbrevName": "Pan L", + "email": null, + "isCollectiveName": false, + "name": "Lifeng Pan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.299776.117", + "pmid": "28701375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Genes Dev 31 2017", + "title": "SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination." + } + }, + { + "pmid": "22362767", + "pubmed": { + "ISODate": "2012-04-27T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).", + "authors": { + "abbreviation": "Linde Duprez, Mathieu J M Bertrand, Tom Vanden Berghe, ..., Peter Vandenabeele", + "authorList": [ + { + "ForeName": "Linde", + "LastName": "Duprez", + "abbrevName": "Duprez L", + "email": null, + "isCollectiveName": false, + "name": "Linde Duprez", + "orcid": null + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJ", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Vanden Berghe", + "abbrevName": "Vanden Berghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Vanden Berghe", + "orcid": null + }, + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Nele", + "LastName": "Festjens", + "abbrevName": "Festjens N", + "email": null, + "isCollectiveName": false, + "name": "Nele Festjens", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.288670", + "pmid": "22362767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis." + } + }, + { + "pmid": "23727581", + "pubmed": { + "ISODate": "2013-06-28T00:00:00.000Z", + "abstract": "While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas-associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFα or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec-1) significantly blocked TNFα-induced cell death and ROS accumulation in NF-κB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFα stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFα-induced necroptosis and ROS accumulation in NF-κB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFα-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFα-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation.", + "authors": { + "abbreviation": "Ryodai Shindo, Hidenao Kakehashi, Ko Okumura, ..., Hiroyasu Nakano", + "authorList": [ + { + "ForeName": "Ryodai", + "LastName": "Shindo", + "abbrevName": "Shindo R", + "email": null, + "isCollectiveName": false, + "name": "Ryodai Shindo", + "orcid": null + }, + { + "ForeName": "Hidenao", + "LastName": "Kakehashi", + "abbrevName": "Kakehashi H", + "email": null, + "isCollectiveName": false, + "name": "Hidenao Kakehashi", + "orcid": null + }, + { + "ForeName": "Ko", + "LastName": "Okumura", + "abbrevName": "Okumura K", + "email": null, + "isCollectiveName": false, + "name": "Ko Okumura", + "orcid": null + }, + { + "ForeName": "Yoshito", + "LastName": "Kumagai", + "abbrevName": "Kumagai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshito Kumagai", + "orcid": null + }, + { + "ForeName": "Hiroyasu", + "LastName": "Nakano", + "abbrevName": "Nakano H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyasu Nakano", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2013.05.075", + "pmid": "23727581", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 436 2013", + "title": "Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation." + } + }, + { + "pmid": "30867408", + "pubmed": { + "ISODate": "2019-03-13T00:00:00.000Z", + "abstract": "RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD-/- mice but in stark contrast to the normal embryogenesis of RIPK1-/- null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1D324A/D324A mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.", + "authors": { + "abbreviation": "Xuhua Zhang, John P Dowling, Jianke Zhang", + "authorList": [ + { + "ForeName": "Xuhua", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xuhua Zhang", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Dowling", + "abbrevName": "Dowling JP", + "email": null, + "isCollectiveName": false, + "name": "John P Dowling", + "orcid": null + }, + { + "ForeName": "Jianke", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": "jianke.zhang@jefferson.edu", + "isCollectiveName": false, + "name": "Jianke Zhang", + "orcid": "0000-0001-9880-8435" + } + ], + "contacts": [ + { + "ForeName": "Jianke", + "LastName": "Zhang", + "email": [ + "jianke.zhang@jefferson.edu" + ], + "name": "Jianke Zhang" + } + ] + }, + "doi": "10.1038/s41419-019-1490-8", + "pmid": "30867408", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Death Dis 10 2019", + "title": "RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development." + } + }, + { + "pmid": "29593066", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": "Necroptosis, a form of regulated necrotic cell death mediated by RIPK1 (receptor-interacting protein kinase 1) kinase activity, RIPK3, and MLKL (mixed-lineage kinase domain-like pseudokinase), can be activated under apoptosis-deficient conditions. Modulating the activation of RIPK1 by ubiquitination and phosphorylation is critical to control both necroptosis and apoptosis. Mutant mice with kinase-dead RIPK1 or RIPK3 and MLKL deficiency show no detrimental phenotype in regard to development and adult homeostasis. However, necroptosis and apoptosis can be activated in response to various mutations that result in the abortion of the defective embryos and human inflammatory and neurodegenerative pathologies. RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial.", + "authors": { + "abbreviation": "Bing Shan, Heling Pan, Ayaz Najafov, Junying Yuan", + "authorList": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": null, + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1101/gad.312561.118", + "pmid": "29593066", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Genes Dev 32 2018", + "title": "Necroptosis in development and diseases." + } + }, + { + "pmid": "34813352", + "pubmed": { + "ISODate": "2021-11-23T00:00:00.000Z", + "abstract": "The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.", + "authors": { + "abbreviation": "Daichao Xu, Chengyu Zou, Junying Yuan", + "authorList": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "abbrevName": "Zou C", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Chengyu Zou", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Daichao", + "LastName": "Xu", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Daichao Xu" + }, + { + "ForeName": "Chengyu", + "LastName": "Zou", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Chengyu Zou" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1146/annurev-genet-071719-022748", + "pmid": "34813352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Annu Rev Genet 55 2021", + "title": "Genetic Regulation of RIPK1 and Necroptosis." + } + }, + { + "pmid": "31028177", + "pubmed": { + "ISODate": "2019-05-20T00:00:00.000Z", + "abstract": "Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified, no report had indicated that FK506-binding protein 12 (FKBP12, also known as FKBP1A), an endogenous protein that regulates protein folding and conformation alteration, is involved in mediating necroptosis. In this study, we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition, FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation, which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore, FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis in vitro and in vivo Collectively, our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.", + "authors": { + "abbreviation": "Zicheng Wang, Jiannan Feng, Jiyun Yu, Guozhu Chen", + "authorList": [ + { + "ForeName": "Zicheng", + "LastName": "Wang", + "abbrevName": "Wang Z", + "email": null, + "isCollectiveName": false, + "name": "Zicheng Wang", + "orcid": "0000-0003-2648-8289" + }, + { + "ForeName": "Jiannan", + "LastName": "Feng", + "abbrevName": "Feng J", + "email": null, + "isCollectiveName": false, + "name": "Jiannan Feng", + "orcid": null + }, + { + "ForeName": "Jiyun", + "LastName": "Yu", + "abbrevName": "Yu J", + "email": null, + "isCollectiveName": false, + "name": "Jiyun Yu", + "orcid": "0000-0003-3475-1956" + }, + { + "ForeName": "Guozhu", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": "chenguozhu2002@126.com", + "isCollectiveName": false, + "name": "Guozhu Chen", + "orcid": "0000-0002-6067-8150" + } + ], + "contacts": [ + { + "ForeName": "Guozhu", + "LastName": "Chen", + "email": [ + "chenguozhu2002@126.com" + ], + "name": "Guozhu Chen" + } + ] + }, + "doi": "10.1242/jcs.227777", + "pmid": "31028177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "FKBP12 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation." + } + }, + { + "pmid": "28920954", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.", + "authors": { + "abbreviation": "Manoj B Menon, Julia Gropengießer, Jessica Fischer, ..., Klaus Ruckdeschel", + "authorList": [ + { + "ForeName": "Manoj", + "LastName": "Menon", + "abbrevName": "Menon MB", + "email": null, + "isCollectiveName": false, + "name": "Manoj B Menon", + "orcid": "0000-0001-5859-0347" + }, + { + "ForeName": "Julia", + "LastName": "Gropengießer", + "abbrevName": "Gropengießer J", + "email": null, + "isCollectiveName": false, + "name": "Julia Gropengießer", + "orcid": null + }, + { + "ForeName": "Jessica", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Jessica Fischer", + "orcid": null + }, + { + "ForeName": "Lena", + "LastName": "Novikova", + "abbrevName": "Novikova L", + "email": null, + "isCollectiveName": false, + "name": "Lena Novikova", + "orcid": null + }, + { + "ForeName": "Anne", + "LastName": "Deuretzbacher", + "abbrevName": "Deuretzbacher A", + "email": null, + "isCollectiveName": false, + "name": "Anne Deuretzbacher", + "orcid": null + }, + { + "ForeName": "Juri", + "LastName": "Lafera", + "abbrevName": "Lafera J", + "email": null, + "isCollectiveName": false, + "name": "Juri Lafera", + "orcid": null + }, + { + "ForeName": "Hanna", + "LastName": "Schimmeck", + "abbrevName": "Schimmeck H", + "email": null, + "isCollectiveName": false, + "name": "Hanna Schimmeck", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Czymmeck", + "abbrevName": "Czymmeck N", + "email": null, + "isCollectiveName": false, + "name": "Nicole Czymmeck", + "orcid": null + }, + { + "ForeName": "Natalia", + "LastName": "Ronkina", + "abbrevName": "Ronkina N", + "email": null, + "isCollectiveName": false, + "name": "Natalia Ronkina", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Martin", + "LastName": "Aepfelbacher", + "abbrevName": "Aepfelbacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Aepfelbacher", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": "0000-0002-4944-4652" + }, + { + "ForeName": "Klaus", + "LastName": "Ruckdeschel", + "abbrevName": "Ruckdeschel K", + "email": null, + "isCollectiveName": false, + "name": "Klaus Ruckdeschel", + "orcid": "0000-0002-0164-9085" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3614", + "pmid": "28920954", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection." + } + }, + { + "pmid": "28920952", + "pubmed": { + "ISODate": "2017-10-01T00:00:00.000Z", + "abstract": "TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.", + "authors": { + "abbreviation": "Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, ..., Mathieu J M Bertrand", + "authorList": [ + { + "ForeName": "Yves", + "LastName": "Dondelinger", + "abbrevName": "Dondelinger Y", + "email": null, + "isCollectiveName": false, + "name": "Yves Dondelinger", + "orcid": null + }, + { + "ForeName": "Tom", + "LastName": "Delanghe", + "abbrevName": "Delanghe T", + "email": null, + "isCollectiveName": false, + "name": "Tom Delanghe", + "orcid": null + }, + { + "ForeName": "Diego", + "LastName": "Rojas-Rivera", + "abbrevName": "Rojas-Rivera D", + "email": null, + "isCollectiveName": false, + "name": "Diego Rojas-Rivera", + "orcid": "0000-0002-4253-8680" + }, + { + "ForeName": "Dario", + "LastName": "Priem", + "abbrevName": "Priem D", + "email": null, + "isCollectiveName": false, + "name": "Dario Priem", + "orcid": null + }, + { + "ForeName": "Tinneke", + "LastName": "Delvaeye", + "abbrevName": "Delvaeye T", + "email": null, + "isCollectiveName": false, + "name": "Tinneke Delvaeye", + "orcid": null + }, + { + "ForeName": "Inge", + "LastName": "Bruggeman", + "abbrevName": "Bruggeman I", + "email": null, + "isCollectiveName": false, + "name": "Inge Bruggeman", + "orcid": null + }, + { + "ForeName": "Franky", + "LastName": "Van Herreweghe", + "abbrevName": "Van Herreweghe F", + "email": null, + "isCollectiveName": false, + "name": "Franky Van Herreweghe", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Vandenabeele", + "abbrevName": "Vandenabeele P", + "email": null, + "isCollectiveName": false, + "name": "Peter Vandenabeele", + "orcid": "0000-0002-6669-8822" + }, + { + "ForeName": "Mathieu", + "LastName": "Bertrand", + "abbrevName": "Bertrand MJM", + "email": null, + "isCollectiveName": false, + "name": "Mathieu J M Bertrand", + "orcid": "0000-0001-9000-0626" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3608", + "pmid": "28920952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 19 2017", + "title": "MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death." + } + }, + { + "pmid": "33858959", + "pubmed": { + "ISODate": "2021-06-01T00:00:00.000Z", + "abstract": "Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB-dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation.", + "authors": { + "abbreviation": "Snehlata Kumari, Trieu-My Van, Daniela Preukschat, ..., Manolis Pasparakis", + "authorList": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "abbrevName": "Kumari S", + "email": "s.kumari@uq.edu.au", + "isCollectiveName": false, + "name": "Snehlata Kumari", + "orcid": "0000-0002-4971-3162" + }, + { + "ForeName": "Trieu-My", + "LastName": "Van", + "abbrevName": "Van TM", + "email": null, + "isCollectiveName": false, + "name": "Trieu-My Van", + "orcid": null + }, + { + "ForeName": "Daniela", + "LastName": "Preukschat", + "abbrevName": "Preukschat D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Preukschat", + "orcid": null + }, + { + "ForeName": "Hannah", + "LastName": "Schuenke", + "abbrevName": "Schuenke H", + "email": null, + "isCollectiveName": false, + "name": "Hannah Schuenke", + "orcid": null + }, + { + "ForeName": "Marijana", + "LastName": "Basic", + "abbrevName": "Basic M", + "email": null, + "isCollectiveName": false, + "name": "Marijana Basic", + "orcid": null + }, + { + "ForeName": "André", + "LastName": "Bleich", + "abbrevName": "Bleich A", + "email": null, + "isCollectiveName": false, + "name": "André Bleich", + "orcid": null + }, + { + "ForeName": "Ulf", + "LastName": "Klein", + "abbrevName": "Klein U", + "email": null, + "isCollectiveName": false, + "name": "Ulf Klein", + "orcid": null + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "abbrevName": "Pasparakis M", + "email": "pasparakis@uni-koeln.de", + "isCollectiveName": false, + "name": "Manolis Pasparakis", + "orcid": "0000-0002-9870-0966" + } + ], + "contacts": [ + { + "ForeName": "Snehlata", + "LastName": "Kumari", + "email": [ + "s.kumari@uq.edu.au" + ], + "name": "Snehlata Kumari" + }, + { + "ForeName": "Manolis", + "LastName": "Pasparakis", + "email": [ + "pasparakis@uni-koeln.de" + ], + "name": "Manolis Pasparakis" + } + ] + }, + "doi": "10.26508/lsa.202000956", + "pmid": "33858959", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Life Sci Alliance 4 2021", + "title": "NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation." + } + }, + { + "pmid": "29078411", + "pubmed": { + "ISODate": "2017-11-07T00:00:00.000Z", + "abstract": "Apoptosis and necroptosis are two distinct cell death mechanisms that may be activated in cells on stimulation by TNFα. It is still unclear, however, how apoptosis and necroptosis may be differentially regulated. Here we screened for E3 ubiquitin ligases that could mediate necroptosis. We found that deficiency of Pellino 1 (PELI1), an E3 ubiquitin ligase, blocked necroptosis. We show that PELI1 mediates K63 ubiquitination on K115 of RIPK1 in a kinase-dependent manner during necroptosis. Ubiquitination of RIPK1 by PELI1 promotes the formation of necrosome and execution of necroptosis. Although PELI1 is not directly involved in mediating the activation of RIPK1, it is indispensable for promoting the binding of activated RIPK1 with its downstream mediator RIPK3 to promote the activation of RIPK3 and MLKL. Inhibition of RIPK1 kinase activity blocks PELI1-mediated ubiquitination of RIPK1 in necroptosis. However, we show that PELI1 deficiency sensitizes cells to both RIPK1-dependent and RIPK1-independent apoptosis as a result of down-regulated expression of c-FLIP, an inhibitor of caspase-8. Finally, we show that Peli1-/- mice are sensitized to TNFα-induced apoptosis. Thus, PELI1 is a key modulator of RIPK1 that differentially controls the activation of necroptosis and apoptosis.", + "authors": { + "abbreviation": "Huibing Wang, Huyan Meng, Xingyan Li, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Huibing", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Huibing Wang", + "orcid": null + }, + { + "ForeName": "Huyan", + "LastName": "Meng", + "abbrevName": "Meng H", + "email": null, + "isCollectiveName": false, + "name": "Huyan Meng", + "orcid": null + }, + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Kezhou", + "LastName": "Zhu", + "abbrevName": "Zhu K", + "email": null, + "isCollectiveName": false, + "name": "Kezhou Zhu", + "orcid": null + }, + { + "ForeName": "Kangyun", + "LastName": "Dong", + "abbrevName": "Dong K", + "email": null, + "isCollectiveName": false, + "name": "Kangyun Dong", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan K Mookhtiar", + "orcid": null + }, + { + "ForeName": "Huiting", + "LastName": "Wei", + "abbrevName": "Wei H", + "email": null, + "isCollectiveName": false, + "name": "Huiting Wei", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Li", + "orcid": null + }, + { + "ForeName": "Shao-Cong", + "LastName": "Sun", + "abbrevName": "Sun SC", + "email": null, + "isCollectiveName": false, + "name": "Shao-Cong Sun", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": "0000-0003-2405-6036" + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1073/pnas.1715742114", + "pmid": "29078411", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 114 2017", + "title": "PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP." + } + }, + { + "pmid": "33311474", + "pubmed": { + "ISODate": "2020-12-11T00:00:00.000Z", + "abstract": "RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to be regulated by its DD-mediated interaction and ubiquitination, though underlying mechanisms remain incompletely understood. Here we show that K627 in human RIPK1-DD and its equivalent K612 in murine RIPK1-DD is a key ubiquitination site that regulates the overall ubiquitination pattern of RIPK1 and its DD-mediated interactions with other DD-containing proteins. K627R/K612R mutation inhibits the activation of RIPK1 and blocks both apoptosis and necroptosis mediated by TNFR1 signaling. However, Ripk1K612R/K612R mutation sensitizes cells to necroptosis and caspase-1 activation in response to TLRs signaling. Ripk1K612R/K612R mice are viable, but develop age-dependent reduction of RIPK1 expression, spontaneous intestinal inflammation and splenomegaly, which can be rescued by antibiotic treatment and partially by Ripk3 deficiency. Furthermore, we show that the interaction of RIPK1 with FADD contributes to suppressing the activation of RIPK3 mediated by TLRs signaling. Our study demonstrates the distinct roles of K612 ubiquitination in mRIPK1/K627 ubiquitination in hRIPK1 in regulating its pro-death kinase activity in response to TNFα and pro-survival activity in response to TLRs signaling.", + "authors": { + "abbreviation": "Xingyan Li, Mengmeng Zhang, Xinyue Huang, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Xingyan", + "LastName": "Li", + "abbrevName": "Li X", + "email": null, + "isCollectiveName": false, + "name": "Xingyan Li", + "orcid": null + }, + { + "ForeName": "Mengmeng", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mengmeng Zhang", + "orcid": null + }, + { + "ForeName": "Xinyue", + "LastName": "Huang", + "abbrevName": "Huang X", + "email": null, + "isCollectiveName": false, + "name": "Xinyue Huang", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Liang", + "abbrevName": "Liang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liang", + "orcid": null + }, + { + "ForeName": "Ganquan", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Ganquan Li", + "orcid": null + }, + { + "ForeName": "Xiaojuan", + "LastName": "Lu", + "abbrevName": "Lu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaojuan Lu", + "orcid": null + }, + { + "ForeName": "Yanxia", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yanxia Li", + "orcid": null + }, + { + "ForeName": "Heling", + "LastName": "Pan", + "abbrevName": "Pan H", + "email": null, + "isCollectiveName": false, + "name": "Heling Pan", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Hong", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Zhu", + "orcid": null + }, + { + "ForeName": "Lihui", + "LastName": "Qian", + "abbrevName": "Qian L", + "email": null, + "isCollectiveName": false, + "name": "Lihui Qian", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": "shanbing@sioc.ac.cn", + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "junying_yuan@sioc.ac.cn", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Bing", + "LastName": "Shan", + "email": [ + "shanbing@sioc.ac.cn" + ], + "name": "Bing Shan" + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "junying_yuan@sioc.ac.cn" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-020-19935-y", + "pmid": "33311474", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners." + } + }, + { + "pmid": "28842570", + "pubmed": { + "ISODate": "2017-08-25T00:00:00.000Z", + "abstract": "Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFα can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision.", + "authors": { + "abbreviation": "Jiefei Geng, Yasushi Ito, Linyu Shi, ..., Junying Yuan", + "authorList": [ + { + "ForeName": "Jiefei", + "LastName": "Geng", + "abbrevName": "Geng J", + "email": null, + "isCollectiveName": false, + "name": "Jiefei Geng", + "orcid": null + }, + { + "ForeName": "Yasushi", + "LastName": "Ito", + "abbrevName": "Ito Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Ito", + "orcid": null + }, + { + "ForeName": "Linyu", + "LastName": "Shi", + "abbrevName": "Shi L", + "email": null, + "isCollectiveName": false, + "name": "Linyu Shi", + "orcid": null + }, + { + "ForeName": "Palak", + "LastName": "Amin", + "abbrevName": "Amin P", + "email": null, + "isCollectiveName": false, + "name": "Palak Amin", + "orcid": "0000-0001-5617-8703" + }, + { + "ForeName": "Jiachen", + "LastName": "Chu", + "abbrevName": "Chu J", + "email": null, + "isCollectiveName": false, + "name": "Jiachen Chu", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Ouchida", + "abbrevName": "Ouchida AT", + "email": null, + "isCollectiveName": false, + "name": "Amanda Tomie Ouchida", + "orcid": null + }, + { + "ForeName": "Adnan", + "LastName": "Mookhtiar", + "abbrevName": "Mookhtiar AK", + "email": null, + "isCollectiveName": false, + "name": "Adnan Kasim Mookhtiar", + "orcid": null + }, + { + "ForeName": "Heng", + "LastName": "Zhao", + "abbrevName": "Zhao H", + "email": null, + "isCollectiveName": false, + "name": "Heng Zhao", + "orcid": null + }, + { + "ForeName": "Daichao", + "LastName": "Xu", + "abbrevName": "Xu D", + "email": null, + "isCollectiveName": false, + "name": "Daichao Xu", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Shan", + "abbrevName": "Shan B", + "email": null, + "isCollectiveName": false, + "name": "Bing Shan", + "orcid": null + }, + { + "ForeName": "Ayaz", + "LastName": "Najafov", + "abbrevName": "Najafov A", + "email": null, + "isCollectiveName": false, + "name": "Ayaz Najafov", + "orcid": "0000-0002-1350-2056" + }, + { + "ForeName": "Guangping", + "LastName": "Gao", + "abbrevName": "Gao G", + "email": null, + "isCollectiveName": false, + "name": "Guangping Gao", + "orcid": null + }, + { + "ForeName": "Shizuo", + "LastName": "Akira", + "abbrevName": "Akira S", + "email": null, + "isCollectiveName": false, + "name": "Shizuo Akira", + "orcid": null + }, + { + "ForeName": "Junying", + "LastName": "Yuan", + "abbrevName": "Yuan J", + "email": "jyuan@hms.harvard.edu", + "isCollectiveName": false, + "name": "Junying Yuan", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Junying", + "LastName": "Yuan", + "email": [ + "jyuan@hms.harvard.edu" + ], + "name": "Junying Yuan" + } + ] + }, + "doi": "10.1038/s41467-017-00406-w", + "pmid": "28842570", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 8 2017", + "title": "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis." + } + } + ], + "secret": "read-only", + "type": "protein" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/complex_tests_6.json b/neo4j-test/document/complex_tests_6.json new file mode 100644 index 000000000..24f409144 --- /dev/null +++ b/neo4j-test/document/complex_tests_6.json @@ -0,0 +1,36639 @@ +{ + "document": [ + { + "_creationTimestamp": "2021-12-21T23:27:37.173Z", + "_newestOpId": "c275c29a-9a6e-416b-b812-c96c916abfd3", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "ArticleTitle": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Hao-Chun", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0003-2705-0027" + } + ], + "Initials": "HC", + "LastName": "Chang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ran N", + "Identifier": [], + "Initials": "RN", + "LastName": "Tao" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Chong Teik", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-9503-8364" + } + ], + "Initials": "CT", + "LastName": "Tan" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ya Jun", + "Identifier": [], + "Initials": "YJ", + "LastName": "Wu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Boon Huat", + "Identifier": [], + "Initials": "BH", + "LastName": "Bay" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Victor C", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0003-3270-4734" + } + ], + "Initials": "VC", + "LastName": "Yu" + } + ], + "Journal": { + "ISOAbbreviation": "Autophagy", + "ISSN": { + "IssnType": "Electronic", + "value": "1554-8635" + }, + "JournalIssue": { + 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PMID: 23287718; PubMed Central PMCID: PMC3795411." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang", + "orcid": "0000-0003-2705-0027" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao", + "orcid": null + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan", + "orcid": "0000-0002-9503-8364" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu", + "orcid": null + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay", + "orcid": null + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu", + "orcid": "0000-0003-3270-4734" + } + ], + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1640129257, + "entries": [ + { + "id": "96076d2b-34a6-46b6-8ff3-6c87ffc8446a" + }, + { + "id": "98c82649-da0e-45bc-8388-847980cc46d7" + }, + { + "id": "7eb9b9f7-03d4-4c8e-a9d1-2eb68249fc36" + }, + { + "id": "e3b47c0f-f6e5-440c-be32-1bc5ca0591c2" + }, + { + "id": "93630a56-a9dc-4324-b2bd-a9cc2724d6de" + }, + { + "id": "76edd724-c6ec-4ba8-af1d-af8d1ad1259f" + }, + { + "id": "4295ec14-fcfa-4245-a88f-01025b6543ae" + }, + { + "id": "3b8e906f-d7ea-476b-a15c-4d383a603f22" + }, + { + "id": "002147fb-ea3d-4b4c-a486-b968b317259a" + } + ], + "id": "27a7e755-3b47-44aa-96e1-19e4858f395c", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1640135131, + "liveId": "6fea3ea4-acbc-411c-840b-b15b99f574ae", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "30030437", + "pubmed": { + "ISODate": "2018-07-20T00:00:00.000Z", + "abstract": "The mechanism of phagophore closure remains unclear due to technical limitations in distinguishing unclosed and closed autophagosomal membranes. Here, we report the HaloTag-LC3 autophagosome completion assay that specifically detects phagophores, nascent autophagosomes, and mature autophagic structures. Using this assay, we identify the endosomal sorting complexes required for transport (ESCRT)-III component CHMP2A as a critical regulator of phagophore closure. During autophagy, CHMP2A translocates to the phagophore and regulates the separation of the inner and outer autophagosomal membranes to form double-membrane autophagosomes. Consistently, inhibition of the AAA-ATPase VPS4 activity impairs autophagosome completion. The ESCRT-mediated membrane abscission appears to be a critical step in forming functional autolysosomes by preventing mislocalization of lysosome-associated membrane glycoprotein 1 to the inner autophagosomal membrane. Collectively, our work reveals a function for the ESCRT machinery in the final step of autophagosome formation and provides a useful tool for quantitative analysis of autophagosome biogenesis and maturation.", + "authors": { + "abbreviation": "Yoshinori Takahashi, Haiyan He, Zhenyuan Tang, ..., Hong-Gang Wang", + "authorList": [ + { + "ForeName": "Yoshinori", + "LastName": "Takahashi", + "abbrevName": "Takahashi Y", + "email": "ytakahashi@pennstatehealth.psu.edu", + "isCollectiveName": false, + "name": "Yoshinori Takahashi" + }, + { + "ForeName": "Haiyan", + "LastName": "He", + "abbrevName": "He H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan He" + }, + { + "ForeName": "Zhenyuan", + "LastName": "Tang", + "abbrevName": "Tang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenyuan Tang" + }, + { + "ForeName": "Tatsuya", + "LastName": "Hattori", + "abbrevName": "Hattori T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuya Hattori" + }, + { + "ForeName": "Ying", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Liu" + }, + { + "ForeName": "Megan", + "LastName": "Young", + "abbrevName": "Young MM", + "email": null, + "isCollectiveName": false, + "name": "Megan M Young" + }, + { + "ForeName": "Jacob", + "LastName": "Serfass", + "abbrevName": "Serfass JM", + "email": null, + "isCollectiveName": false, + "name": "Jacob M Serfass" + }, + { + "ForeName": "Longgui", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Longgui Chen" + }, + { + "ForeName": "Melat", + "LastName": "Gebru", + "abbrevName": "Gebru M", + "email": null, + "isCollectiveName": false, + "name": "Melat Gebru" + }, + { + "ForeName": "Chong", + "LastName": "Chen", + "abbrevName": "Chen C", + "email": null, + "isCollectiveName": false, + "name": "Chong Chen" + }, + { + "ForeName": "Carson", + "LastName": "Wills", + "abbrevName": "Wills CA", + "email": null, + "isCollectiveName": false, + "name": "Carson A Wills" + }, + { + "ForeName": "Jennifer", + "LastName": "Atkinson", + "abbrevName": "Atkinson JM", + "email": null, + "isCollectiveName": false, + "name": "Jennifer M Atkinson" + }, + { + "ForeName": "Han", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Han Chen" + }, + { + "ForeName": "Thomas", + "LastName": "Abraham", + "abbrevName": "Abraham T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Abraham" + }, + { + "ForeName": "Hong-Gang", + "LastName": "Wang", + "abbrevName": "Wang HG", + "email": "huw11@pus.edu", + "isCollectiveName": false, + "name": "Hong-Gang Wang" + } + ], + "contacts": [ + { + "ForeName": "Yoshinori", + "LastName": "Takahashi", + "email": [ + "ytakahashi@pennstatehealth.psu.edu" + ], + "name": "Yoshinori Takahashi" + }, + { + "ForeName": "Hong-Gang", + "LastName": "Wang", + "email": [ + "huw11@pus.edu" + ], + "name": "Hong-Gang Wang" + } + ] + }, + "doi": "10.1038/s41467-018-05254-w", + "pmid": "30030437", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure." + } + }, + { + "pmid": "29618831", + "pubmed": { + "ISODate": "2018-06-01T00:00:00.000Z", + "abstract": "Autophagy is a highly conserved catabolic process induced under various conditions of cellular stress, which prevents cell damage and promotes survival in the event of energy or nutrient shortage and responds to various cytotoxic insults. Thus, autophagy has primarily cytoprotective functions and needs to be tightly regulated to respond correctly to the different stimuli that cells experience, thereby conferring adaptation to the ever-changing environment. It is now apparent that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach.", + "authors": { + "abbreviation": "Ivan Dikic, Zvulun Elazar", + "authorList": [ + { + "ForeName": "Ivan", + "LastName": "Dikic", + "abbrevName": "Dikic I", + "email": "Ivan.Dikic@biochem2.de", + "isCollectiveName": false, + "name": "Ivan Dikic" + }, + { + "ForeName": "Zvulun", + "LastName": "Elazar", + "abbrevName": "Elazar Z", + "email": "Zvulun.Elazar@weizmann.ac.il", + "isCollectiveName": false, + "name": "Zvulun Elazar" + } + ], + "contacts": [ + { + "ForeName": "Ivan", + "LastName": "Dikic", + "email": [ + "Ivan.Dikic@biochem2.de" + ], + "name": "Ivan Dikic" + }, + { + "ForeName": "Zvulun", + "LastName": "Elazar", + "email": [ + "Zvulun.Elazar@weizmann.ac.il" + ], + "name": "Zvulun Elazar" + } + ] + }, + "doi": "10.1038/s41580-018-0003-4", + "pmid": "29618831", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 19 2018", + "title": "Mechanism and medical implications of mammalian autophagy." + } + }, + { + "pmid": "29420192", + "pubmed": { + "ISODate": "2018-03-05T00:00:00.000Z", + "abstract": "Autophagy is a conserved eukaryotic process with metabolic, immune, and general homeostatic functions in mammalian cells. Mammalian autophagosomes fuse with lysosomes in a SNARE-driven process that includes syntaxin 17 (Stx17). How Stx17 translocates to autophagosomes is unknown. In this study, we show that the mechanism of Stx17 recruitment to autophagosomes in human cells entails the small guanosine triphosphatase IRGM. Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM. Both IRGM and Stx17 directly interact with mammalian Atg8 proteins, thus being guided to autophagosomes. We also show that Stx17 is significant in defense against infectious agents and that Stx17-IRGM interaction is targeted by an HIV virulence factor Nef.", + "authors": { + "abbreviation": "Suresh Kumar, Ashish Jain, Farzin Farzam, ..., Vojo Deretic", + "authorList": [ + { + "ForeName": "Suresh", + "LastName": "Kumar", + "abbrevName": "Kumar S", + "email": null, + "isCollectiveName": false, + "name": "Suresh Kumar" + }, + { + "ForeName": "Ashish", + "LastName": "Jain", + "abbrevName": "Jain A", + "email": null, + "isCollectiveName": false, + "name": "Ashish Jain" + }, + { + "ForeName": "Farzin", + "LastName": "Farzam", + "abbrevName": "Farzam F", + "email": null, + "isCollectiveName": false, + "name": "Farzin Farzam" + }, + { + "ForeName": "Jingyue", + "LastName": "Jia", + "abbrevName": "Jia J", + "email": null, + "isCollectiveName": false, + "name": "Jingyue Jia" + }, + { + "ForeName": "Yuexi", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuexi Gu" + }, + { + "ForeName": "Seong", + "LastName": "Choi", + "abbrevName": "Choi SW", + "email": null, + "isCollectiveName": false, + "name": "Seong Won Choi" + }, + { + "ForeName": "Michal", + "LastName": "Mudd", + "abbrevName": "Mudd MH", + "email": null, + "isCollectiveName": false, + "name": "Michal H Mudd" + }, + { + "ForeName": "Aurore", + "LastName": "Claude-Taupin", + "abbrevName": "Claude-Taupin A", + "email": null, + "isCollectiveName": false, + "name": "Aurore Claude-Taupin" + }, + { + "ForeName": "Michael", + "LastName": "Wester", + "abbrevName": "Wester MJ", + "email": null, + "isCollectiveName": false, + "name": "Michael J Wester" + }, + { + "ForeName": "Keith", + "LastName": "Lidke", + "abbrevName": "Lidke KA", + "email": null, + "isCollectiveName": false, + "name": "Keith A Lidke" + }, + { + "ForeName": "Tor-Erik", + "LastName": "Rusten", + "abbrevName": "Rusten TE", + "email": null, + "isCollectiveName": false, + "name": "Tor-Erik Rusten" + }, + { + "ForeName": "Vojo", + "LastName": "Deretic", + "abbrevName": "Deretic V", + "email": "vderetic@salud.unm.edu", + "isCollectiveName": false, + "name": "Vojo Deretic" + } + ], + "contacts": [ + { + "ForeName": "Vojo", + "LastName": "Deretic", + "email": [ + "vderetic@salud.unm.edu" + ], + "name": "Vojo Deretic" + } + ] + }, + "doi": "10.1083/jcb.201708039", + "pmid": "29420192", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins." + } + }, + { + "pmid": "27885029", + "pubmed": { + "ISODate": "2016-11-25T00:00:00.000Z", + "abstract": "In macroautophagy, cytoplasmic contents are sequestered into the double-membrane autophagosome, which fuses with the lysosome to become the autolysosome. It has been thought that the autophagy-related (ATG) conjugation systems are required for autophagosome formation. Here, we found that autophagosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) syntaxin 17-positive autophagosome-like structures could be generated even in the absence of the ATG conjugation systems, although at a reduced rate. These syntaxin 17-positive structures could further fuse with lysosomes, but degradation of the inner autophagosomal membrane was significantly delayed. Accordingly, autophagic activity in ATG conjugation-deficient cells was strongly suppressed. We suggest that the ATG conjugation systems, which are likely required for the closure (i.e., fission) of the autophagosomal edge, are not absolutely essential for autolysosome formation but are important for efficient degradation of the inner autophagosomal membrane.", + "authors": { + "abbreviation": "Kotaro Tsuboyama, Ikuko Koyama-Honda, Yuriko Sakamaki, ..., Noboru Mizushima", + "authorList": [ + { + "ForeName": "Kotaro", + "LastName": "Tsuboyama", + "abbrevName": "Tsuboyama K", + "email": null, + "isCollectiveName": false, + "name": "Kotaro Tsuboyama" + }, + { + "ForeName": "Ikuko", + "LastName": "Koyama-Honda", + "abbrevName": "Koyama-Honda I", + "email": null, + "isCollectiveName": false, + "name": "Ikuko Koyama-Honda" + }, + { + "ForeName": "Yuriko", + "LastName": "Sakamaki", + "abbrevName": "Sakamaki Y", + "email": null, + "isCollectiveName": false, + "name": "Yuriko Sakamaki" + }, + { + "ForeName": "Masato", + "LastName": "Koike", + "abbrevName": "Koike M", + "email": null, + "isCollectiveName": false, + "name": "Masato Koike" + }, + { + "ForeName": "Hideaki", + "LastName": "Morishita", + "abbrevName": "Morishita H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Morishita" + }, + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": "nmizu@m.u-tokyo.ac.jp", + "isCollectiveName": false, + "name": "Noboru Mizushima" + } + ], + "contacts": [ + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "email": [ + "nmizu@m.u-tokyo.ac.jp" + ], + "name": "Noboru Mizushima" + } + ] + }, + "doi": "10.1126/science.aaf6136", + "pmid": "27885029", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 354 2016", + "title": "The ATG conjugation systems are important for degradation of the inner autophagosomal membrane." + } + }, + { + "pmid": "27864321", + "pubmed": { + "ISODate": "2016-12-19T00:00:00.000Z", + "abstract": "Members of the Atg8 family of proteins are conjugated to autophagosomal membranes, where they have been proposed to drive autophagosome formation and selective sequestration of cargo. In mammals, the Atg8 family consists of six members divided into the LC3 and GABARAP subfamilies. To define Atg8 function, we used genome editing to generate knockouts of the LC3 and GABARAP subfamilies as well as all six Atg8 family members in HeLa cells. We show that Atg8s are dispensable for autophagosome formation and selective engulfment of mitochondria, but essential for autophagosome-lysosome fusion. We find that the GABARAP subfamily promotes PLEKHM1 recruitment and governs autophagosome-lysosome fusion, whereas the LC3 subfamily plays a less prominent role in these processes. Although neither GABARAPs nor LC3s are required for autophagosome biogenesis, loss of all Atg8s yields smaller autophagosomes and a slowed initial rate of autophagosome formation. Our results clarify the essential function of the Atg8 family and identify GABARAP subfamily members as primary contributors to PINK1/Parkin mitophagy and starvation autophagy.", + "authors": { + "abbreviation": "Thanh Ngoc Nguyen, Benjamin Scott Padman, Joanne Usher, ..., Michael Lazarou", + "authorList": [ + { + "ForeName": "Thanh", + "LastName": "Nguyen", + "abbrevName": "Nguyen TN", + "email": null, + "isCollectiveName": false, + "name": "Thanh Ngoc Nguyen" + }, + { + "ForeName": "Benjamin", + "LastName": "Padman", + "abbrevName": "Padman BS", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Scott Padman" + }, + { + "ForeName": "Joanne", + "LastName": "Usher", + "abbrevName": "Usher J", + "email": null, + "isCollectiveName": false, + "name": "Joanne Usher" + }, + { + "ForeName": "Viola", + "LastName": "Oorschot", + "abbrevName": "Oorschot V", + "email": null, + "isCollectiveName": false, + "name": "Viola Oorschot" + }, + { + "ForeName": "Georg", + "LastName": "Ramm", + "abbrevName": "Ramm G", + "email": null, + "isCollectiveName": false, + "name": "Georg Ramm" + }, + { + "ForeName": "Michael", + "LastName": "Lazarou", + "abbrevName": "Lazarou M", + "email": "michael.lazarou@monash.edu", + "isCollectiveName": false, + "name": "Michael Lazarou" + } + ], + "contacts": [ + { + "ForeName": "Michael", + "LastName": "Lazarou", + "email": [ + "michael.lazarou@monash.edu" + ], + "name": "Michael Lazarou" + } + ] + }, + "doi": "10.1083/jcb.201607039", + "pmid": "27864321", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biol 215 2016", + "title": "Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation." + } + }, + { + "pmid": "27818143", + "pubmed": { + "ISODate": "2016-11-17T00:00:00.000Z", + "abstract": "Macroautophagy is an intracellular degradation system that utilizes the autophagosome to deliver cytoplasmic components to the lysosome. Measuring autophagic activity is critically important but remains complicated and challenging. Here, we have developed GFP-LC3-RFP-LC3ΔG, a fluorescent probe to evaluate autophagic flux. This probe is cleaved by endogenous ATG4 proteases into equimolar amounts of GFP-LC3 and RFP-LC3ΔG. GFP-LC3 is degraded by autophagy, while RFP-LC3ΔG remains in the cytosol, serving as an internal control. Thus, autophagic flux can be estimated by calculating the GFP/RFP signal ratio. Using this probe, we re-evaluated previously reported autophagy-modulating compounds, performed a high-throughput screen of an approved drug library, and identified autophagy modulators. Furthermore, we succeeded in measuring both induced and basal autophagic flux in embryos and tissues of zebrafish and mice. The GFP-LC3-RFP-LC3ΔG probe is a simple and quantitative method to evaluate autophagic flux in cultured cells and whole organisms.", + "authors": { + "abbreviation": "Takeshi Kaizuka, Hideaki Morishita, Yutaro Hama, ..., Noboru Mizushima", + "authorList": [ + { + "ForeName": "Takeshi", + "LastName": "Kaizuka", + "abbrevName": "Kaizuka T", + "email": null, + "isCollectiveName": false, + "name": "Takeshi Kaizuka" + }, + { + "ForeName": "Hideaki", + "LastName": "Morishita", + "abbrevName": "Morishita H", + "email": null, + "isCollectiveName": false, + "name": "Hideaki Morishita" + }, + { + "ForeName": "Yutaro", + "LastName": "Hama", + "abbrevName": "Hama Y", + "email": null, + "isCollectiveName": false, + "name": "Yutaro Hama" + }, + { + "ForeName": "Satoshi", + "LastName": "Tsukamoto", + "abbrevName": "Tsukamoto S", + "email": null, + "isCollectiveName": false, + "name": "Satoshi Tsukamoto" + }, + { + "ForeName": "Takahide", + "LastName": "Matsui", + "abbrevName": "Matsui T", + "email": null, + "isCollectiveName": false, + "name": "Takahide Matsui" + }, + { + "ForeName": "Yuichiro", + "LastName": "Toyota", + "abbrevName": "Toyota Y", + "email": null, + "isCollectiveName": false, + "name": "Yuichiro Toyota" + }, + { + "ForeName": "Akihiko", + "LastName": "Kodama", + "abbrevName": "Kodama A", + "email": null, + "isCollectiveName": false, + "name": "Akihiko Kodama" + }, + { + "ForeName": "Tomoaki", + "LastName": "Ishihara", + "abbrevName": "Ishihara T", + "email": null, + "isCollectiveName": false, + "name": "Tomoaki Ishihara" + }, + { + "ForeName": "Tohru", + "LastName": "Mizushima", + "abbrevName": "Mizushima T", + "email": null, + "isCollectiveName": false, + "name": "Tohru Mizushima" + }, + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": "nmizu@m.u-tokyo.ac.jp", + "isCollectiveName": false, + "name": "Noboru Mizushima" + } + ], + "contacts": [ + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "email": [ + "nmizu@m.u-tokyo.ac.jp" + ], + "name": "Noboru Mizushima" + } + ] + }, + "doi": "10.1016/j.molcel.2016.09.037", + "pmid": "27818143", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cell 64 2016", + "title": "An Autophagic Flux Probe that Releases an Internal Control." + } + }, + { + "pmid": "27320914", + "pubmed": { + "ISODate": "2016-06-28T00:00:00.000Z", + "abstract": "Fas apoptotic signaling regulates diverse physiological processes. Acute activation of Fas signaling triggers massive apoptosis in liver. Upon Fas receptor stimulation, the BH3-only protein Bid is cleaved into the active form, tBid. Subsequent tBid recruitment to mitochondria, which is facilitated by its receptor MTCH2 at the outer mitochondrial membrane (OMM), is a critical step for commitment to apoptosis via the effector proteins Bax or Bak. MOAP-1 is a Bax-binding protein enriched at the OMM. Here, we show that MOAP-1-deficient mice are resistant to Fas-induced hepatocellular apoptosis and lethality. In the absence of MOAP-1, mitochondrial accumulation of tBid is markedly impaired. MOAP-1 binds to MTCH2, and this interaction appears necessary for MTCH2 to engage tBid. These findings reveal a role for MOAP-1 in Fas signaling in the liver by promoting MTCH2-mediated tBid recruitment to mitochondria.", + "authors": { + "abbreviation": "Chong Teik Tan, Qi-Ling Zhou, Yu-Chin Su, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Qi-Ling", + "LastName": "Zhou", + "abbrevName": "Zhou QL", + "email": null, + "isCollectiveName": false, + "name": "Qi-Ling Zhou" + }, + { + "ForeName": "Yu-Chin", + "LastName": "Su", + "abbrevName": "Su YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chin Su" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Shairaz", + "LastName": "Baksh", + "abbrevName": "Baksh S", + "email": null, + "isCollectiveName": false, + "name": "Shairaz Baksh" + }, + { + "ForeName": "Yee-Joo", + "LastName": "Tan", + "abbrevName": "Tan YJ", + "email": null, + "isCollectiveName": false, + "name": "Yee-Joo Tan" + }, + { + "ForeName": "Kanaga", + "LastName": "Sabapathy", + "abbrevName": "Sabapathy K", + "email": null, + "isCollectiveName": false, + "name": "Kanaga Sabapathy" + }, + { + "ForeName": "Chun-Dong", + "LastName": "Yu", + "abbrevName": "Yu CD", + "email": null, + "isCollectiveName": false, + "name": "Chun-Dong Yu" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": "phayuv@nus.edu.sg", + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [ + { + "ForeName": "Victor", + "LastName": "Yu", + "email": [ + "phayuv@nus.edu.sg" + ], + "name": "Victor C Yu" + } + ] + }, + "doi": "10.1016/j.celrep.2016.05.068", + "pmid": "27320914", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell Rep 16 2016", + "title": "MOAP-1 Mediates Fas-Induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria." + } + }, + { + "pmid": "26799652", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Daniel J Klionsky, Kotb Abdelmohsen, Akihisa Abe, ..., Susu M Zughaier", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Klionsky", + "abbrevName": "Klionsky DJ", + "email": null, + "isCollectiveName": false, + "name": "Daniel J Klionsky" + }, + { + "ForeName": "Kotb", + "LastName": "Abdelmohsen", + "abbrevName": "Abdelmohsen K", + "email": null, + "isCollectiveName": false, + "name": "Kotb Abdelmohsen" + }, + { + "ForeName": "Akihisa", + "LastName": "Abe", + "abbrevName": "Abe A", + "email": null, + "isCollectiveName": false, + "name": "Akihisa Abe" + }, + { + "ForeName": "Md", + "LastName": "Abedin", + "abbrevName": "Abedin MJ", + "email": null, + "isCollectiveName": false, + "name": "Md Joynal Abedin" + }, + { + "ForeName": "Hagai", + "LastName": "Abeliovich", + "abbrevName": "Abeliovich H", + "email": null, + "isCollectiveName": false, + "name": "Hagai Abeliovich" + }, + { + "ForeName": "Abraham", + "LastName": "Acevedo Arozena", + "abbrevName": "Acevedo Arozena A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Acevedo Arozena" + }, + { + "ForeName": "Hiroaki", + "LastName": "Adachi", + "abbrevName": "Adachi H", + "email": null, + "isCollectiveName": false, + "name": "Hiroaki Adachi" + }, + { + "ForeName": "Christopher", + "LastName": "Adams", + "abbrevName": "Adams CM", + "email": null, + "isCollectiveName": false, + "name": "Christopher M Adams" + }, + { + "ForeName": "Peter", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Peter D Adams" + }, + { + "ForeName": "Khosrow", + "LastName": "Adeli", + "abbrevName": "Adeli K", + "email": null, + "isCollectiveName": false, + "name": "Khosrow Adeli" + }, + { + "ForeName": "Peter", + "LastName": "Adhihetty", + "abbrevName": "Adhihetty PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Adhihetty" + }, + { + "ForeName": "Sharon", + "LastName": "Adler", + "abbrevName": "Adler SG", + "email": null, + "isCollectiveName": false, + "name": "Sharon G Adler" + }, + { + "ForeName": "Galila", + "LastName": "Agam", + "abbrevName": "Agam G", + "email": null, + "isCollectiveName": false, + "name": "Galila Agam" + }, + { + "ForeName": "Rajesh", + "LastName": "Agarwal", + "abbrevName": "Agarwal R", + "email": null, + "isCollectiveName": false, + "name": "Rajesh Agarwal" + }, + { + "ForeName": "Manish", + "LastName": "Aghi", + "abbrevName": "Aghi MK", + "email": null, + "isCollectiveName": false, + "name": "Manish K Aghi" + }, + { + "ForeName": "Maria", + "LastName": "Agnello", + "abbrevName": "Agnello M", + "email": null, + "isCollectiveName": false, + "name": "Maria Agnello" + }, + { + "ForeName": "Patrizia", + "LastName": "Agostinis", + "abbrevName": "Agostinis P", + "email": null, + "isCollectiveName": false, + "name": "Patrizia Agostinis" + }, + { + "ForeName": "Patricia", + "LastName": "Aguilar", + "abbrevName": "Aguilar PV", + "email": null, + "isCollectiveName": false, + "name": "Patricia V Aguilar" + }, + { + "ForeName": "Julio", + "LastName": "Aguirre-Ghiso", + "abbrevName": "Aguirre-Ghiso J", + "email": null, + "isCollectiveName": false, + "name": "Julio Aguirre-Ghiso" + }, + { + "ForeName": "Edoardo", + "LastName": "Airoldi", + "abbrevName": "Airoldi EM", + "email": null, + "isCollectiveName": false, + "name": "Edoardo M Airoldi" + }, + { + "ForeName": "Slimane", + "LastName": "Ait-Si-Ali", + "abbrevName": "Ait-Si-Ali S", + "email": null, + "isCollectiveName": false, + "name": "Slimane Ait-Si-Ali" + }, + { + "ForeName": "Takahiko", + "LastName": "Akematsu", + "abbrevName": "Akematsu T", + "email": null, + "isCollectiveName": false, + "name": "Takahiko Akematsu" + }, + { + "ForeName": "Emmanuel", + "LastName": "Akporiaye", + "abbrevName": "Akporiaye ET", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel T Akporiaye" + }, + { + "ForeName": "Mohamed", + "LastName": "Al-Rubeai", + "abbrevName": "Al-Rubeai M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Al-Rubeai" + }, + { + "ForeName": "Guillermo", + "LastName": "Albaiceta", + "abbrevName": "Albaiceta GM", + "email": null, + "isCollectiveName": false, + "name": "Guillermo M Albaiceta" + }, + { + "ForeName": "Chris", + "LastName": "Albanese", + "abbrevName": "Albanese C", + "email": null, + "isCollectiveName": false, + "name": "Chris Albanese" + }, + { + "ForeName": "Diego", + "LastName": "Albani", + "abbrevName": "Albani D", + "email": null, + "isCollectiveName": false, + "name": "Diego Albani" + }, + { + "ForeName": "Matthew", + "LastName": "Albert", + "abbrevName": "Albert ML", + "email": null, + "isCollectiveName": false, + "name": "Matthew L Albert" + }, + { + "ForeName": "Jesus", + "LastName": "Aldudo", + "abbrevName": "Aldudo J", + "email": null, + "isCollectiveName": false, + "name": "Jesus Aldudo" + }, + { + "ForeName": "Hana", + "LastName": "Algül", + "abbrevName": "Algül H", + "email": null, + "isCollectiveName": false, + "name": "Hana Algül" + }, + { + "ForeName": "Mehrdad", + "LastName": "Alirezaei", + "abbrevName": "Alirezaei M", + "email": null, + "isCollectiveName": false, + "name": "Mehrdad Alirezaei" + }, + { + "ForeName": "Iraide", + "LastName": "Alloza", + "abbrevName": "Alloza I", + "email": null, + "isCollectiveName": false, + "name": "Iraide Alloza" + }, + { + "ForeName": "Alexandru", + "LastName": "Almasan", + "abbrevName": "Almasan A", + "email": null, + "isCollectiveName": false, + "name": "Alexandru Almasan" + }, + { + "ForeName": "Maylin", + "LastName": "Almonte-Beceril", + "abbrevName": "Almonte-Beceril M", + "email": null, + "isCollectiveName": false, + "name": "Maylin Almonte-Beceril" + }, + { + "ForeName": "Emad", + "LastName": "Alnemri", + "abbrevName": "Alnemri ES", + "email": null, + "isCollectiveName": false, + "name": "Emad S Alnemri" + }, + { + "ForeName": "Covadonga", + "LastName": "Alonso", + "abbrevName": "Alonso C", + "email": null, + "isCollectiveName": false, + "name": "Covadonga Alonso" + }, + { + "ForeName": "Nihal", + "LastName": "Altan-Bonnet", + "abbrevName": "Altan-Bonnet N", + "email": null, + "isCollectiveName": false, + "name": "Nihal Altan-Bonnet" + }, + { + "ForeName": "Dario", + "LastName": "Altieri", + "abbrevName": "Altieri DC", + "email": null, + "isCollectiveName": false, + "name": "Dario C Altieri" + }, + { + "ForeName": "Silvia", + "LastName": "Alvarez", + "abbrevName": "Alvarez S", + "email": null, + "isCollectiveName": false, + "name": "Silvia Alvarez" + }, + { + "ForeName": "Lydia", + "LastName": "Alvarez-Erviti", + "abbrevName": "Alvarez-Erviti L", + "email": null, + "isCollectiveName": false, + "name": "Lydia Alvarez-Erviti" + }, + { + "ForeName": "Sandro", + "LastName": "Alves", + "abbrevName": "Alves S", + "email": null, + "isCollectiveName": false, + "name": "Sandro Alves" + }, + { + "ForeName": "Giuseppina", + "LastName": "Amadoro", + "abbrevName": "Amadoro G", + "email": null, + "isCollectiveName": false, + "name": "Giuseppina Amadoro" + }, + { + "ForeName": "Atsuo", + "LastName": "Amano", + "abbrevName": "Amano A", + "email": null, + "isCollectiveName": false, + "name": "Atsuo Amano" + }, + { + "ForeName": "Consuelo", + "LastName": "Amantini", + "abbrevName": "Amantini C", + "email": null, + "isCollectiveName": false, + "name": "Consuelo Amantini" + }, + { + "ForeName": "Santiago", + "LastName": "Ambrosio", + "abbrevName": "Ambrosio S", + "email": null, + "isCollectiveName": false, + "name": "Santiago Ambrosio" + }, + { + "ForeName": "Ivano", + "LastName": "Amelio", + "abbrevName": "Amelio I", + "email": null, + "isCollectiveName": false, + "name": "Ivano Amelio" + }, + { + "ForeName": "Amal", + "LastName": "Amer", + "abbrevName": "Amer AO", + "email": null, + "isCollectiveName": false, + "name": "Amal O Amer" + }, + { + "ForeName": "Mohamed", + "LastName": "Amessou", + "abbrevName": "Amessou M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Amessou" + }, + { + "ForeName": "Angelika", + "LastName": "Amon", + "abbrevName": "Amon A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Amon" + }, + { + "ForeName": "Zhenyi", + "LastName": "An", + "abbrevName": "An Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenyi An" + }, + { + "ForeName": "Frank", + "LastName": "Anania", + "abbrevName": "Anania FA", + "email": null, + "isCollectiveName": false, + "name": "Frank A Anania" + }, + { + "ForeName": "Stig", + "LastName": "Andersen", + "abbrevName": "Andersen SU", + "email": null, + "isCollectiveName": false, + "name": "Stig U Andersen" + }, + { + "ForeName": "Usha", + "LastName": "Andley", + "abbrevName": "Andley UP", + "email": null, + "isCollectiveName": false, + "name": "Usha P Andley" + }, + { + "ForeName": "Catherine", + "LastName": "Andreadi", + "abbrevName": "Andreadi CK", + "email": null, + "isCollectiveName": false, + "name": "Catherine K Andreadi" + }, + { + "ForeName": "Nathalie", + "LastName": "Andrieu-Abadie", + "abbrevName": "Andrieu-Abadie N", + "email": null, + "isCollectiveName": false, + "name": "Nathalie Andrieu-Abadie" + }, + { + "ForeName": "Alberto", + "LastName": "Anel", + "abbrevName": "Anel A", + "email": null, + "isCollectiveName": false, + "name": "Alberto Anel" + }, + { + "ForeName": "David", + "LastName": "Ann", + "abbrevName": "Ann DK", + "email": null, + "isCollectiveName": false, + "name": "David K Ann" + }, + { + "ForeName": "Shailendra", + "LastName": "Anoopkumar-Dukie", + "abbrevName": "Anoopkumar-Dukie S", + "email": null, + "isCollectiveName": false, + "name": "Shailendra Anoopkumar-Dukie" + }, + { + "ForeName": "Manuela", + "LastName": "Antonioli", + "abbrevName": "Antonioli M", + "email": null, + "isCollectiveName": false, + "name": "Manuela Antonioli" + }, + { + "ForeName": "Hiroshi", + "LastName": "Aoki", + "abbrevName": "Aoki H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Aoki" + }, + { + "ForeName": "Nadezda", + "LastName": "Apostolova", + "abbrevName": "Apostolova N", + "email": null, + "isCollectiveName": false, + "name": "Nadezda Apostolova" + }, + { + "ForeName": "Saveria", + "LastName": "Aquila", + "abbrevName": "Aquila S", + "email": null, + "isCollectiveName": false, + "name": "Saveria Aquila" + }, + { + "ForeName": "Katia", + "LastName": "Aquilano", + 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"email": null, + "isCollectiveName": false, + "name": "Jianhua Zhang" + }, + { + "ForeName": "Jing-Pu", + "LastName": "Zhang", + "abbrevName": "Zhang JP", + "email": null, + "isCollectiveName": false, + "name": "Jing-Pu Zhang" + }, + { + "ForeName": "Li", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhang" + }, + { + "ForeName": "Lin", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Lin Zhang" + }, + { + "ForeName": "Lin", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Lin Zhang" + }, + { + "ForeName": "Long", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Long Zhang" + }, + { + "ForeName": "Ming-Yong", + "LastName": "Zhang", + "abbrevName": "Zhang MY", + "email": null, + "isCollectiveName": false, + "name": "Ming-Yong Zhang" + }, + { + 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"email": null, + "isCollectiveName": false, + "name": "Yunjiao Zhang" + }, + { + "ForeName": "Mei", + "LastName": "Zhao", + "abbrevName": "Zhao M", + "email": null, + "isCollectiveName": false, + "name": "Mei Zhao" + }, + { + "ForeName": "Wei-Li", + "LastName": "Zhao", + "abbrevName": "Zhao WL", + "email": null, + "isCollectiveName": false, + "name": "Wei-Li Zhao" + }, + { + "ForeName": "Xiaonan", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaonan Zhao" + }, + { + "ForeName": "Yan", + "LastName": "Zhao", + "abbrevName": "Zhao YG", + "email": null, + "isCollectiveName": false, + "name": "Yan G Zhao" + }, + { + "ForeName": "Ying", + "LastName": "Zhao", + "abbrevName": "Zhao Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Zhao" + }, + { + "ForeName": "Yongchao", + "LastName": "Zhao", + "abbrevName": "Zhao Y", + "email": null, + "isCollectiveName": false, + "name": "Yongchao Zhao" + }, + { + "ForeName": "Yu-Xia", + "LastName": "Zhao", + "abbrevName": "Zhao YX", + "email": null, + "isCollectiveName": false, + "name": "Yu-Xia Zhao" + }, + { + "ForeName": "Zhendong", + "LastName": "Zhao", + "abbrevName": "Zhao Z", + "email": null, + "isCollectiveName": false, + "name": "Zhendong Zhao" + }, + { + "ForeName": "Zhizhuang", + "LastName": "Zhao", + "abbrevName": "Zhao ZJ", + "email": null, + "isCollectiveName": false, + "name": "Zhizhuang J Zhao" + }, + { + "ForeName": "Dexian", + "LastName": "Zheng", + "abbrevName": "Zheng D", + "email": null, + "isCollectiveName": false, + "name": "Dexian Zheng" + }, + { + "ForeName": "Xi-Long", + "LastName": "Zheng", + "abbrevName": "Zheng XL", + "email": null, + "isCollectiveName": false, + "name": "Xi-Long Zheng" + }, + { + "ForeName": "Xiaoxiang", + "LastName": "Zheng", + "abbrevName": "Zheng X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoxiang Zheng" + }, + { + "ForeName": "Boris", + "LastName": "Zhivotovsky", + "abbrevName": "Zhivotovsky B", + "email": null, + "isCollectiveName": false, + "name": "Boris Zhivotovsky" + }, + { + "ForeName": "Qing", + "LastName": "Zhong", + "abbrevName": "Zhong Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Zhong" + }, + { + "ForeName": "Guang-Zhou", + "LastName": "Zhou", + "abbrevName": "Zhou GZ", + "email": null, + "isCollectiveName": false, + "name": "Guang-Zhou Zhou" + }, + { + "ForeName": "Guofei", + "LastName": "Zhou", + "abbrevName": "Zhou G", + "email": null, + "isCollectiveName": false, + "name": "Guofei Zhou" + }, + { + "ForeName": "Huiping", + "LastName": "Zhou", + "abbrevName": "Zhou H", + "email": null, + "isCollectiveName": false, + "name": "Huiping Zhou" + }, + { + "ForeName": "Shu-Feng", + "LastName": "Zhou", + "abbrevName": "Zhou SF", + "email": null, + "isCollectiveName": false, + "name": "Shu-Feng Zhou" + }, + { + "ForeName": "Xu-Jie", + "LastName": "Zhou", + "abbrevName": "Zhou XJ", + "email": null, + "isCollectiveName": false, + "name": "Xu-Jie Zhou" + }, + { + "ForeName": "Hongxin", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hongxin Zhu" + }, + { + "ForeName": "Hua", + "LastName": "Zhu", + "abbrevName": "Zhu H", + "email": null, + "isCollectiveName": false, + "name": "Hua Zhu" + }, + { + "ForeName": "Wei-Guo", + "LastName": "Zhu", + "abbrevName": "Zhu WG", + "email": null, + "isCollectiveName": false, + "name": "Wei-Guo Zhu" + }, + { + "ForeName": "Wenhua", + "LastName": "Zhu", + "abbrevName": "Zhu W", + "email": null, + "isCollectiveName": false, + "name": "Wenhua Zhu" + }, + { + "ForeName": "Xiao-Feng", + "LastName": "Zhu", + "abbrevName": "Zhu XF", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Feng Zhu" + }, + { + "ForeName": "Yuhua", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuhua Zhu" + }, + { + "ForeName": "Shi-Mei", + "LastName": "Zhuang", + "abbrevName": "Zhuang SM", + "email": null, + "isCollectiveName": false, + "name": "Shi-Mei Zhuang" + }, + { + "ForeName": "Xiaohong", + "LastName": "Zhuang", + "abbrevName": "Zhuang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaohong Zhuang" + }, + { + "ForeName": "Elio", + "LastName": "Ziparo", + "abbrevName": "Ziparo E", + "email": null, + "isCollectiveName": false, + "name": "Elio Ziparo" + }, + { + "ForeName": "Christos", + "LastName": "Zois", + "abbrevName": "Zois CE", + "email": null, + "isCollectiveName": false, + "name": "Christos E Zois" + }, + { + "ForeName": "Teresa", + "LastName": "Zoladek", + "abbrevName": "Zoladek T", + "email": null, + "isCollectiveName": false, + "name": "Teresa Zoladek" + }, + { + "ForeName": "Wei-Xing", + "LastName": "Zong", + "abbrevName": "Zong WX", + "email": null, + "isCollectiveName": false, + "name": "Wei-Xing Zong" + }, + { + "ForeName": "Antonio", + "LastName": "Zorzano", + "abbrevName": "Zorzano A", + "email": null, + "isCollectiveName": false, + "name": "Antonio Zorzano" + }, + { + "ForeName": "Susu", + "LastName": "Zughaier", + "abbrevName": "Zughaier SM", + "email": null, + "isCollectiveName": false, + "name": "Susu M Zughaier" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2015.1100356", + "pmid": "26799652", + "pubTypes": [ + { + "UI": "D016431", + "value": "Guideline" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Autophagy 12 2016", + "title": "Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)." + } + }, + { + "pmid": "26177004", + "pubmed": { + "ISODate": "2015-08-01T00:00:00.000Z", + "abstract": "Autophagy is a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome. Starvation-induced protein degradation is a salient feature of autophagy but recent progress has illuminated how autophagy, during both starvation and nutrient-replete conditions, can mobilize diverse cellular energy and nutrient stores such as lipids, carbohydrates and iron. Processes such as lipophagy, glycophagy and ferritinophagy enable cells to salvage key metabolites to sustain and facilitate core anabolic functions. Here, we discuss the established and emerging roles of autophagy in fuelling biosynthetic capacity and in promoting metabolic and nutrient homeostasis. ", + "authors": { + "abbreviation": "Jasvinder Kaur, Jayanta Debnath", + "authorList": [ + { + "ForeName": "Jasvinder", + "LastName": "Kaur", + "abbrevName": "Kaur J", + "email": null, + "isCollectiveName": false, + "name": "Jasvinder Kaur" + }, + { + "ForeName": "Jayanta", + "LastName": "Debnath", + "abbrevName": "Debnath J", + "email": null, + "isCollectiveName": false, + "name": "Jayanta Debnath" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm4024", + "pmid": "26177004", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 16 2015", + "title": "Autophagy at the crossroads of catabolism and anabolism." + } + }, + { + "pmid": "25498145", + "pubmed": { + "ISODate": "2015-01-08T00:00:00.000Z", + "abstract": "The lysosome is the final destination for degradation of endocytic cargo, plasma membrane constituents, and intracellular components sequestered by macroautophagy. Fusion of endosomes and autophagosomes with the lysosome depends on the GTPase Rab7 and the homotypic fusion and protein sorting (HOPS) complex, but adaptor proteins that link endocytic and autophagy pathways with lysosomes are poorly characterized. Herein, we show that Pleckstrin homology domain containing protein family member 1 (PLEKHM1) directly interacts with HOPS complex and contains a LC3-interacting region (LIR) that mediates its binding to autophagosomal membranes. Depletion of PLEKHM1 blocks lysosomal degradation of endocytic (EGFR) cargo and enhances presentation of MHC class I molecules. Moreover, genetic loss of PLEKHM1 impedes autophagy flux upon mTOR inhibition and PLEKHM1 regulates clearance of protein aggregates in an autophagy- and LIR-dependent manner. PLEKHM1 is thus a multivalent endocytic adaptor involved in the lysosome fusion events controlling selective and nonselective autophagy pathways.", + "authors": { + "abbreviation": "David G McEwan, Doris Popovic, Andrea Gubas, ..., Ivan Dikic", + "authorList": [ + { + "ForeName": "David", + "LastName": "McEwan", + "abbrevName": "McEwan DG", + "email": null, + "isCollectiveName": false, + "name": "David G McEwan" + }, + { + "ForeName": "Doris", + "LastName": "Popovic", + "abbrevName": "Popovic D", + "email": null, + "isCollectiveName": false, + "name": "Doris Popovic" + }, + { + "ForeName": "Andrea", + "LastName": "Gubas", + "abbrevName": "Gubas A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Gubas" + }, + { + "ForeName": "Seigo", + "LastName": "Terawaki", + "abbrevName": "Terawaki S", + "email": null, + "isCollectiveName": false, + "name": "Seigo Terawaki" + }, + { + "ForeName": "Hironori", + "LastName": "Suzuki", + "abbrevName": "Suzuki H", + "email": null, + "isCollectiveName": false, + "name": "Hironori Suzuki" + }, + { + "ForeName": "Daniela", + "LastName": "Stadel", + "abbrevName": "Stadel D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Stadel" + }, + { + "ForeName": "Fraser", + "LastName": "Coxon", + "abbrevName": "Coxon FP", + "email": null, + "isCollectiveName": false, + "name": "Fraser P Coxon" + }, + { + "ForeName": "Diana", + "LastName": "Miranda de Stegmann", + "abbrevName": "Miranda de Stegmann D", + "email": null, + "isCollectiveName": false, + "name": "Diana Miranda de Stegmann" + }, + { + "ForeName": "Sagar", + "LastName": "Bhogaraju", + "abbrevName": "Bhogaraju S", + "email": null, + "isCollectiveName": false, + "name": "Sagar Bhogaraju" + }, + { + "ForeName": "Karthik", + "LastName": "Maddi", + "abbrevName": "Maddi K", + "email": null, + "isCollectiveName": false, + "name": "Karthik Maddi" + }, + { + "ForeName": "Anja", + "LastName": "Kirchof", + "abbrevName": "Kirchof A", + "email": null, + "isCollectiveName": false, + "name": "Anja Kirchof" + }, + { + "ForeName": "Evelina", + "LastName": "Gatti", + "abbrevName": "Gatti E", + "email": null, + "isCollectiveName": false, + "name": "Evelina Gatti" + }, + { + "ForeName": "Miep", + "LastName": "Helfrich", + "abbrevName": "Helfrich MH", + "email": null, + "isCollectiveName": false, + "name": "Miep H Helfrich" + }, + { + "ForeName": "Soichi", + "LastName": "Wakatsuki", + "abbrevName": "Wakatsuki S", + "email": null, + "isCollectiveName": false, + "name": "Soichi Wakatsuki" + }, + { + "ForeName": "Christian", + "LastName": "Behrends", + "abbrevName": "Behrends C", + "email": null, + "isCollectiveName": false, + "name": "Christian Behrends" + }, + { + "ForeName": "Philippe", + "LastName": "Pierre", + "abbrevName": "Pierre P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Pierre" + }, + { + "ForeName": "Ivan", + "LastName": "Dikic", + "abbrevName": "Dikic I", + "email": "Ivan.Dikic@biochem2.de", + "isCollectiveName": false, + "name": "Ivan Dikic" + } + ], + "contacts": [ + { + "ForeName": "Ivan", + "LastName": "Dikic", + "email": [ + "Ivan.Dikic@biochem2.de" + ], + "name": "Ivan Dikic" + } + ] + }, + "doi": "10.1016/j.molcel.2014.11.006", + "pmid": "25498145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 57 2015", + "title": "PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins." + } + }, + { + "pmid": "24954904", + "pubmed": { + "ISODate": "2014-07-17T00:00:00.000Z", + "abstract": "Mammalian cell homeostasis during starvation depends on initiation of autophagy by endoplasmic reticulum-localized phosphatidylinositol 3-phosphate (PtdIns(3)P) synthesis. Formation of double-membrane autophagosomes that engulf cytosolic components requires the LC3-conjugating Atg12-5-16L1 complex. The molecular mechanisms of Atg12-5-16L1 recruitment and significance of PtdIns(3)P synthesis at autophagosome formation sites are unknown. By identifying interacting partners of WIPIs, WD-repeat PtdIns(3)P effector proteins, we found that Atg16L1 directly binds WIPI2b. Mutation experiments and ectopic localization of WIPI2b to plasma membrane show that WIPI2b is a PtdIns(3)P effector upstream of Atg16L1 and is required for LC3 conjugation and starvation-induced autophagy through recruitment of the Atg12-5-16L1 complex. Atg16L1 mutants, which do not bind WIPI2b but bind FIP200, cannot rescue starvation-induced autophagy in Atg16L1-deficient MEFs. WIPI2b is also required for autophagic clearance of pathogenic bacteria. WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella. ", + "authors": { + "abbreviation": "Hannah C Dooley, Minoo Razi, Hannah E J Polson, ..., Sharon A Tooze", + "authorList": [ + { + "ForeName": "Hannah", + "LastName": "Dooley", + "abbrevName": "Dooley HC", + "email": null, + "isCollectiveName": false, + "name": "Hannah C Dooley" + }, + { + "ForeName": "Minoo", + "LastName": "Razi", + "abbrevName": "Razi M", + "email": null, + "isCollectiveName": false, + "name": "Minoo Razi" + }, + { + "ForeName": "Hannah", + "LastName": "Polson", + "abbrevName": "Polson HE", + "email": null, + "isCollectiveName": false, + "name": "Hannah E J Polson" + }, + { + "ForeName": "Stephen", + "LastName": "Girardin", + "abbrevName": "Girardin SE", + "email": null, + "isCollectiveName": false, + "name": "Stephen E Girardin" + }, + { + "ForeName": "Michael", + "LastName": "Wilson", + "abbrevName": "Wilson MI", + "email": null, + "isCollectiveName": false, + "name": "Michael I Wilson" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": "sharon.tooze@cancer.org.uk", + "isCollectiveName": false, + "name": "Sharon A Tooze" + } + ], + "contacts": [ + { + "ForeName": "Sharon", + "LastName": "Tooze", + "email": [ + "sharon.tooze@cancer.org.uk" + ], + "name": "Sharon A Tooze" + } + ] + }, + "doi": "10.1016/j.molcel.2014.05.021", + "pmid": "24954904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 55 2014", + "title": "WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1." + } + }, + { + "pmid": "24875736", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking events. Here we discuss the current view on how cargo selection and transport are achieved during selective autophagy, and point out molecular mechanisms that are congruent between autophagy and vesicle trafficking pathways. ", + "authors": { + "abbreviation": "Alexandra Stolz, Andreas Ernst, Ivan Dikic", + "authorList": [ + { + "ForeName": "Alexandra", + "LastName": "Stolz", + "abbrevName": "Stolz A", + "email": null, + "isCollectiveName": false, + "name": "Alexandra Stolz" + }, + { + "ForeName": "Andreas", + "LastName": "Ernst", + "abbrevName": "Ernst A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ernst" + }, + { + "ForeName": "Ivan", + "LastName": "Dikic", + "abbrevName": "Dikic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Dikic" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2979", + "pmid": "24875736", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "Cargo recognition and trafficking in selective autophagy." + } + }, + { + "pmid": "24675368", + "pubmed": { + "ISODate": "2014-05-01T00:00:00.000Z", + "abstract": "Autophagy is a catabolic process during which cellular components including protein aggregates and organelles are degraded via a lysosome-dependent process to sustain metabolic homeostasis during nutrient or energy deprivation. Measuring the rate of proteolysis of long-lived proteins is a classical assay for measurement of autophagic flux. However, traditional methods, such as a radioisotope labeling assay, are technically tedious and have low sensitivity. Here, we report a novel method for quantification of long-lived protein degradation based on L-azidohomoalanine (AHA) labeling in mouse embryonic fibroblasts (MEFs) and in human cancer cells. AHA is a surrogate for L-methionine, containing a bio-orthogonalazide moiety. When added to cultured cells, AHA is incorporated into proteins during active protein synthesis. After a click reaction between an azide and an alkyne, the azide-containing proteins can be detected with an alkyne-tagged fluorescent dye, coupled with flow cytometry. Induction of autophagy by starvation or mechanistic target of rapamycin (MTOR) inhibitors was able to induce a significant reduction of the fluorescence intensity, consistent with other autophagic markers. Coincidently, inhibition of autophagy by pharmacological agents or by Atg gene deletion abolished the reduction of the fluorescence intensity. Compared with the classical radioisotope pulse-labeling method, we think that our method is sensitive, quantitative, nonradioactive, and easy to perform, and can be applied to both human and animal cell culture systems.", + "authors": { + "abbreviation": "Jianbin Zhang, Jigang Wang, Shukie Ng, ..., Han-Ming Shen", + "authorList": [ + { + "ForeName": "Jianbin", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jianbin Zhang" + }, + { + "ForeName": "Jigang", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jigang Wang" + }, + { + "ForeName": "Shukie", + "LastName": "Ng", + "abbrevName": "Ng S", + "email": null, + "isCollectiveName": false, + "name": "Shukie Ng" + }, + { + "ForeName": "Qingsong", + "LastName": "Lin", + "abbrevName": "Lin Q", + "email": null, + "isCollectiveName": false, + "name": "Qingsong Lin" + }, + { + "ForeName": "Han-Ming", + "LastName": "Shen", + "abbrevName": "Shen HM", + "email": null, + "isCollectiveName": false, + "name": "Han-Ming Shen" + } + ], + "contacts": [] + }, + "doi": "10.4161/auto.28267", + "pmid": "24675368", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 10 2014", + "title": "Development of a novel method for quantification of autophagic protein degradation by AHA labeling." + } + }, + { + "pmid": "24485455", + "pubmed": { + "ISODate": "2014-01-30T00:00:00.000Z", + "abstract": "Autophagy is a catabolic pathway that sequesters undesired cellular material into autophagosomes for delivery to lysosomes for degradation. A key step in the pathway is the covalent conjugation of the ubiquitin-related protein Atg8 to phosphatidylethanolamine (Atg8-PE) in autophagic membranes by a complex consisting of Atg16 and the Atg12-Atg5 conjugate. Atg8 controls the expansion of autophagic precursor membranes, but the underlying mechanism remains unclear. Here, we reconstitute Atg8 conjugation on giant unilamellar vesicles and supported lipid bilayers. We found that Atg8-PE associates with Atg12-Atg5-Atg16 into a membrane scaffold. By contrast, scaffold formation is counteracted by the mitochondrial cargo adaptor Atg32 through competition with Atg12-Atg5 for Atg8 binding. Atg4, previously known to recycle Atg8 from membranes, disassembles the scaffold. Importantly, mutants of Atg12 and Atg16 deficient in scaffold formation in vitro impair autophagy in vivo. This suggests that autophagic scaffolds are critical for phagophore biogenesis and thus autophagy. ", + "authors": { + "abbreviation": "Anna Kaufmann, Viola Beier, Henri G Franquelim, Thomas Wollert", + "authorList": [ + { + "ForeName": "Anna", + "LastName": "Kaufmann", + "abbrevName": "Kaufmann A", + "email": null, + "isCollectiveName": false, + "name": "Anna Kaufmann" + }, + { + "ForeName": "Viola", + "LastName": "Beier", + "abbrevName": "Beier V", + "email": null, + "isCollectiveName": false, + "name": "Viola Beier" + }, + { + "ForeName": "Henri", + "LastName": "Franquelim", + "abbrevName": "Franquelim HG", + "email": null, + "isCollectiveName": false, + "name": "Henri G Franquelim" + }, + { + "ForeName": "Thomas", + "LastName": "Wollert", + "abbrevName": "Wollert T", + "email": "wollert@biochem.mpg.de", + "isCollectiveName": false, + "name": "Thomas Wollert" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Wollert", + "email": [ + "wollert@biochem.mpg.de" + ], + "name": "Thomas Wollert" + } + ] + }, + "doi": "10.1016/j.cell.2013.12.022", + "pmid": "24485455", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 156 2014", + "title": "Molecular mechanism of autophagic membrane-scaffold assembly and disassembly." + } + }, + { + "pmid": "23930225", + "pubmed": { + "ISODate": "2013-08-06T00:00:00.000Z", + "abstract": "Autophagy is a catabolic process for bulk degradation of cytosolic materials mediated by double-membraned autophagosomes. The membrane determinant to initiate the formation of autophagosomes remains elusive. Here, we establish a cell-free assay based on LC3 lipidation to define the organelle membrane supporting early autophagosome formation. In vitro LC3 lipidation requires energy and is subject to regulation by the pathways modulating autophagy in vivo. We developed a systematic membrane isolation scheme to identify the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) as a primary membrane source both necessary and sufficient to trigger LC3 lipidation in vitro. Functional studies demonstrate that the ERGIC is required for autophagosome biogenesis in vivo. Moreover, we find that the ERGIC acts by recruiting the early autophagosome marker ATG14, a critical step for the generation of preautophagosomal membranes. DOI:http://dx.doi.org/10.7554/eLife.00947.001. ", + "authors": { + "abbreviation": "Liang Ge, David Melville, Min Zhang, Randy Schekman", + "authorList": [ + { + "ForeName": "Liang", + "LastName": "Ge", + "abbrevName": "Ge L", + "email": null, + "isCollectiveName": false, + "name": "Liang Ge" + }, + { + "ForeName": "David", + "LastName": "Melville", + "abbrevName": "Melville D", + "email": null, + "isCollectiveName": false, + "name": "David Melville" + }, + { + "ForeName": "Min", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Min Zhang" + }, + { + "ForeName": "Randy", + "LastName": "Schekman", + "abbrevName": "Schekman R", + "email": null, + "isCollectiveName": false, + "name": "Randy Schekman" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.00947", + "pmid": "23930225", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Elife 2 2013", + "title": "The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis." + } + }, + { + "pmid": "23575358", + "pubmed": { + "ISODate": "2013-06-01T00:00:00.000Z", + "abstract": "Macroautophagy mediates recycling of intracellular material by a multistep pathway, ultimately leading to the fusion of closed double-membrane structures, called autophagosomes, with the lysosome. This event ensures the degradation of the autophagosome content by lysosomal proteases followed by the release of macromolecules by permeases and, thus, it accomplishes the purpose of macroautophagy (hereafter referred to as autophagy). Because fusion of unclosed autophagosomes (i.e., phagophores) with the lysosome would fail to degrade the autophagic cargo, this critical step has to be tightly controlled. Yet, until recently, little was known about the regulation of this event and the factors orchestrating it. A punctum in this issue highlights the recent paper by Noboru Mizushima and his collaborators that answered the question of how premature fusion of phagophores with the lysosome is prevented prior to completion of autophagosome closure.", + "authors": { + "abbreviation": "Amélie Bernard, Hana Popelka, Daniel J Klionsky", + "authorList": [ + { + "ForeName": "Amélie", + "LastName": "Bernard", + "abbrevName": "Bernard A", + "email": null, + "isCollectiveName": false, + "name": "Amélie Bernard" + }, + { + "ForeName": "Hana", + "LastName": "Popelka", + "abbrevName": "Popelka H", + "email": null, + "isCollectiveName": false, + "name": "Hana Popelka" + }, + { + "ForeName": "Daniel", + "LastName": "Klionsky", + "abbrevName": "Klionsky DJ", + "email": null, + "isCollectiveName": false, + "name": "Daniel J Klionsky" + } + ], + "contacts": [] + }, + "doi": "10.4161/auto.24359", + "pmid": "23575358", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Autophagy 9 2013", + "title": "A unique hairpin-type tail-anchored SNARE starts to solve a long-time puzzle." + } + }, + { + "pmid": "23287718", + "pubmed": { + "ISODate": "2013-02-15T00:00:00.000Z", + "abstract": "Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.", + "authors": { + "abbreviation": "Le Cong, F Ann Ran, David Cox, ..., Feng Zhang", + "authorList": [ + { + "ForeName": "Le", + "LastName": "Cong", + "abbrevName": "Cong L", + "email": null, + "isCollectiveName": false, + "name": "Le Cong" + }, + { + "ForeName": "F", + "LastName": "Ran", + "abbrevName": "Ran FA", + "email": null, + "isCollectiveName": false, + "name": "F Ann Ran" + }, + { + "ForeName": "David", + "LastName": "Cox", + "abbrevName": "Cox D", + "email": null, + "isCollectiveName": false, + "name": "David Cox" + }, + { + "ForeName": "Shuailiang", + "LastName": "Lin", + "abbrevName": "Lin S", + "email": null, + "isCollectiveName": false, + "name": "Shuailiang Lin" + }, + { + "ForeName": "Robert", + "LastName": "Barretto", + "abbrevName": "Barretto R", + "email": null, + "isCollectiveName": false, + "name": "Robert Barretto" + }, + { + "ForeName": "Naomi", + "LastName": "Habib", + "abbrevName": "Habib N", + "email": null, + "isCollectiveName": false, + "name": "Naomi Habib" + }, + { + "ForeName": "Patrick", + "LastName": "Hsu", + "abbrevName": "Hsu PD", + "email": null, + "isCollectiveName": false, + "name": "Patrick D Hsu" + }, + { + "ForeName": "Xuebing", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "Xuebing Wu" + }, + { + "ForeName": "Wenyan", + "LastName": "Jiang", + "abbrevName": "Jiang W", + "email": null, + "isCollectiveName": false, + "name": "Wenyan Jiang" + }, + { + "ForeName": "Luciano", + "LastName": "Marraffini", + "abbrevName": "Marraffini LA", + "email": null, + "isCollectiveName": false, + "name": "Luciano A Marraffini" + }, + { + "ForeName": "Feng", + "LastName": "Zhang", + "abbrevName": "Zhang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1231143", + "pmid": "23287718", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 339 2013", + "title": "Multiplex genome engineering using CRISPR/Cas systems." + } + }, + { + "pmid": "23217709", + "pubmed": { + "ISODate": "2012-12-07T00:00:00.000Z", + "abstract": "The lysosome is a degradative organelle, and its fusion with other organelles is strictly regulated. In contrast to fusion with the late endosome, the mechanisms underlying autophagosome-lysosome fusion remain unknown. Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. Depletion of Stx17 causes accumulation of autophagosomes without degradation. Stx17 has a unique C-terminal hairpin structure mediated by two tandem transmembrane domains containing glycine zipper-like motifs, which is essential for its association with the autophagosomal membrane. These findings reveal a mechanism by which the SNARE protein is available to the completed autophagosome.", + "authors": { + "abbreviation": "Eisuke Itakura, Chieko Kishi-Itakura, Noboru Mizushima", + "authorList": [ + { + "ForeName": "Eisuke", + "LastName": "Itakura", + "abbrevName": "Itakura E", + "email": null, + "isCollectiveName": false, + "name": "Eisuke Itakura" + }, + { + "ForeName": "Chieko", + "LastName": "Kishi-Itakura", + "abbrevName": "Kishi-Itakura C", + "email": null, + "isCollectiveName": false, + "name": "Chieko Kishi-Itakura" + }, + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": null, + "isCollectiveName": false, + "name": "Noboru Mizushima" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2012.11.001", + "pmid": "23217709", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 151 2012", + "title": "The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes." + } + }, + { + "pmid": "22529100", + "pubmed": { + "ISODate": "2012-04-30T00:00:00.000Z", + "abstract": "Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/C(Cdh1)) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/C(Cdh1)-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid-mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1.", + "authors": { + "abbreviation": "Nai-Jia Huang, Liguo Zhang, Wanli Tang, ..., Sally Kornbluth", + "authorList": [ + { + "ForeName": "Nai-Jia", + "LastName": "Huang", + "abbrevName": "Huang NJ", + "email": null, + "isCollectiveName": false, + "name": "Nai-Jia Huang" + }, + { + "ForeName": "Liguo", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Liguo Zhang" + }, + { + "ForeName": "Wanli", + "LastName": "Tang", + "abbrevName": "Tang W", + "email": null, + "isCollectiveName": false, + "name": "Wanli Tang" + }, + { + "ForeName": "Chen", + "LastName": "Chen", + "abbrevName": "Chen C", + "email": null, + "isCollectiveName": false, + "name": "Chen Chen" + }, + { + "ForeName": "Chih-Sheng", + "LastName": "Yang", + "abbrevName": "Yang CS", + "email": null, + "isCollectiveName": false, + "name": "Chih-Sheng Yang" + }, + { + "ForeName": "Sally", + "LastName": "Kornbluth", + "abbrevName": "Kornbluth S", + "email": null, + "isCollectiveName": false, + "name": "Sally Kornbluth" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201111141", + "pmid": "22529100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 197 2012", + "title": "The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1." + } + }, + { + "pmid": "21801009", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.", + "authors": { + "abbreviation": "Noboru Mizushima, Tamotsu Yoshimori, Yoshinori Ohsumi", + "authorList": [ + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": "nmizu.phy2@tmd.ac.jp", + "isCollectiveName": false, + "name": "Noboru Mizushima" + }, + { + "ForeName": "Tamotsu", + "LastName": "Yoshimori", + "abbrevName": "Yoshimori T", + "email": null, + "isCollectiveName": false, + "name": "Tamotsu Yoshimori" + }, + { + "ForeName": "Yoshinori", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshinori Ohsumi" + } + ], + "contacts": [ + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "email": [ + "nmizu.phy2@tmd.ac.jp" + ], + "name": "Noboru Mizushima" + } + ] + }, + "doi": "10.1146/annurev-cellbio-092910-154005", + "pmid": "21801009", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Annu Rev Cell Dev Biol 27 2011", + "title": "The role of Atg proteins in autophagosome formation." + } + }, + { + "pmid": "21412051", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "BCL-2 homologues lie at the interface between apoptosis and autophagy, regulating these two critical cellular pathways. However, the mechanisms controlling their coordinate regulation and the consequences on cellular survival are not fully understood. We recently showed that MCL-1 is a critical regulator of autophagy in cell lines and neurons. Our findings indicate that activation of apoptosis and autophagy is controlled in a developmentally regulated manner. In addition, the fact that MCL-1 null neurons die in an autophagy-dependent manner suggests that while a basal level of autophagy is required for neuronal survival, its sustained activation may be detrimental. This could have major implications for the treatment of neurodegenerative diseases using strategies involving activation of autophagy to clear protein aggregates from the brain.", + "authors": { + "abbreviation": "Marc Germain, Ruth S Slack", + "authorList": [ + { + "ForeName": "Marc", + "LastName": "Germain", + "abbrevName": "Germain M", + "email": null, + "isCollectiveName": false, + "name": "Marc Germain" + }, + { + "ForeName": "Ruth", + "LastName": "Slack", + "abbrevName": "Slack RS", + "email": null, + "isCollectiveName": false, + "name": "Ruth S Slack" + } + ], + "contacts": [] + }, + "doi": "10.4161/auto.7.5.15098", + "pmid": "21412051", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 7 2011", + "title": "MCL-1 regulates the balance between autophagy and apoptosis." + } + }, + { + "pmid": "21311563", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy.", + "authors": { + "abbreviation": "R Kang, H J Zeh, M T Lotze, D Tang", + "authorList": [ + { + "ForeName": "R", + "LastName": "Kang", + "abbrevName": "Kang R", + "email": null, + "isCollectiveName": false, + "name": "R Kang" + }, + { + "ForeName": "H", + "LastName": "Zeh", + "abbrevName": "Zeh HJ", + "email": null, + "isCollectiveName": false, + "name": "H J Zeh" + }, + { + "ForeName": "M", + "LastName": "Lotze", + "abbrevName": "Lotze MT", + "email": null, + "isCollectiveName": false, + "name": "M T Lotze" + }, + { + "ForeName": "D", + "LastName": "Tang", + "abbrevName": "Tang D", + "email": null, + "isCollectiveName": false, + "name": "D Tang" + } + ], + "contacts": [] + }, + "doi": "10.1038/cdd.2010.191", + "pmid": "21311563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell Death Differ 18 2011", + "title": "The Beclin 1 network regulates autophagy and apoptosis." + } + }, + { + "pmid": "20965422", + "pubmed": { + "ISODate": "2010-10-22T00:00:00.000Z", + "abstract": "Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response.", + "authors": { + "abbreviation": "Guido Kroemer, Guillermo Mariño, Beth Levine", + "authorList": [ + { + "ForeName": "Guido", + "LastName": "Kroemer", + "abbrevName": "Kroemer G", + "email": "kroemer@orange.fr", + "isCollectiveName": false, + "name": "Guido Kroemer" + }, + { + "ForeName": "Guillermo", + "LastName": "Mariño", + "abbrevName": "Mariño G", + "email": null, + "isCollectiveName": false, + "name": "Guillermo Mariño" + }, + { + "ForeName": "Beth", + "LastName": "Levine", + "abbrevName": "Levine B", + "email": null, + "isCollectiveName": false, + "name": "Beth Levine" + } + ], + "contacts": [ + { + "ForeName": "Guido", + "LastName": "Kroemer", + "email": [ + "kroemer@orange.fr" + ], + "name": "Guido Kroemer" + } + ] + }, + "doi": "10.1016/j.molcel.2010.09.023", + "pmid": "20965422", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Mol Cell 40 2010", + "title": "Autophagy and the integrated stress response." + } + }, + { + "pmid": "20811354", + "pubmed": { + "ISODate": "2010-09-01T00:00:00.000Z", + "abstract": "It has been known for many decades that autophagy, a conserved lysosomal degradation pathway, is highly active during differentiation and development. However, until the discovery of the autophagy-related (ATG) genes in the 1990s, the functional significance of this activity was unknown. Initially, genetic knockout studies of ATG genes in lower eukaryotes revealed an essential role for the autophagy pathway in differentiation and development. In recent years, the analyses of systemic and tissue-specific knockout models of ATG genes in mice has led to an explosion of knowledge about the functions of autophagy in mammalian development and differentiation. Here we review the main advances in our understanding of these functions.", + "authors": { + "abbreviation": "Noboru Mizushima, Beth Levine", + "authorList": [ + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": "nmizu.phy2@tmd.ac.jp", + "isCollectiveName": false, + "name": "Noboru Mizushima" + }, + { + "ForeName": "Beth", + "LastName": "Levine", + "abbrevName": "Levine B", + "email": null, + "isCollectiveName": false, + "name": "Beth Levine" + } + ], + "contacts": [ + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "email": [ + "nmizu.phy2@tmd.ac.jp" + ], + "name": "Noboru Mizushima" + } + ] + }, + "doi": "10.1038/ncb0910-823", + "pmid": "20811354", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Cell Biol 12 2010", + "title": "Autophagy in mammalian development and differentiation." + } + }, + { + "pmid": "20436477", + "pubmed": { + "ISODate": "2010-06-01T00:00:00.000Z", + "abstract": "The BH3-only BID protein (BH3-interacting domain death agonist) has a critical function in the death-receptor pathway in the liver by triggering mitochondrial outer membrane permeabilization (MOMP). Here we show that MTCH2/MIMP (mitochondrial carrier homologue 2/Met-induced mitochondrial protein), a novel truncated BID (tBID)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tBID to mitochondria. Knockout of MTCH2/MIMP in embryonic stem cells and in mouse embryonic fibroblasts hinders the recruitment of tBID to mitochondria, the activation of Bax/Bak, MOMP, and apoptosis. Moreover, conditional knockout of MTCH2/MIMP in the liver decreases the sensitivity of mice to Fas-induced hepatocellular apoptosis and prevents the recruitment of tBID to liver mitochondria both in vivo and in vitro. In contrast, MTCH2/MIMP deletion had no effect on apoptosis induced by other pro-apoptotic Bcl-2 family members and no detectable effect on the outer membrane lipid composition. These loss-of-function models indicate that MTCH2/MIMP has a critical function in liver apoptosis by regulating the recruitment of tBID to mitochondria.", + "authors": { + "abbreviation": "Yehudit Zaltsman, Liat Shachnai, Natalie Yivgi-Ohana, ..., Atan Gross", + "authorList": [ + { + "ForeName": "Yehudit", + "LastName": "Zaltsman", + "abbrevName": "Zaltsman Y", + "email": null, + "isCollectiveName": false, + "name": "Yehudit Zaltsman" + }, + { + "ForeName": "Liat", + "LastName": "Shachnai", + "abbrevName": "Shachnai L", + "email": null, + "isCollectiveName": false, + "name": "Liat Shachnai" + }, + { + "ForeName": "Natalie", + "LastName": "Yivgi-Ohana", + "abbrevName": "Yivgi-Ohana N", + "email": null, + "isCollectiveName": false, + "name": "Natalie Yivgi-Ohana" + }, + { + "ForeName": "Michal", + "LastName": "Schwarz", + "abbrevName": "Schwarz M", + "email": null, + "isCollectiveName": false, + "name": "Michal Schwarz" + }, + { + "ForeName": "Maria", + "LastName": "Maryanovich", + "abbrevName": "Maryanovich M", + "email": null, + "isCollectiveName": false, + "name": "Maria Maryanovich" + }, + { + "ForeName": "Riekelt", + "LastName": "Houtkooper", + "abbrevName": "Houtkooper RH", + "email": null, + "isCollectiveName": false, + "name": "Riekelt H Houtkooper" + }, + { + "ForeName": "Frédéric", + "LastName": "Vaz", + "abbrevName": "Vaz FM", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Maxime Vaz" + }, + { + "ForeName": "Francesco", + "LastName": "De Leonardis", + "abbrevName": "De Leonardis F", + "email": null, + "isCollectiveName": false, + "name": "Francesco De Leonardis" + }, + { + "ForeName": "Giuseppe", + "LastName": "Fiermonte", + "abbrevName": "Fiermonte G", + "email": null, + "isCollectiveName": false, + "name": "Giuseppe Fiermonte" + }, + { + "ForeName": "Ferdinando", + "LastName": "Palmieri", + "abbrevName": "Palmieri F", + "email": null, + "isCollectiveName": false, + "name": "Ferdinando Palmieri" + }, + { + "ForeName": "Bernhard", + "LastName": "Gillissen", + "abbrevName": "Gillissen B", + "email": null, + "isCollectiveName": false, + "name": "Bernhard Gillissen" + }, + { + "ForeName": "Peter", + "LastName": "Daniel", + "abbrevName": "Daniel PT", + "email": null, + "isCollectiveName": false, + "name": "Peter T Daniel" + }, + { + "ForeName": "Erin", + "LastName": "Jimenez", + "abbrevName": "Jimenez E", + "email": null, + "isCollectiveName": false, + "name": "Erin Jimenez" + }, + { + "ForeName": "Susan", + "LastName": "Walsh", + "abbrevName": "Walsh S", + "email": null, + "isCollectiveName": false, + "name": "Susan Walsh" + }, + { + "ForeName": "Carla", + "LastName": "Koehler", + "abbrevName": "Koehler CM", + "email": null, + "isCollectiveName": false, + "name": "Carla M Koehler" + }, + { + "ForeName": "Soumya", + "LastName": "Roy", + "abbrevName": "Roy SS", + "email": null, + "isCollectiveName": false, + "name": "Soumya Sinha Roy" + }, + { + "ForeName": "Ludivine", + "LastName": "Walter", + "abbrevName": "Walter L", + "email": null, + "isCollectiveName": false, + "name": "Ludivine Walter" + }, + { + "ForeName": "György", + "LastName": "Hajnóczky", + "abbrevName": "Hajnóczky G", + "email": null, + "isCollectiveName": false, + "name": "György Hajnóczky" + }, + { + "ForeName": "Atan", + "LastName": "Gross", + "abbrevName": "Gross A", + "email": null, + "isCollectiveName": false, + "name": "Atan Gross" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2057", + "pmid": "20436477", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 12 2010", + "title": "MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria." + } + }, + { + "pmid": "20225336", + "pubmed": { + "ISODate": "2010-05-01T00:00:00.000Z", + "abstract": "Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is generally thought of as a survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy can be either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates, although the mechanisms regulating aspects of selective autophagy are not fully worked out. In addition to elimination of intracellular aggregates and damaged organelles, autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents necrosis, giving it a key role in preventing diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections. This review summarizes the most up-to-date findings on how autophagy is executed and regulated at the molecular level and how its disruption can lead to disease.", + "authors": { + "abbreviation": "Danielle Glick, Sandra Barth, Kay F Macleod", + "authorList": [ + { + "ForeName": "Danielle", + "LastName": "Glick", + "abbrevName": "Glick D", + "email": null, + "isCollectiveName": false, + "name": "Danielle Glick" + }, + { + "ForeName": "Sandra", + "LastName": "Barth", + "abbrevName": "Barth S", + "email": null, + "isCollectiveName": false, + "name": "Sandra Barth" + }, + { + "ForeName": "Kay", + "LastName": "Macleod", + "abbrevName": "Macleod KF", + "email": null, + "isCollectiveName": false, + "name": "Kay F Macleod" + } + ], + "contacts": [] + }, + "doi": "10.1002/path.2697", + "pmid": "20225336", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Pathol 221 2010", + "title": "Autophagy: cellular and molecular mechanisms." + } + }, + { + "pmid": "20097051", + "pubmed": { + "ISODate": "2010-04-01T00:00:00.000Z", + "abstract": "The mammalian ortholog of yeast Atg6/Vps30, Beclin 1, is an essential autophagy protein that has been linked to diverse biological processes, including immunity, development, tumor suppression, lifespan extension, and protection against certain cardiac and neurodegenerative diseases. In recent years, major advances have been made in identifying components of functionally distinct Beclin 1/class III phosphatidylinositol 3-kinase complexes, in characterizing the molecular regulation of interactions between Beclin 1 and the autophagy inhibitors, Bcl-2/BcL-X(L), and in uncovering a role for viral antagonists of Beclin 1 in viral pathogenesis. The rapidly growing list of components of the 'Beclin 1 interactome' supports a model in which autophagy, and potentially other membrane trafficking functions of Beclin 1, are governed by differential interactions with different binding partners in different physiological or pathophysiological contexts.", + "authors": { + "abbreviation": "Congcong He, Beth Levine", + "authorList": [ + { + "ForeName": "Congcong", + "LastName": "He", + "abbrevName": "He C", + "email": null, + "isCollectiveName": false, + "name": "Congcong He" + }, + { + "ForeName": "Beth", + "LastName": "Levine", + "abbrevName": "Levine B", + "email": null, + "isCollectiveName": false, + "name": "Beth Levine" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ceb.2010.01.001", + "pmid": "20097051", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Opin Cell Biol 22 2010", + "title": "The Beclin 1 interactome." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "18321988", + "pubmed": { + "ISODate": "2008-05-01T00:00:00.000Z", + "abstract": "Two ubiquitin-like molecules, Atg12 and LC3/Atg8, are involved in autophagosome biogenesis. Atg12 is conjugated to Atg5 and forms an approximately 800-kDa protein complex with Atg16L (referred to as Atg16L complex). LC3/Atg8 is conjugated to phosphatidylethanolamine and is associated with autophagosome formation, perhaps by enabling membrane elongation. Although the Atg16L complex is required for efficient LC3 lipidation, its role is unknown. Here, we show that overexpression of Atg12 or Atg16L inhibits autophagosome formation. Mechanistically, the site of LC3 lipidation is determined by the membrane localization of the Atg16L complex as well as the interaction of Atg12 with Atg3, the E2 enzyme for the LC3 lipidation process. Forced localization of Atg16L to the plasma membrane enabled ectopic LC3 lipidation at that site. We propose that the Atg16L complex is a new type of E3-like enzyme that functions as a scaffold for LC3 lipidation by dynamically localizing to the putative source membranes for autophagosome formation.", + "authors": { + "abbreviation": "Naonobu Fujita, Takashi Itoh, Hiroko Omori, ..., Tamotsu Yoshimori", + "authorList": [ + { + "ForeName": "Naonobu", + "LastName": "Fujita", + "abbrevName": "Fujita N", + "email": null, + "isCollectiveName": false, + "name": "Naonobu Fujita" + }, + { + "ForeName": "Takashi", + "LastName": "Itoh", + "abbrevName": "Itoh T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Itoh" + }, + { + "ForeName": "Hiroko", + "LastName": "Omori", + "abbrevName": "Omori H", + "email": null, + "isCollectiveName": false, + "name": "Hiroko Omori" + }, + { + "ForeName": "Mitsunori", + "LastName": "Fukuda", + "abbrevName": "Fukuda M", + "email": null, + "isCollectiveName": false, + "name": "Mitsunori Fukuda" + }, + { + "ForeName": "Takeshi", + "LastName": "Noda", + "abbrevName": "Noda T", + "email": null, + "isCollectiveName": false, + "name": "Takeshi Noda" + }, + { + "ForeName": "Tamotsu", + "LastName": "Yoshimori", + "abbrevName": "Yoshimori T", + "email": null, + "isCollectiveName": false, + "name": "Tamotsu Yoshimori" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e07-12-1257", + "pmid": "18321988", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biol Cell 19 2008", + "title": "The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy." + } + }, + { + "pmid": "18069693", + "pubmed": { + "ISODate": "2008-01-01T00:00:00.000Z", + "abstract": "Murine light chain 3 (LC3) exists as two isoforms, LC3alpha and beta: LC3beta is an RNA-binding protein that enhances fibronectin (FN) mRNA translation, and is also a marker of autophagy. We report embryonic expression patterns for LC3alpha and LC3beta, with some overlap but notable differences in the brain, and in tissues of non-neuronal origin. LC3beta knockout (-/-) mice develop normally without a compensatory increase in LC3alpha. LC3beta-/- embryonic fibroblasts (MEFs) exhibit reduced FN synthesis but maintain wild type (WT) levels of FN protein. No significant changes in proteins associated with FN turnover, i.e., caveolin-1, LRP-1, or matrix metalloproteinases were identified. Autophagosomes form in amino acid-starved LC3beta-/-MEFs, and Caesarean-delivered pups survive as long as WT pups without an increase in LC3-related proteins linked to autophagy. These results suggest novel compensatory mechanisms for loss of LC3beta, ensuring proper FN accumulation and autophagy during fetal and neonatal life.", + "authors": { + "abbreviation": "Gordon M Cann, Christophe Guignabert, Lihua Ying, ..., Marlene Rabinovitch", + "authorList": [ + { + "ForeName": "Gordon", + "LastName": "Cann", + "abbrevName": "Cann GM", + "email": null, + "isCollectiveName": false, + "name": "Gordon M Cann" + }, + { + "ForeName": "Christophe", + "LastName": "Guignabert", + "abbrevName": "Guignabert C", + "email": null, + "isCollectiveName": false, + "name": "Christophe Guignabert" + }, + { + "ForeName": "Lihua", + "LastName": "Ying", + "abbrevName": "Ying L", + "email": null, + "isCollectiveName": false, + "name": "Lihua Ying" + }, + { + "ForeName": "Niru", + "LastName": "Deshpande", + "abbrevName": "Deshpande N", + "email": null, + "isCollectiveName": false, + "name": "Niru Deshpande" + }, + { + "ForeName": "Janine", + "LastName": "Bekker", + "abbrevName": "Bekker JM", + "email": null, + "isCollectiveName": false, + "name": "Janine M Bekker" + }, + { + "ForeName": "Lingli", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Lingli Wang" + }, + { + "ForeName": "Bin", + "LastName": "Zhou", + "abbrevName": "Zhou B", + "email": null, + "isCollectiveName": false, + "name": "Bin Zhou" + }, + { + "ForeName": "Marlene", + "LastName": "Rabinovitch", + "abbrevName": "Rabinovitch M", + "email": null, + "isCollectiveName": false, + "name": "Marlene Rabinovitch" + } + ], + "contacts": [] + }, + "doi": "10.1002/dvdy.21392", + "pmid": "18069693", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Dyn 237 2008", + "title": "Developmental expression of LC3alpha and beta: absence of fibronectin or autophagy phenotype in LC3beta knockout mice." + } + }, + { + "pmid": "17891140", + "pubmed": { + "ISODate": "2007-10-01T00:00:00.000Z", + "abstract": "Autophagy is an evolutionarily conserved 'self-eating' process. Although the genes essential for autophagy (named Atg) have been identified in yeast, the molecular mechanism of how Atg proteins control autophagosome formation in mammalian cells remains to be elucidated. Here, we demonstrate that Bif-1 (also known as Endophilin B1) interacts with Beclin 1 through ultraviolet irradiation resistance-associated gene (UVRAG) and functions as a positive mediator of the class III PI(3) kinase (PI(3)KC3). In response to nutrient deprivation, Bif-1 localizes to autophagosomes where it colocalizes with Atg5, as well as microtubule-associated protein light chain 3 (LC3). Furthermore, loss of Bif-1 suppresses autophagosome formation. Although the SH3 domain of Bif-1 is sufficient for binding to UVRAG, both the BAR and SH3 domains are required for Bif-1 to activate PI(3)KC3 and induce autophagosome formation. We also observed that Bif-1 ablation prolongs cell survival under starvation conditions. Moreover, knockout of Bif-1 significantly enhances the development of spontaneous tumours in mice. These findings suggest that Bif-1 joins the UVRAG-Beclin 1 complex as a potential activator of autophagy and tumour suppressor.", + "authors": { + "abbreviation": "Yoshinori Takahashi, Domenico Coppola, Norimasa Matsushita, ..., Hong-Gang Wang", + "authorList": [ + { + "ForeName": "Yoshinori", + "LastName": "Takahashi", + "abbrevName": "Takahashi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshinori Takahashi" + }, + { + "ForeName": "Domenico", + "LastName": "Coppola", + "abbrevName": "Coppola D", + "email": null, + "isCollectiveName": false, + "name": "Domenico Coppola" + }, + { + "ForeName": "Norimasa", + "LastName": "Matsushita", + "abbrevName": "Matsushita N", + "email": null, + "isCollectiveName": false, + "name": "Norimasa Matsushita" + }, + { + "ForeName": "Hernani", + "LastName": "Cualing", + "abbrevName": "Cualing HD", + "email": null, + "isCollectiveName": false, + "name": "Hernani D Cualing" + }, + { + "ForeName": "Mei", + "LastName": "Sun", + "abbrevName": "Sun M", + "email": null, + "isCollectiveName": false, + "name": "Mei Sun" + }, + { + "ForeName": "Yuya", + "LastName": "Sato", + "abbrevName": "Sato Y", + "email": null, + "isCollectiveName": false, + "name": "Yuya Sato" + }, + { + "ForeName": "Chengyu", + "LastName": "Liang", + "abbrevName": "Liang C", + "email": null, + "isCollectiveName": false, + "name": "Chengyu Liang" + }, + { + "ForeName": "Jae", + "LastName": "Jung", + "abbrevName": "Jung JU", + "email": null, + "isCollectiveName": false, + "name": "Jae U Jung" + }, + { + "ForeName": "Jin", + "LastName": "Cheng", + "abbrevName": "Cheng JQ", + "email": null, + "isCollectiveName": false, + "name": "Jin Q Cheng" + }, + { + "ForeName": "James", + "LastName": "Mulé", + "abbrevName": "Mulé JJ", + "email": null, + "isCollectiveName": false, + "name": "James J Mulé" + }, + { + "ForeName": "W", + "LastName": "Pledger", + "abbrevName": "Pledger WJ", + "email": null, + "isCollectiveName": false, + "name": "W Jack Pledger" + }, + { + "ForeName": "Hong-Gang", + "LastName": "Wang", + "abbrevName": "Wang HG", + "email": null, + "isCollectiveName": false, + "name": "Hong-Gang Wang" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1634", + "pmid": "17891140", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 9 2007", + "title": "Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis." + } + }, + { + "pmid": "17717517", + "pubmed": { + "ISODate": "2007-09-01T00:00:00.000Z", + "abstract": "The functional relationship between apoptosis ('self-killing') and autophagy ('self-eating') is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner. On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses.", + "authors": { + "abbreviation": "M Chiara Maiuri, Einat Zalckvar, Adi Kimchi, Guido Kroemer", + "authorList": [ + { + "ForeName": "M", + "LastName": "Maiuri", + "abbrevName": "Maiuri MC", + "email": null, + "isCollectiveName": false, + "name": "M Chiara Maiuri" + }, + { + "ForeName": "Einat", + "LastName": "Zalckvar", + "abbrevName": "Zalckvar E", + "email": null, + "isCollectiveName": false, + "name": "Einat Zalckvar" + }, + { + "ForeName": "Adi", + "LastName": "Kimchi", + "abbrevName": "Kimchi A", + "email": null, + "isCollectiveName": false, + "name": "Adi Kimchi" + }, + { + "ForeName": "Guido", + "LastName": "Kroemer", + "abbrevName": "Kroemer G", + "email": null, + "isCollectiveName": false, + "name": "Guido Kroemer" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm2239", + "pmid": "17717517", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 8 2007", + "title": "Self-eating and self-killing: crosstalk between autophagy and apoptosis." + } + }, + { + "pmid": "17535899", + "pubmed": { + "ISODate": "2007-06-12T00:00:00.000Z", + "abstract": "The multidomain proapoptotic protein Bax of the Bcl-2 family is a central regulator for controlling the release of apoptogenic factors from mitochondria. Recent evidence suggests that the Bax-associating protein MOAP-1 may act as an effector for promoting Bax function in mitochondria. Here, we report that MOAP-1 protein is rapidly up-regulated by multiple apoptotic stimuli in mammalian cells. MOAP-1 is a short-lived protein (t(1/2) approximately 25 min) that is constitutively degraded by the ubiquitin-proteasome system. Induction of MOAP-1 by apoptotic stimuli ensues through inhibition of its polyubiquitination process. Elevation of MOAP-1 levels sensitizes cells to apoptotic stimuli and promotes recombinant Bax-mediated cytochrome c release from isolated mitochondria. Mitochondria depleted of short-lived proteins by cycloheximide (CHX) become resistant to Bax-mediated cytochrome c release. Remarkably, incubation of these mitochondria with in vitro-translated MOAP-1 effectively restores the cytochrome c releasing effect of recombinant Bax. We propose that apoptotic stimuli can facilitate the proapoptotic function of Bax in mitochondria through stabilization of MOAP-1.", + "authors": { + "abbreviation": "Nai Yang Fu, Sunil K Sukumaran, Victor C Yu", + "authorList": [ + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0700007104", + "pmid": "17535899", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 104 2007", + "title": "Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria." + } + }, + { + "pmid": "16199525", + "pubmed": { + "ISODate": "2005-10-11T00:00:00.000Z", + "abstract": "Apoptotic stimuli induce conformational changes in Bax and trigger its translocation from cytosol to mitochondria. Upon assembling into the mitochondrial membrane, Bax initiates a death program through a series of events, culminating in the release of apoptogenic factors such as cytochrome c. Although it is known that Bax is one of the key factors for integrating multiple death signals, the mechanism by which Bax functions in mitochondria remains controversial. We have previously identified modulator of apoptosis-1 (MAP-1) as a Bax-associating protein, but its functional relationship with Bax in contributing to apoptosis regulation remains to be established. In this study, we show that MAP-1 is a critical mitochondrial effector of Bax. MAP-1 is a mitochondria-enriched protein that associates with Bax only upon apoptotic induction, which coincides with the release of cytochrome c from mitochondria. Small interfering RNAs that diminish MAP-1 levels in mammalian cell lines confer selective inhibition of Bax-mediated apoptosis. Mammalian cells with stable expression of MAP-1 small interfering RNAs are resistant to multiple apoptotic stimuli in triggering apoptotic death as well as in inducing conformation change and translocation of Bax. Similar to Bax-deficient cells, MAP-1-deficient cells exhibit aggressive anchorage-independent growth. Remarkably, recombinant Bax- or tBid-mediated release of cytochrome c from isolated mitochondria is significantly compromised in the MAP-1 knockdown cells. We propose that MAP-1 is a direct mitochondrial target of Bax.", + "authors": { + "abbreviation": "Kuan Onn Tan, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Kuan", + "LastName": "Tan", + "abbrevName": "Tan KO", + "email": null, + "isCollectiveName": false, + "name": "Kuan Onn Tan" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Shing-Leng", + "LastName": "Chan", + "abbrevName": "Chan SL", + "email": null, + "isCollectiveName": false, + "name": "Shing-Leng Chan" + }, + { + "ForeName": "Jiunn", + "LastName": "Kang", + "abbrevName": "Kang JH", + "email": null, + "isCollectiveName": false, + "name": "Jiunn Hian Kang" + }, + { + "ForeName": "Kar", + "LastName": "Poon", + "abbrevName": "Poon KL", + "email": null, + "isCollectiveName": false, + "name": "Kar Lai Poon" + }, + { + "ForeName": "Bin", + "LastName": "Chen", + "abbrevName": "Chen BS", + "email": null, + "isCollectiveName": false, + "name": "Bin Shun Chen" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0503524102", + "pmid": "16199525", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 102 2005", + "title": "MAP-1 is a mitochondrial effector of Bax." + } + }, + { + "pmid": "16179260", + "pubmed": { + "ISODate": "2005-09-23T00:00:00.000Z", + "abstract": "Apoptosis and autophagy are both tightly regulated biological processes that play a central role in tissue homeostasis, development, and disease. The anti-apoptotic protein, Bcl-2, interacts with the evolutionarily conserved autophagy protein, Beclin 1. However, little is known about the functional significance of this interaction. Here, we show that wild-type Bcl-2 antiapoptotic proteins, but not Beclin 1 binding defective mutants of Bcl-2, inhibit Beclin 1-dependent autophagy in yeast and mammalian cells and that cardiac Bcl-2 transgenic expression inhibits autophagy in mouse heart muscle. Furthermore, Beclin 1 mutants that cannot bind to Bcl-2 induce more autophagy than wild-type Beclin 1 and, unlike wild-type Beclin 1, promote cell death. Thus, Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1. This antiautophagy function of Bcl-2 may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.", + "authors": { + "abbreviation": "Sophie Pattingre, Amina Tassa, Xueping Qu, ..., Beth Levine", + "authorList": [ + { + "ForeName": "Sophie", + "LastName": "Pattingre", + "abbrevName": "Pattingre S", + "email": null, + "isCollectiveName": false, + "name": "Sophie Pattingre" + }, + { + "ForeName": "Amina", + "LastName": "Tassa", + "abbrevName": "Tassa A", + "email": null, + "isCollectiveName": false, + "name": "Amina Tassa" + }, + { + "ForeName": "Xueping", + "LastName": "Qu", + "abbrevName": "Qu X", + "email": null, + "isCollectiveName": false, + "name": "Xueping Qu" + }, + { + "ForeName": "Rita", + "LastName": "Garuti", + "abbrevName": "Garuti R", + "email": null, + "isCollectiveName": false, + "name": "Rita Garuti" + }, + { + "ForeName": "Xiao", + "LastName": "Liang", + "abbrevName": "Liang XH", + "email": null, + "isCollectiveName": false, + "name": "Xiao Huan Liang" + }, + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": null, + "isCollectiveName": false, + "name": "Noboru Mizushima" + }, + { + "ForeName": "Milton", + "LastName": "Packer", + "abbrevName": "Packer M", + "email": null, + "isCollectiveName": false, + "name": "Milton Packer" + }, + { + "ForeName": "Michael", + "LastName": "Schneider", + "abbrevName": "Schneider MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schneider" + }, + { + "ForeName": "Beth", + "LastName": "Levine", + "abbrevName": "Levine B", + "email": null, + "isCollectiveName": false, + "name": "Beth Levine" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2005.07.002", + "pmid": "16179260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Cell 122 2005", + "title": "Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy." + } + }, + { + "pmid": "16027116", + "pubmed": { + "ISODate": "2005-09-09T00:00:00.000Z", + "abstract": "Autophagy is a transport system of cytoplasmic components to the lysosome/vacuole for degradation well conserved in eukaryotes. Autophagy is strongly induced by nutrient starvation. Several specific proteins, including amino acid synthesis enzymes and vacuolar enzymes, are increased during nitrogen starvation in wild-type cells but not in autophagy-defective delta atg7 cells despite similar mRNA levels. We further examined deficiencies in these cells. Bulk protein synthesis was substantially reduced in delta atg7 cells under nitrogen starvation compared with wild-type cells. The total intracellular amino acid pool was reduced in delta atg7 cells, and the levels of several amino acids fell below critical values. In contrast, wild-type cells maintained amino acid levels compatible with life. Autophagy-defective cells fail to maintain physiologic amino acid levels, and their inability to synthesize new proteins may explain most phenotypes associated with autophagy mutants at least partly.", + "authors": { + "abbreviation": "Jun Onodera, Yoshinori Ohsumi", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Onodera", + "abbrevName": "Onodera J", + "email": null, + "isCollectiveName": false, + "name": "Jun Onodera" + }, + { + "ForeName": "Yoshinori", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshinori Ohsumi" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M506736200", + "pmid": "16027116", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation." + } + }, + { + "pmid": "15949439", + "pubmed": { + "ISODate": "2005-06-10T00:00:00.000Z", + "abstract": "Tumor cells typically resist programmed cell death (apoptosis) induced by death receptors. Activated death receptors evoke Bax conformational change, cytochrome c release, and cell death. We report that the tumor suppressor gene RASSF1A is required for death receptor-induced Bax conformational change and apoptosis. TNFalpha or TRAIL stimulation induced recruitment of RASSF1A and MAP-1 to receptor complexes and promoted complex formation between RASSF1A and the BH3-like protein MAP-1. Normally, MAP-1 is inhibited by an intramolecular interaction. RASSF1A/MAP-1 binding relieved this inhibitory interaction, resulting in MAP-1 association with Bax. Deletion of the RASSF1A gene or short hairpin silencing of either RASSF1A or MAP-1 expression blocked MAP-1/Bax interaction, Bax conformational change and mitochondrial membrane insertion, cytochrome c release, and apoptosis in response to death receptors. Our findings identify RASSF1A and MAP-1 as important components between death receptors and the apoptotic machinery and reveal a potential link between tumor suppression and death receptor signaling.", + "authors": { + "abbreviation": "Shairaz Baksh, Stella Tommasi, Sarah Fenton, ..., Benjamin G Neel", + "authorList": [ + { + "ForeName": "Shairaz", + "LastName": "Baksh", + "abbrevName": "Baksh S", + "email": "sbaksh@bidmc.harvard.edu", + "isCollectiveName": false, + "name": "Shairaz Baksh" + }, + { + "ForeName": "Stella", + "LastName": "Tommasi", + "abbrevName": "Tommasi S", + "email": null, + "isCollectiveName": false, + "name": "Stella Tommasi" + }, + { + "ForeName": "Sarah", + "LastName": "Fenton", + "abbrevName": "Fenton S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Fenton" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + }, + { + "ForeName": "L", + "LastName": "Martins", + "abbrevName": "Martins LM", + "email": null, + "isCollectiveName": false, + "name": "L Miguel Martins" + }, + { + "ForeName": "Gerd", + "LastName": "Pfeifer", + "abbrevName": "Pfeifer GP", + "email": null, + "isCollectiveName": false, + "name": "Gerd P Pfeifer" + }, + { + "ForeName": "Farida", + "LastName": "Latif", + "abbrevName": "Latif F", + "email": null, + "isCollectiveName": false, + "name": "Farida Latif" + }, + { + "ForeName": "Julian", + "LastName": "Downward", + "abbrevName": "Downward J", + "email": null, + "isCollectiveName": false, + "name": "Julian Downward" + }, + { + "ForeName": "Benjamin", + "LastName": "Neel", + "abbrevName": "Neel BG", + "email": null, + "isCollectiveName": false, + "name": "Benjamin G Neel" + } + ], + "contacts": [ + { + "ForeName": "Shairaz", + "LastName": "Baksh", + "email": [ + "sbaksh@bidmc.harvard.edu" + ], + "name": "Shairaz Baksh" + } + ] + }, + "doi": "10.1016/j.molcel.2005.05.010", + "pmid": "15949439", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Cell 18 2005", + "title": "The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death." + } + }, + { + "pmid": "15525940", + "pubmed": { + "ISODate": "2004-12-23T00:00:00.000Z", + "abstract": "At birth the trans-placental nutrient supply is suddenly interrupted, and neonates face severe starvation until supply can be restored through milk nutrients. Here, we show that neonates adapt to this adverse circumstance by inducing autophagy. Autophagy is the primary means for the degradation of cytoplasmic constituents within lysosomes. The level of autophagy in mice remains low during embryogenesis; however, autophagy is immediately upregulated in various tissues after birth and is maintained at high levels for 3-12 h before returning to basal levels within 1-2 days. Mice deficient for Atg5, which is essential for autophagosome formation, appear almost normal at birth but die within 1 day of delivery. The survival time of starved Atg5-deficient neonates (approximately 12 h) is much shorter than that of wild-type mice (approximately 21 h) but can be prolonged by forced milk feeding. Atg5-deficient neonates exhibit reduced amino acid concentrations in plasma and tissues, and display signs of energy depletion. These results suggest that the production of amino acids by autophagic degradation of 'self' proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.", + "authors": { + "abbreviation": "Akiko Kuma, Masahiko Hatano, Makoto Matsui, ..., Noboru Mizushima", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Kuma", + "abbrevName": "Kuma A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Kuma" + }, + { + "ForeName": "Masahiko", + "LastName": "Hatano", + "abbrevName": "Hatano M", + "email": null, + "isCollectiveName": false, + "name": "Masahiko Hatano" + }, + { + "ForeName": "Makoto", + "LastName": "Matsui", + "abbrevName": "Matsui M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Matsui" + }, + { + "ForeName": "Akitsugu", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto A", + "email": null, + "isCollectiveName": false, + "name": "Akitsugu Yamamoto" + }, + { + "ForeName": "Haruaki", + "LastName": "Nakaya", + "abbrevName": "Nakaya H", + "email": null, + "isCollectiveName": false, + "name": "Haruaki Nakaya" + }, + { + "ForeName": "Tamotsu", + "LastName": "Yoshimori", + "abbrevName": "Yoshimori T", + "email": null, + "isCollectiveName": false, + "name": "Tamotsu Yoshimori" + }, + { + "ForeName": "Yoshinori", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshinori Ohsumi" + }, + { + "ForeName": "Takeshi", + "LastName": "Tokuhisa", + "abbrevName": "Tokuhisa T", + "email": null, + "isCollectiveName": false, + "name": "Takeshi Tokuhisa" + }, + { + "ForeName": "Noboru", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": null, + "isCollectiveName": false, + "name": "Noboru Mizushima" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature03029", + "pmid": "15525940", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 432 2004", + "title": "The role of autophagy during the early neonatal starvation period." + } + }, + { + "pmid": "15325588", + "pubmed": { + "ISODate": "2004-12-01T00:00:00.000Z", + "abstract": "Autophagy is the bulk degradation of proteins and organelles, a process essential for cellular maintenance, cell viability, differentiation and development in mammals. Autophagy has significant associations with neurodegenerative diseases, cardiomyopathies, cancer, programmed cell death, and bacterial and viral infections. During autophagy, a cup-shaped structure, the preautophagosome, engulfs cytosolic components, including organelles, and closes, forming an autophagosome, which subsequently fuses with a lysosome, leading to the proteolytic degradation of internal components of the autophagosome by lysosomal lytic enzymes. During the formation of mammalian autophagosomes, two ubiquitylation-like modifications are required, Atg12-conjugation and LC3-modification. LC3 is an autophagosomal ortholog of yeast Atg8. A lipidated form of LC3, LC3-II, has been shown to be an autophagosomal marker in mammals, and has been used to study autophagy in neurodegenerative and neuromuscular diseases, tumorigenesis, and bacterial and viral infections. The other Atg8 homologues, GABARAP and GATE-16, are also modified by the same mechanism. In non-starved rats, the tissue distribution of LC3-II differs from those of the lipidated forms of GABARAP and GATE-16, GABARAP-II and GATE-16-II, suggesting that there is a functional divergence among these three modified proteins. Delipidation of LC3-II and GABARAP-II is mediated by hAtg4B. We review the molecular mechanism of LC3-modification, the crosstalk between LC3-modification and mammalian Atg12-conjugation, and the cycle of LC3-lipidation and delipidation mediated by hAtg4B, as well as recent findings concerning the other two Atg8 homologues, GABARAP and GATE-16. We also highlight recent findings regarding the pathobiology of LC3-modification, including its role in microbial infection, cancer and neuromuscular diseases.", + "authors": { + "abbreviation": "Isei Tanida, Takashi Ueno, Eiki Kominami", + "authorList": [ + { + "ForeName": "Isei", + "LastName": "Tanida", + "abbrevName": "Tanida I", + "email": null, + "isCollectiveName": false, + "name": "Isei Tanida" + }, + { + "ForeName": "Takashi", + "LastName": "Ueno", + "abbrevName": "Ueno T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ueno" + }, + { + "ForeName": "Eiki", + "LastName": "Kominami", + "abbrevName": "Kominami E", + "email": null, + "isCollectiveName": false, + "name": "Eiki Kominami" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.biocel.2004.05.009", + "pmid": "15325588", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 36 2004", + "title": "LC3 conjugation system in mammalian autophagy." + } + }, + { + "pmid": "14530254", + "pubmed": { + "ISODate": "2003-12-19T00:00:00.000Z", + "abstract": "Apg8 is a ubiquitin-like protein involved in autophagy in yeast. Apg8 is covalently but transiently attached to membrane lipids through the actions of activating, conjugating, and processing/deconjugating enzymes. The mammalian Apg8 homologues GATE-16, GARARAP, and MAP1-LC3 have been implicated in intra-Golgi transport, receptor sorting, and autophagy, respectively. All are served by a single set of activating and conjugating enzymes. Here we identify a novel mammalian Apg8 homologue, which we name Apg8L, and describe the synthesis of electrophilic probes based on the GATE-16, GARARAP, MAP1-LC3, and Apg8L proteins. These probes not only form specific adducts in crude cell lysates, but also allow identification of the cellular proteases specific for the C termini of these Apg8 homologues. We find a single protease, Apg4B/autophagin-1, capable of acting on GATE-16, GABARAP, MAP1-LC3, and Apg8L. The Apg4B/autophagin-1 protease thus serves as a processing/deconjugating enzyme for these four highly divergent mammalian Apg8 homologues.", + "authors": { + "abbreviation": "Joris Hemelaar, Victor S Lelyveld, Benedikt M Kessler, Hidde L Ploegh", + "authorList": [ + { + "ForeName": "Joris", + "LastName": "Hemelaar", + "abbrevName": "Hemelaar J", + "email": null, + "isCollectiveName": false, + "name": "Joris Hemelaar" + }, + { + "ForeName": "Victor", + "LastName": "Lelyveld", + "abbrevName": "Lelyveld VS", + "email": null, + "isCollectiveName": false, + "name": "Victor S Lelyveld" + }, + { + "ForeName": "Benedikt", + "LastName": "Kessler", + "abbrevName": "Kessler BM", + "email": null, + "isCollectiveName": false, + "name": "Benedikt M Kessler" + }, + { + "ForeName": "Hidde", + "LastName": "Ploegh", + "abbrevName": "Ploegh HL", + "email": null, + "isCollectiveName": false, + "name": "Hidde L Ploegh" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M308762200", + "pmid": "14530254", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 278 2003", + "title": "A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L." + } + }, + { + "pmid": "11326099", + "pubmed": { + "ISODate": "2001-04-27T00:00:00.000Z", + "abstract": "Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a \"BH3-domain-only\" BCL-2 family member, triggers the homooligomerization of \"multidomain\" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a \"multidomain\" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.", + "authors": { + "abbreviation": "M C Wei, W X Zong, E H Cheng, ..., S J Korsmeyer", + "authorList": [ + { + "ForeName": "M", + "LastName": "Wei", + "abbrevName": "Wei MC", + "email": null, + "isCollectiveName": false, + "name": "M C Wei" + }, + { + "ForeName": "W", + "LastName": "Zong", + "abbrevName": "Zong WX", + "email": null, + "isCollectiveName": false, + "name": "W X Zong" + }, + { + "ForeName": "E", + "LastName": "Cheng", + "abbrevName": "Cheng EH", + "email": null, + "isCollectiveName": false, + "name": "E H Cheng" + }, + { + "ForeName": "T", + "LastName": "Lindsten", + "abbrevName": "Lindsten T", + "email": null, + "isCollectiveName": false, + "name": "T Lindsten" + }, + { + "ForeName": "V", + "LastName": "Panoutsakopoulou", + "abbrevName": "Panoutsakopoulou V", + "email": null, + "isCollectiveName": false, + "name": "V Panoutsakopoulou" + }, + { + "ForeName": "A", + "LastName": "Ross", + "abbrevName": "Ross AJ", + "email": null, + "isCollectiveName": false, + "name": "A J Ross" + }, + { + "ForeName": "K", + "LastName": "Roth", + "abbrevName": "Roth KA", + "email": null, + "isCollectiveName": false, + "name": "K A Roth" + }, + { + "ForeName": "G", + "LastName": "MacGregor", + "abbrevName": "MacGregor GR", + "email": null, + "isCollectiveName": false, + "name": "G R MacGregor" + }, + { + "ForeName": "C", + "LastName": "Thompson", + "abbrevName": "Thompson CB", + "email": null, + "isCollectiveName": false, + "name": "C B Thompson" + }, + { + "ForeName": "S", + "LastName": "Korsmeyer", + "abbrevName": "Korsmeyer SJ", + "email": null, + "isCollectiveName": false, + "name": "S J Korsmeyer" + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1059108", + "pmid": "11326099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Science 292 2001", + "title": "Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death." + } + }, + { + "pmid": "11259440", + "pubmed": { + "ISODate": "2001-06-08T00:00:00.000Z", + "abstract": "Bax is a proapoptotic member of the Bcl-2 protein family that commits the cell to undergo programmed cell death in response to apoptotic stimuli. To gain further insights into Bax mechanisms, we have identified a novel Bax-binding protein, termed Bif-1, by using a yeast two-hybrid cloning technique. Bif-1 is an evolutionarily conserved cytoplasmic protein that contains a predicted Src homology 3 (SH3) domain located near its C terminus but shares no significant homology with members of the Bcl-2 family. A Northern blot analysis indicates that Bif-1 is expressed in most tissues with abundant expression in heart and skeletal muscle. Bif-1 is capable of interacting with Bax as demonstrated by yeast two-hybrid, coimmunoprecipitation, and immunofluorescence studies. Induction of apoptosis in murine pre-B hematopoietic cells FL5.12 by interleukin-3 withdrawal results in increased association of Bax with Bif-1, which is accompanied by a conformational change in the Bax protein. Overexpression of Bif-1 promotes Bax conformational change, caspase activation, and apoptotic cell death in FL5.12 cells following interleukin-3 deprivation. Bif-1 thus represents a new type of regulator of Bax-mediated signaling pathways for apoptosis.", + "authors": { + "abbreviation": "S M Cuddeback, H Yamaguchi, K Komatsu, ..., H G Wang", + "authorList": [ + { + "ForeName": "S", + "LastName": "Cuddeback", + "abbrevName": "Cuddeback SM", + "email": null, + "isCollectiveName": false, + "name": "S M Cuddeback" + }, + { + "ForeName": "H", + "LastName": "Yamaguchi", + "abbrevName": "Yamaguchi H", + "email": null, + "isCollectiveName": false, + "name": "H Yamaguchi" + }, + { + "ForeName": "K", + "LastName": "Komatsu", + "abbrevName": "Komatsu K", + "email": null, + "isCollectiveName": false, + "name": "K Komatsu" + }, + { + "ForeName": "T", + "LastName": "Miyashita", + "abbrevName": "Miyashita T", + "email": null, + "isCollectiveName": false, + "name": "T Miyashita" + }, + { + "ForeName": "M", + "LastName": "Yamada", + "abbrevName": "Yamada M", + "email": null, + "isCollectiveName": false, + "name": "M Yamada" + }, + { + "ForeName": "C", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": null, + "isCollectiveName": false, + "name": "C Wu" + }, + { + "ForeName": "S", + "LastName": "Singh", + "abbrevName": "Singh S", + "email": null, + "isCollectiveName": false, + "name": "S Singh" + }, + { + "ForeName": "H", + "LastName": "Wang", + "abbrevName": "Wang HG", + "email": null, + "isCollectiveName": false, + "name": "H G Wang" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M101527200", + "pmid": "11259440", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 276 2001", + "title": "Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax." + } + }, + { + "pmid": "11100732", + "pubmed": { + "ISODate": "2000-11-23T00:00:00.000Z", + "abstract": "Autophagy is a dynamic membrane phenomenon for bulk protein degradation in the lysosome/vacuole. Apg8/Aut7 is an essential factor for autophagy in yeast. We previously found that the carboxy-terminal arginine of nascent Apg8 is removed by Apg4/Aut2 protease, leaving a glycine residue at the C terminus. Apg8 is then converted to a form (Apg8-X) that is tightly bound to the membrane. Here we report a new mode of protein lipidation. Apg8 is covalently conjugated to phosphatidylethanolamine through an amide bond between the C-terminal glycine and the amino group of phosphatidylethanolamine. This lipidation is mediated by a ubiquitination-like system. Apg8 is a ubiquitin-like protein that is activated by an E1 protein, Apg7 (refs 7, 8), and is transferred subsequently to the E2 enzymes Apg3/Aut1 (ref. 9). Apg7 activates two different ubiquitin-like proteins, Apg12 (ref. 10) and Apg8, and assigns them to specific E2 enzymes, Apg10 (ref. 11) and Apg3, respectively. These reactions are necessary for the formation of Apg8-phosphatidylethanolamine. This lipidation has an essential role in membrane dynamics during autophagy.", + "authors": { + "abbreviation": "Y Ichimura, T Kirisako, T Takao, ..., Y Ohsumi", + "authorList": [ + { + "ForeName": "Y", + "LastName": "Ichimura", + "abbrevName": "Ichimura Y", + "email": null, + "isCollectiveName": false, + "name": "Y Ichimura" + }, + { + "ForeName": "T", + "LastName": "Kirisako", + "abbrevName": "Kirisako T", + "email": null, + "isCollectiveName": false, + "name": "T Kirisako" + }, + { + "ForeName": "T", + "LastName": "Takao", + "abbrevName": "Takao T", + "email": null, + "isCollectiveName": false, + "name": "T Takao" + }, + { + "ForeName": "Y", + "LastName": "Satomi", + "abbrevName": "Satomi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Satomi" + }, + { + "ForeName": "Y", + "LastName": "Shimonishi", + "abbrevName": "Shimonishi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Shimonishi" + }, + { + "ForeName": "N", + "LastName": "Ishihara", + "abbrevName": "Ishihara N", + "email": null, + "isCollectiveName": false, + "name": "N Ishihara" + }, + { + "ForeName": "N", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": null, + "isCollectiveName": false, + "name": "N Mizushima" + }, + { + "ForeName": "I", + "LastName": "Tanida", + "abbrevName": "Tanida I", + "email": null, + "isCollectiveName": false, + "name": "I Tanida" + }, + { + "ForeName": "E", + "LastName": "Kominami", + "abbrevName": "Kominami E", + "email": null, + "isCollectiveName": false, + "name": "E Kominami" + }, + { + "ForeName": "M", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi M", + "email": null, + "isCollectiveName": false, + "name": "M Ohsumi" + }, + { + "ForeName": "T", + "LastName": "Noda", + "abbrevName": "Noda T", + "email": null, + "isCollectiveName": false, + "name": "T Noda" + }, + { + "ForeName": "Y", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Ohsumi" + } + ], + "contacts": [] + }, + "doi": "10.1038/35044114", + "pmid": "11100732", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 408 2000", + "title": "A ubiquitin-like system mediates protein lipidation." + } + }, + { + "pmid": "11060313", + "pubmed": { + "ISODate": "2001-01-26T00:00:00.000Z", + "abstract": "A novel Bax-associating protein, named MAP-1 (Modulator of Apoptosis), has been identified in a yeast two-hybrid screen. MAP-1 contains a BH3-like (BH: Bcl-2 homology) motif and mediates caspase-dependent apoptosis in mammalian cells when overexpressed. MAP-1 homodimerizes and associates with the proapoptotic Bax and the prosurvival Bcl-2 and Bcl-X(L) of the Bcl-2 family in vitro and in vivo in mammalian cells. Mutagenesis analyses revealed that the BH3-like domain in MAP-1 is not required for its association with Bcl-X(L) but is required for association with Bax and for mediating apoptosis. Interestingly, in contrast to other Bax-associating proteins such as Bcl-X(L) and Bid, which require the BH3 and BH1 domains of Bax, respectively, for binding, the binding of MAP-1 to Bax appears to require all three BH domains (BH1, BH2, and BH3) of Bax, because point mutation of the critical amino acid in any one of these domains is sufficient to abolish its binding to MAP-1. These data suggest that MAP-1 mediates apoptosis through a mechanism that involves binding to Bax.", + "authors": { + "abbreviation": "K O Tan, K M Tan, S L Chan, ..., V C Yu", + "authorList": [ + { + "ForeName": "K", + "LastName": "Tan", + "abbrevName": "Tan KO", + "email": null, + "isCollectiveName": false, + "name": "K O Tan" + }, + { + "ForeName": "K", + "LastName": "Tan", + "abbrevName": "Tan KM", + "email": null, + "isCollectiveName": false, + "name": "K M Tan" + }, + { + "ForeName": "S", + "LastName": "Chan", + "abbrevName": "Chan SL", + "email": null, + "isCollectiveName": false, + "name": "S L Chan" + }, + { + "ForeName": "K", + "LastName": "Yee", + "abbrevName": "Yee KS", + "email": null, + "isCollectiveName": false, + "name": "K S Yee" + }, + { + "ForeName": "M", + "LastName": "Bevort", + "abbrevName": "Bevort M", + "email": null, + "isCollectiveName": false, + "name": "M Bevort" + }, + { + "ForeName": "K", + "LastName": "Ang", + "abbrevName": "Ang KC", + "email": null, + "isCollectiveName": false, + "name": "K C Ang" + }, + { + "ForeName": "V", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "V C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M008955200", + "pmid": "11060313", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 276 2001", + "title": "MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains." + } + }, + { + "pmid": "11060023", + "pubmed": { + "ISODate": "2000-11-01T00:00:00.000Z", + "abstract": "Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.", + "authors": { + "abbreviation": "Y Kabeya, N Mizushima, T Ueno, ..., T Yoshimori", + "authorList": [ + { + "ForeName": "Y", + "LastName": "Kabeya", + "abbrevName": "Kabeya Y", + "email": null, + "isCollectiveName": false, + "name": "Y Kabeya" + }, + { + "ForeName": "N", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": null, + "isCollectiveName": false, + "name": "N Mizushima" + }, + { + "ForeName": "T", + "LastName": "Ueno", + "abbrevName": "Ueno T", + "email": null, + "isCollectiveName": false, + "name": "T Ueno" + }, + { + "ForeName": "A", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto A", + "email": null, + "isCollectiveName": false, + "name": "A Yamamoto" + }, + { + "ForeName": "T", + "LastName": "Kirisako", + "abbrevName": "Kirisako T", + "email": null, + "isCollectiveName": false, + "name": "T Kirisako" + }, + { + "ForeName": "T", + "LastName": "Noda", + "abbrevName": "Noda T", + "email": null, + "isCollectiveName": false, + "name": "T Noda" + }, + { + "ForeName": "E", + "LastName": "Kominami", + "abbrevName": "Kominami E", + "email": null, + "isCollectiveName": false, + "name": "E Kominami" + }, + { + "ForeName": "Y", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Ohsumi" + }, + { + "ForeName": "T", + "LastName": "Yoshimori", + "abbrevName": "Yoshimori T", + "email": null, + "isCollectiveName": false, + "name": "T Yoshimori" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/19.21.5720", + "pmid": "11060023", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 19 2000", + "title": "LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing." + } + }, + { + "pmid": "10970851", + "pubmed": { + "ISODate": "2000-09-01T00:00:00.000Z", + "abstract": "Phosphatidylinositol 3-kinase (PI3K) regulates several vital cellular processes, including signal transduction and membrane trafficking. In order to study the intracellular localization of the PI3K product, phosphatidylinositol 3-phosphate [PI(3)P], we constructed a probe consisting of two PI(3)P-binding FYVE domains. The probe was found to bind specifically, and with high affinity, to PI(3)P both in vitro and in vivo. When expressed in fibroblasts, a tagged probe localized to endosomes, as detected by fluorescence microscopy. Electron microscopy of untransfected fibroblasts showed that PI(3)P is highly enriched on early endosomes and in the internal vesicles of multivesicular endosomes. While yeast cells deficient in PI3K activity (vps15 and vps34 mutants) were not labelled, PI(3)P was found on intralumenal vesicles of endosomes and vacuoles of wild-type yeast. vps27Delta yeast cells, which have impaired endosome to vacuole trafficking, showed a decreased vacuolar labelling and increased endosome labelling. Thus PI(3)P follows a conserved intralumenal degradation pathway, and its generation, accessibility and turnover are likely to play a crucial role in defining the early endosome and the subsequent steps leading to multivesicular endosome formation.", + "authors": { + "abbreviation": "D J Gillooly, I C Morrow, M Lindsay, ..., H Stenmark", + "authorList": [ + { + "ForeName": "D", + "LastName": "Gillooly", + "abbrevName": "Gillooly DJ", + "email": null, + "isCollectiveName": false, + "name": "D J Gillooly" + }, + { + "ForeName": "I", + "LastName": "Morrow", + "abbrevName": "Morrow IC", + "email": null, + "isCollectiveName": false, + "name": "I C Morrow" + }, + { + "ForeName": "M", + "LastName": "Lindsay", + "abbrevName": "Lindsay M", + "email": null, + "isCollectiveName": false, + "name": "M Lindsay" + }, + { + "ForeName": "R", + "LastName": "Gould", + "abbrevName": "Gould R", + "email": null, + "isCollectiveName": false, + "name": "R Gould" + }, + { + "ForeName": "N", + "LastName": "Bryant", + "abbrevName": "Bryant NJ", + "email": null, + "isCollectiveName": false, + "name": "N J Bryant" + }, + { + "ForeName": "J", + "LastName": "Gaullier", + "abbrevName": "Gaullier JM", + "email": null, + "isCollectiveName": false, + "name": "J M Gaullier" + }, + { + "ForeName": "R", + "LastName": "Parton", + "abbrevName": "Parton RG", + "email": null, + "isCollectiveName": false, + "name": "R G Parton" + }, + { + "ForeName": "H", + "LastName": "Stenmark", + "abbrevName": "Stenmark H", + "email": null, + "isCollectiveName": false, + "name": "H Stenmark" + } + ], + "contacts": [] + }, + "doi": "10.1093/emboj/19.17.4577", + "pmid": "10970851", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 19 2000", + "title": "Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells." + } + }, + { + "pmid": "9759731", + "pubmed": { + "ISODate": "1998-09-24T00:00:00.000Z", + "abstract": "Autophagy is a process for the bulk degradation of proteins, in which cytoplasmic components of the cell are enclosed by double-membrane structures known as autophagosomes for delivery to lysosomes or vacuoles for degradation. This process is crucial for survival during starvation and cell differentiation. No molecules have been identified that are involved in autophagy in higher eukaryotes. We have isolated 14 autophagy-defective (apg) mutants of the yeast Saccharomyces cerevisiae and examined the autophagic process at the molecular level. We show here that a unique covalent-modification system is essential for autophagy to occur. The carboxy-terminal glycine residue of Apg12, a 186-amino-acid protein, is conjugated to a lysine at residue 149 of Apg5, a 294-amino-acid protein. Of the apg mutants, we found that apg7 and apg10 were unable to form an Apg5/Apg12 conjugate. By cloning APG7, we discovered that Apg7 is a ubiquitin-E1-like enzyme. This conjugation can be reconstituted in vitro and depends on ATP. To our knowledge, this is the first report of a protein unrelated to ubiquitin that uses a ubiquitination-like conjugation system. Furthermore, Apg5 and Apg12 have mammalian homologues, suggesting that this new modification system is conserved from yeast to mammalian cells.", + "authors": { + "abbreviation": "N Mizushima, T Noda, T Yoshimori, ..., Y Ohsumi", + "authorList": [ + { + "ForeName": "N", + "LastName": "Mizushima", + "abbrevName": "Mizushima N", + "email": null, + "isCollectiveName": false, + "name": "N Mizushima" + }, + { + "ForeName": "T", + "LastName": "Noda", + "abbrevName": "Noda T", + "email": null, + "isCollectiveName": false, + "name": "T Noda" + }, + { + "ForeName": "T", + "LastName": "Yoshimori", + "abbrevName": "Yoshimori T", + "email": null, + "isCollectiveName": false, + "name": "T Yoshimori" + }, + { + "ForeName": "Y", + "LastName": "Tanaka", + "abbrevName": "Tanaka Y", + "email": null, + "isCollectiveName": false, + "name": "Y Tanaka" + }, + { + "ForeName": "T", + "LastName": "Ishii", + "abbrevName": "Ishii T", + "email": null, + "isCollectiveName": false, + "name": "T Ishii" + }, + { + "ForeName": "M", + "LastName": "George", + "abbrevName": "George MD", + "email": null, + "isCollectiveName": false, + "name": "M D George" + }, + { + "ForeName": "D", + "LastName": "Klionsky", + "abbrevName": "Klionsky DJ", + "email": null, + "isCollectiveName": false, + "name": "D J Klionsky" + }, + { + "ForeName": "M", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi M", + "email": null, + "isCollectiveName": false, + "name": "M Ohsumi" + }, + { + "ForeName": "Y", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Ohsumi" + } + ], + "contacts": [] + }, + "doi": "10.1038/26506", + "pmid": "9759731", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nature 395 1998", + "title": "A protein conjugation system essential for autophagy." + } + }, + { + "pmid": "8224160", + "pubmed": { + "ISODate": "1993-10-25T00:00:00.000Z", + "abstract": "Autophagy in the yeast is similar to that in mammalian cells. A mutant designated as apg1 (autophagy) defective in accumulation of autophagic bodies in the vacuoles was isolated by selection using a light microscope from a mutagenized proteinase-deficient strain. In the apg1 strain, which has normal vacuolar proteinases, nitrogen starvation did not induce protein degradation. The apg1 mutant lost its viability faster than wild-type cells during nitrogen starvation. By using the loss of viability as a first screening test, 75 other apg mutants were selected. These apg mutants including apg1 fell into 15 complementation groups. Genetic analyses of representative apg mutants revealed that they all had single recessive chromosomal mutations. Strains with each apg mutation were defective in protein degradation in the vacuoles induced by nitrogen starvation and homozygous diploids for each apg mutation did not sporulate. These results on the apg mutants suggest that autophagy via autophagic bodies is indispensable for protein degradation in the vacuoles under starvation conditions, and that at least 15 APG genes are involved in autophagy in yeast.", + "authors": { + "abbreviation": "M Tsukada, Y Ohsumi", + "authorList": [ + { + "ForeName": "M", + "LastName": "Tsukada", + "abbrevName": "Tsukada M", + "email": null, + "isCollectiveName": false, + "name": "M Tsukada" + }, + { + "ForeName": "Y", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Ohsumi" + } + ], + "contacts": [] + }, + "doi": "10.1016/0014-5793(93)80398-e", + "pmid": "8224160", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 333 1993", + "title": "Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae." + } + }, + { + "pmid": "1400575", + "pubmed": { + "ISODate": "1992-10-01T00:00:00.000Z", + "abstract": "For determination of the physiological role and mechanism of vacuolar proteolysis in the yeast Saccharomyces cerevisiae, mutant cells lacking proteinase A, B, and carboxypeptidase Y were transferred from a nutrient medium to a synthetic medium devoid of various nutrients and morphological changes of their vacuoles were investigated. After incubation for 1 h in nutrient-deficient media, a few spherical bodies appeared in the vacuoles and moved actively by Brownian movement. These bodies gradually increased in number and after 3 h they filled the vacuoles almost completely. During their accumulation, the volume of the vacuolar compartment also increased. Electron microscopic examination showed that these bodies were surrounded by a unit membrane which appeared thinner than any other intracellular membrane. The contents of the bodies were morphologically indistinguishable from the cytosol; these bodies contained cytoplasmic ribosomes, RER, mitochondria, lipid granules and glycogen granules, and the density of the cytoplasmic ribosomes in the bodies was almost the same as that of ribosomes in the cytosol. The diameter of the bodies ranged from 400 to 900 nm. Vacuoles that had accumulated these bodies were prepared by a modification of the method of Ohsumi and Anraku (Ohsumi, Y., and Y. Anraku. 1981. J. Biol. Chem. 256:2079-2082). The isolated vacuoles contained ribosomes and showed latent activity of the cytosolic enzyme glucose-6-phosphate dehydrogenase. These results suggest that these bodies sequestered the cytosol in the vacuoles. We named these spherical bodies \"autophagic bodies.\" Accumulation of autophagic bodies in the vacuoles was induced not only by nitrogen starvation, but also by depletion of nutrients such as carbon and single amino acids that caused cessation of the cell cycle. Genetic analysis revealed that the accumulation of autophagic bodies in the vacuoles was the result of lack of the PRB1 product proteinase B, and disruption of the PRB1 gene confirmed this result. In the presence of PMSF, wild-type cells accumulated autophagic bodies in the vacuoles under nutrient-deficient conditions in the same manner as did multiple protease-deficient mutants or cells with a disrupted PRB1 gene. As the autophagic bodies disappeared rapidly after removal of PMSF from cultures of normal cells, they must be an intermediate in the normal autophagic process. This is the first report that nutrient-deficient conditions induce extensive autophagic degradation of cytosolic components in the vacuoles of yeast cells.", + "authors": { + "abbreviation": "K Takeshige, M Baba, S Tsuboi, ..., Y Ohsumi", + "authorList": [ + { + "ForeName": "K", + "LastName": "Takeshige", + "abbrevName": "Takeshige K", + "email": null, + "isCollectiveName": false, + "name": "K Takeshige" + }, + { + "ForeName": "M", + "LastName": "Baba", + "abbrevName": "Baba M", + "email": null, + "isCollectiveName": false, + "name": "M Baba" + }, + { + "ForeName": "S", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi S", + "email": null, + "isCollectiveName": false, + "name": "S Tsuboi" + }, + { + "ForeName": "T", + "LastName": "Noda", + "abbrevName": "Noda T", + "email": null, + "isCollectiveName": false, + "name": "T Noda" + }, + { + "ForeName": "Y", + "LastName": "Ohsumi", + "abbrevName": "Ohsumi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Ohsumi" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.119.2.301", + "pmid": "1400575", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 119 1992", + "title": "Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction." + } + } + ], + "relatedPapers": [ + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2021-12-22T01:04:52.893Z", + "_newestOpId": "773e10a2-a09a-429e-bf8c-8167cff37def", + "_ops": [], + "association": "interaction", + "completed": false, + "description": "", + "entries": [ + { + "group": null, + "id": "96076d2b-34a6-46b6-8ff3-6c87ffc8446a" + }, + { + "group": "positive", + "id": "98c82649-da0e-45bc-8388-847980cc46d7" + } + ], + "id": "3b8e906f-d7ea-476b-a15c-4d383a603f22", + "liveId": "3f60f279-67a7-41a9-97d1-bef5ed115d9e", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 26.698637519067432, + "y": 36.550751707684434 + }, + "relatedPapers": [ + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + } + ], + "secret": "read-only", + "type": "interaction" + }, + { + "_creationTimestamp": "2021-12-22T01:02:20.830Z", + "_newestOpId": "52ffdc46-e7f4-4f1a-99d1-57371b83de0e", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "609608" + }, + { + "db": "HGNC", + "id": "HGNC:588" + }, + { + "db": "Ensembl", + "id": "ENSG00000145782" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.00498, + "id": "9140", + "name": "ATG12", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "APG12", + "APG12L", + "FBR93", + "HAPG12", + "ubiquitin-like protein ATG12", + "APG12 autophagy 12-like", + "ATG12 autophagy related 12 homolog", + "Apg12 (autophagy, yeast) homolog", + "autophagy related 12" + ], + "synonyms": [ + "APG12", + "APG12L", + "FBR93", + "HAPG12", + "ubiquitin-like protein ATG12", + "APG12 autophagy 12-like", + "ATG12 autophagy related 12 homolog", + "Apg12 (autophagy, yeast) homolog", + "autophagy related 12" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "7eb9b9f7-03d4-4c8e-a9d1-2eb68249fc36", + "liveId": "f8b251c6-ad5d-401c-9043-196cb417b90c", + "lock": null, + "locked": false, + "name": "ATG12", + "parentId": "76edd724-c6ec-4ba8-af1d-af8d1ad1259f", + "position": { + "x": 348.9230061751735, + "y": 83.97029532196956 + }, + "relatedPapers": [ + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-12-22T01:05:05.690Z", + "_newestOpId": "8eeb4b60-5bd0-452d-b44a-b2d45fb2beb7", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "e3b47c0f-f6e5-440c-be32-1bc5ca0591c2" + }, + { + "group": "positive", + "id": "76edd724-c6ec-4ba8-af1d-af8d1ad1259f" + } + ], + "id": "002147fb-ea3d-4b4c-a486-b968b317259a", + "liveId": "4ce9a8ea-70bd-46b6-a45f-ef040a430bda", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 20.98543949324995, + "y": 36.550751707684434 + }, + "relatedPapers": [ + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2021-12-22T01:03:24.315Z", + "_newestOpId": "493cf9d5-b922-4e06-97e3-01bf8cd58c77", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "604261" + }, + { + "db": "HGNC", + "id": "HGNC:589" + }, + { + "db": "Ensembl", + "id": "ENSG00000057663" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.344946, + "id": "9474", + "name": "ATG5", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "APG5", + "APG5-LIKE", + "APG5L", + "ASP", + "SCAR25", + "hAPG5", + "ATG5 autophagy related 5 homolog", + "autophagy related 5", + "APG5 autophagy 5-like", + "autophagy protein 5" + ], + "synonyms": [ + "APG5", + "APG5-LIKE", + "APG5L", + "ASP", + "SCAR25", + "hAPG5", + "autophagy protein 5", + "APG5 autophagy 5-like", + "ATG5 autophagy related 5 homolog", + "apoptosis-specific protein", + "autophagy related 5" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "93630a56-a9dc-4324-b2bd-a9cc2724d6de", + "liveId": "a5aeb044-8c1f-4224-b4d6-247b302a41d1", + "lock": null, + "locked": false, + "name": "ATG5", + "parentId": "76edd724-c6ec-4ba8-af1d-af8d1ad1259f", + "position": { + "x": 362.06336163455387, + "y": 108.5370468329848 + }, + "relatedPapers": [ + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-12-22T00:56:53.963Z", + "_newestOpId": "3caa0300-9f91-4666-ac9a-15f99153bddd", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "601242" + }, + { + "db": "HGNC", + "id": "HGNC:6838" + }, + { + "db": "Ensembl", + "id": "ENSG00000101460" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 10.907403, + "formulae": null, + "id": "84557", + "inchi": null, + "inchiKey": null, + "mass": null, + "monoisotopicMass": null, + "name": "MAP1LC3A", + "nameDistance": 0.5555555555555556, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 56, + "shortSynonyms": [ + "MAP1LC3A", + "ATG8E", + "LC3", + "LC3A", + "MAP1ALC3", + "MAP1BLC3", + "MAP1A/MAP1B LC3 A", + "autophagy-related ubiquitin-like modifier LC3 A", + "microtubule-associated proteins 1A/1B light chain 3", + "MAP1A/1B light chain 3 A", + "MAP1 light chain 3-like protein 1" + ], + "summary": null, + "synonyms": [ + "ATG8E", + "LC3", + "LC3A", + "MAP1ALC3", + "MAP1BLC3", + "microtubule-associated proteins 1A/1B light chain 3A", + "MAP1 light chain 3-like protein 1", + "MAP1A/1B light chain 3 A", + "MAP1A/MAP1B LC3 A", + "MAP1A/MAP1B light chain 3 A", + "autophagy-related ubiquitin-like modifier LC3 A", + "microtubule-associated proteins 1A/1B light chain 3", + "microtubule associated protein 1 light chain 3 alpha" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "98c82649-da0e-45bc-8388-847980cc46d7", + "liveId": "f88708b4-b327-431c-b0fd-62290ec89076", + "lock": null, + "locked": false, + "name": "LC3", + "parentId": "e3b47c0f-f6e5-440c-be32-1bc5ca0591c2", + "position": { + "x": 223.57119944581493, + "y": 71.16848970121538 + }, + "relatedPapers": [ + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-12-22T01:03:34.679Z", + "_newestOpId": "d11b2f49-6500-4ded-a037-71f1ce8f4cf3", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "610767" + }, + { + "db": "HGNC", + "id": "HGNC:21498" + }, + { + "db": "Ensembl", + "id": "ENSG00000085978" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.863279, + "id": "55054", + "name": "ATG16L1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "APG16L", + "ATG16A", + "ATG16L", + "IBD10", + "WDR30", + "autophagy-related protein 16-1", + "APG16L beta", + "ATG16 autophagy related 16-like 1", + "WD repeat domain 30", + "autophagy related 16 like 1" + ], + "synonyms": [ + "APG16L", + "ATG16A", + "ATG16L", + "IBD10", + "WDR30", + "autophagy-related protein 16-1", + "APG16L beta", + "ATG16 autophagy related 16-like 1", + "WD repeat domain 30", + "autophagy related 16 like 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "4295ec14-fcfa-4245-a88f-01025b6543ae", + "liveId": "38da99f2-8de5-41c8-a6d3-972a0b2c4680", + "lock": null, + "locked": false, + "name": "ATG16L1", + "parentId": "76edd724-c6ec-4ba8-af1d-af8d1ad1259f", + "position": { + "x": 364.34864084488083, + "y": 60.546183416117856 + }, + "relatedPapers": [ + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-12-22T01:03:33.521Z", + "_newestOpId": "2c44e817-a745-4a29-8592-90283dfcfa1e", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "93630a56-a9dc-4324-b2bd-a9cc2724d6de" + }, + { + "id": "7eb9b9f7-03d4-4c8e-a9d1-2eb68249fc36" + }, + { + "id": "4295ec14-fcfa-4245-a88f-01025b6543ae" + } + ], + "id": "76edd724-c6ec-4ba8-af1d-af8d1ad1259f", + "liveId": "5df5a268-2150-4cc5-bf27-a1aa8807fd2b", + "lock": null, + "locked": false, + "name": "ATG12-ATG5-ATG16L1 complex", + "position": { + "x": 359.8858235100272, + "y": 84.54161512455133 + }, + "relatedPapers": [ + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + } + ], + "secret": "read-only", + "type": "complex" + }, + { + "_creationTimestamp": "2021-12-22T00:56:44.244Z", + "_newestOpId": "a4aa9c18-7bce-493d-8adc-a812a927b7cc", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "609485" + }, + { + "db": "HGNC", + "id": "HGNC:16658" + }, + { + "db": "Ensembl", + "id": "ENSG00000165943" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.863279, + "id": "64112", + "name": "MOAP1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "MOAP1", + "MAP-1", + "PNMA4", + "modulator of apoptosis 1", + "MAP1", + "paraneoplastic Ma antigen family member 4", + "paraneoplastic antigen Ma4", + "paraneoplastic antigen like 4" + ], + "synonyms": [ + "MAP-1", + "PNMA4", + "modulator of apoptosis 1", + "MAP1", + "paraneoplastic Ma antigen family member 4", + "paraneoplastic antigen Ma4", + "paraneoplastic antigen like 4" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "96076d2b-34a6-46b6-8ff3-6c87ffc8446a", + "liveId": "84b0211d-c1c3-4650-8a84-a7c4c4c4feb1", + "lock": null, + "locked": false, + "name": "MOAP-1", + "parentId": "e3b47c0f-f6e5-440c-be32-1bc5ca0591c2", + "position": { + "x": 206.0930555297365, + "y": 93.11141216327754 + }, + "relatedPapers": [ + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2021-12-22T01:03:02.297Z", + "_newestOpId": "d1668240-a480-4df6-a9ff-ece6a3f593a1", + "_ops": [], + "association": null, + "completed": false, + "description": "", + "entries": [ + { + "id": "98c82649-da0e-45bc-8388-847980cc46d7" + }, + { + "id": "96076d2b-34a6-46b6-8ff3-6c87ffc8446a" + } + ], + "id": "e3b47c0f-f6e5-440c-be32-1bc5ca0591c2", + "liveId": "168066ab-3770-4a9a-892d-b33a68525cd7", + "lock": null, + "locked": false, + "name": "", + "position": { + "x": 210.33212748777572, + "y": 82.13995093224645 + }, + "relatedPapers": [ + { + "pmid": "32543267", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is a membrane-mediated intracellular degradation pathway, through which bulky cytoplasmic content is digested in lysosomes. How the autophagy initiation and maturation steps are regulated is not clear. In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a deubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansion, and therefore inhibits autophagosome maturation. Together, our study provides evidence that LUBAC and OTULIN cooperatively regulate autophagy initiation and autophagosome maturation by mediating the linear ubiquitination and the stabilization of ATG13.Abbreviations: ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; CUL1-FBXL20: cullin 1-F-box and leucine rich repeat protein 20; CUL3-KLHL20: cullin 3-kelch like family member 20; CUL4-AMBRA1: cullin 4-autophagy and beclin 1 regulator 1; CYLD: CYLD lysine 63 deubiquitinase; DAPI: 4',6-diamidino-2-phenylindole; DUB: deubiquitinating enzyme; EBSS: Earle's Balanced Salt Solution; GFP: green fluorescent protein; GST: glutathione S-transferase; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; LUBAC: linear ubiquitin chain assembly complex; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3B; MIM: MIT-interacting motif; mRFP: monomeric red fluorescent protein; NEDD4: NEDD4 E3 ubiquitin protein ligase; NFKB: NF-kappaB complex; OPTN: optineurin; OTULIN: OTU deubiquitinase with linear linkage specificity; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns: phosphatidylinositol; PtdIns3K: class III phosphatidylinositol 3-kinase complex; PtdIns3P: phosphatidylinositol 3-phosphate; RBCK1/HOIL1: RANBP2-type and C3HC4-type zinc finger containing 1; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RIPK1: receptor interacting serine/threonine kinase 1; RNF216: ring finger protein 216; RNF31/HOIP: ring finger protein 31; RT-PCR: reverse transcriptase polymerase chain reaction; S. Typhimurium: Salmonella enterica serovar Typhimurium; SHARPIN: SHANK associated RH domain interactor; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING: stimulator of interferon response cGAMP interactor 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TNF/TNF-alpha: tumor necrosis factor; TNFAIP3/A20: TNF alpha induced protein 3; TRAF6: TNF receptor associated factor 6; TRIM32: tripartite motif containing 32; UBAN: ubiquitin binding in TNIP/ABIN and IKBKG/NEMO proteins; ULK1/2: unc-51 like autophagy activating kinase 1/2; USP: ubiquitin specific peptidase; UVRAG: UV radiation resistance associated; VCPIP1: valosin containing protein interacting protein 1; WIPI2: WD repeat domain, phosphoinositide interacting protein 2; ZBTB16-CUL3-RBX1: zinc finger and BTB domain containing protein 16-cullin 3-ring-box 1; ZRANB1: zinc finger RANBP2-type containing 1.", + "authors": { + "abbreviation": "Yuanyuan Chu, Yingjin Kang, Cong Yan, ..., Yanfen Liu", + "authorList": [ + { + "ForeName": "Yuanyuan", + "LastName": "Chu", + "abbrevName": "Chu Y", + "email": null, + "isCollectiveName": false, + "name": "Yuanyuan Chu" + }, + { + "ForeName": "Yingjin", + "LastName": "Kang", + "abbrevName": "Kang Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjin Kang" + }, + { + "ForeName": "Cong", + "LastName": "Yan", + "abbrevName": "Yan C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yan" + }, + { + "ForeName": "Cuiwei", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuiwei Yang" + }, + { + "ForeName": "Tao", + "LastName": "Zhang", + "abbrevName": "Zhang T", + "email": null, + "isCollectiveName": false, + "name": "Tao Zhang" + }, + { + "ForeName": "Huanhuan", + "LastName": "Huo", + "abbrevName": "Huo H", + "email": null, + "isCollectiveName": false, + "name": "Huanhuan Huo" + }, + { + "ForeName": "Yanfen", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanfen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1781393", + "pmid": "32543267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13." + } + }, + { + "pmid": "31696776", + "pubmed": { + "ISODate": "2020-10-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy. Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Cefan Zhou, Xuehong Qian, Miao Hu, ..., Jingfeng Tang", + "authorList": [ + { + "ForeName": "Cefan", + "LastName": "Zhou", + "abbrevName": "Zhou C", + "email": null, + "isCollectiveName": false, + "name": "Cefan Zhou" + }, + { + "ForeName": "Xuehong", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xuehong Qian" + }, + { + "ForeName": "Miao", + "LastName": "Hu", + "abbrevName": "Hu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Hu" + }, + { + "ForeName": "Rui", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": null, + "isCollectiveName": false, + "name": "Rui Zhang" + }, + { + "ForeName": "Nanxi", + "LastName": "Liu", + "abbrevName": "Liu N", + "email": null, + "isCollectiveName": false, + "name": "Nanxi Liu" + }, + { + "ForeName": "Yuan", + "LastName": "Huang", + "abbrevName": "Huang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Huang" + }, + { + "ForeName": "Jing", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yang" + }, + { + "ForeName": "Juan", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Juan Zhang" + }, + { + "ForeName": "Hua", + "LastName": "Bai", + "abbrevName": "Bai H", + "email": null, + "isCollectiveName": false, + "name": "Hua Bai" + }, + { + "ForeName": "Yuyan", + "LastName": "Yang", + "abbrevName": "Yang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuyan Yang" + }, + { + "ForeName": "Yefu", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yefu Wang" + }, + { + "ForeName": "Declan", + "LastName": "Ali", + "abbrevName": "Ali D", + "email": null, + "isCollectiveName": false, + "name": "Declan Ali" + }, + { + "ForeName": "Marek", + "LastName": "Michalak", + "abbrevName": "Michalak M", + "email": null, + "isCollectiveName": false, + "name": "Marek Michalak" + }, + { + "ForeName": "Xing-Zhen", + "LastName": "Chen", + "abbrevName": "Chen XZ", + "email": null, + "isCollectiveName": false, + "name": "Xing-Zhen Chen" + }, + { + "ForeName": "Jingfeng", + "LastName": "Tang", + "abbrevName": "Tang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Tang" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1687212", + "pmid": "31696776", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I." + } + }, + { + "pmid": "33499712", + "pubmed": { + "ISODate": "2021-08-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular degradation process that delivers cytosolic materials and/or damaged organelles to lysosomes. De novo synthesis of the autophagosome membrane occurs within a phosphatidylinositol-3-phosphate-rich region of the endoplasmic reticulum, and subsequent expansion is critical for cargo encapsulation. This process is complex, especially in mammals, with many regulatory factors. In this study, by utilizing PRKN (parkin RBR E3 ubiquitin protein ligase)-mediated mitochondria autophagy (mitophagy)-inducing conditions in conjunction with chemical crosslinking and mass spectrometry, we identified human BCAS3 (BCAS3 microtubule associated cell migration factor) and C16orf70 (chromosome 16 open reading frame 70) as novel proteins that associate with the autophagosome formation site during both non-selective and selective autophagy. We demonstrate that BCAS3 and C16orf70 form a complex and that their association with the phagophore assembly site requires both proteins. In silico structural modeling, mutational analyses in cells and in vitro phosphoinositide-binding assays indicate that the WD40 repeat domain in human BCAS3 directly binds phosphatidylinositol-3-phosphate. Furthermore, overexpression of the BCAS3-C16orf70 complex affects the recruitment of several core autophagy proteins to the phagophore assembly site. This study demonstrates regulatory roles for human BCAS3 and C16orf70 in autophagic activity.Abbreviations: AO: antimycin A and oligomycin; Ash: assembly helper; ATG: autophagy-related; BCAS3: BCAS3 microtubule associated cell migration factor; C16orf70: chromosome 16 open reading frame 70; DAPI: 4',6-diamidino-2-phenylindole; DKO: double knockout; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; fluoppi: fluorescent-based technology detecting protein-protein interactions; FIS1: fission, mitochondrial 1; FKBP: FKBP prolyl isomerase family member 1C; FRB: FKBP-rapamycin binding; hAG: humanized azami-green; IP: immunoprecipitation; IRES: internal ribosome entry site; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MS: mass spectrometry; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mtDNA: mitochondrial DNA; OPTN: optineurin; PFA: paraformaldehyde; PE: phosphatidylethanolamine; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PROPPIN: β-propellers that bind polyphosphoinositides; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like autophagy activating kinase 1; WDR45B/WIPI3: WD repeat domain 45B; WDR45/WIPI4: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Waka Kojima, Koji Yamano, Hidetaka Kosako, ..., Noriyuki Matsuda", + "authorList": [ + { + "ForeName": "Waka", + "LastName": "Kojima", + "abbrevName": "Kojima W", + "email": null, + "isCollectiveName": false, + "name": "Waka Kojima" + }, + { + "ForeName": "Koji", + "LastName": "Yamano", + "abbrevName": "Yamano K", + "email": null, + "isCollectiveName": false, + "name": "Koji Yamano" + }, + { + "ForeName": "Hidetaka", + "LastName": "Kosako", + "abbrevName": "Kosako H", + "email": null, + "isCollectiveName": false, + "name": "Hidetaka Kosako" + }, + { + "ForeName": "Kenichiro", + "LastName": "Imai", + "abbrevName": "Imai K", + "email": null, + "isCollectiveName": false, + "name": "Kenichiro Imai" + }, + { + "ForeName": "Reika", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi R", + "email": null, + "isCollectiveName": false, + "name": "Reika Kikuchi" + }, + { + "ForeName": "Keiji", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiji Tanaka" + }, + { + "ForeName": "Noriyuki", + "LastName": "Matsuda", + "abbrevName": "Matsuda N", + "email": null, + "isCollectiveName": false, + "name": "Noriyuki Matsuda" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1874133", + "pmid": "33499712", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy." + } + }, + { + "pmid": "32543276", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a nonselective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts with several co-modulators via its coiled-coil domain (CCD). Our data identified a physical and functional interaction between PKD2 and BECN1, which depends on one out of two CCD domains (CC1), located in the carboxy-terminal tail of PKD2. In addition, depletion of intracellular Ca2+ with BAPTA-AM not only blunted starvation-induced autophagy but also disrupted the PKD2-BECN1 complex. Consistently, PKD2 overexpression triggered autophagy by increasing its interaction with BECN1, while overexpression of PKD2D509V, a Ca2+ channel activity-deficient mutant, did not induce autophagy and manifested diminished interaction with BECN1. Our findings show that the PKD2-BECN1 complex is required for the induction of autophagy, and its formation depends on the presence of the CC1 domain of PKD2 and on intracellular Ca2+ mobilization by PKD2. These results provide new insights regarding the molecular mechanisms by which PKD2 controls autophagy.Abbreviations: ADPKD: autosomal dominant polycystic kidney disease; ATG: autophagy-related; ATG14/ATG14L: autophagy related 14; Baf A1: bafilomycin A1; BCL2/Bcl-2: BCL2 apoptosis regulator; BCL2L1/BCL-XL: BCL2 like 1; BECN1: beclin 1; CCD: coiled-coil domain; EBSS: Earle's balanced salt solution; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GOLGA2/GM130: golgin A2; GST: glutathione s-transferase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 autophagy cargo receptor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKD2/PC2: polycystin 2, transient receptor potential cation channel; RTN4/NOGO: reticulon 4; RUBCN/RUBICON: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; UVRAG: UV radiation resistance associated; WIPI2: WD repeat domain, phosphoinositide interacting 2.", + "authors": { + "abbreviation": "Daniel Peña-Oyarzun, Marcelo Rodriguez-Peña, Francesca Burgos-Bravo, ..., Alfredo Criollo", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Peña-Oyarzun", + "abbrevName": "Peña-Oyarzun D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Peña-Oyarzun" + }, + { + "ForeName": "Marcelo", + "LastName": "Rodriguez-Peña", + "abbrevName": "Rodriguez-Peña M", + "email": null, + "isCollectiveName": false, + "name": "Marcelo Rodriguez-Peña" + }, + { + "ForeName": "Francesca", + "LastName": "Burgos-Bravo", + "abbrevName": "Burgos-Bravo F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Burgos-Bravo" + }, + { + "ForeName": "Angelo", + "LastName": "Vergara", + "abbrevName": "Vergara A", + "email": null, + "isCollectiveName": false, + "name": "Angelo Vergara" + }, + { + "ForeName": "Catalina", + "LastName": "Kretschmar", + "abbrevName": "Kretschmar C", + "email": null, + "isCollectiveName": false, + "name": "Catalina Kretschmar" + }, + { + "ForeName": "Cristian", + "LastName": "Sotomayor-Flores", + "abbrevName": "Sotomayor-Flores C", + "email": null, + "isCollectiveName": false, + "name": "Cristian Sotomayor-Flores" + }, + { + "ForeName": "Cesar", + "LastName": "Ramirez-Sarmiento", + "abbrevName": "Ramirez-Sarmiento CA", + "email": null, + "isCollectiveName": false, + "name": "Cesar A Ramirez-Sarmiento" + }, + { + "ForeName": "Humbert", + "LastName": "De Smedt", + "abbrevName": "De Smedt H", + "email": null, + "isCollectiveName": false, + "name": "Humbert De Smedt" + }, + { + "ForeName": "Montserrat", + "LastName": "Reyes", + "abbrevName": "Reyes M", + "email": null, + "isCollectiveName": false, + "name": "Montserrat Reyes" + }, + { + "ForeName": "William", + "LastName": "Perez", + "abbrevName": "Perez W", + "email": null, + "isCollectiveName": false, + "name": "William Perez" + }, + { + "ForeName": "Vicente", + "LastName": "Torres", + "abbrevName": "Torres VA", + "email": null, + "isCollectiveName": false, + "name": "Vicente A Torres" + }, + { + "ForeName": "Eugenia", + "LastName": "Morselli", + "abbrevName": "Morselli E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Morselli" + }, + { + "ForeName": "Francisco", + "LastName": "Altamirano", + "abbrevName": "Altamirano F", + "email": null, + "isCollectiveName": false, + "name": "Francisco Altamirano" + }, + { + "ForeName": "Christian", + "LastName": "Wilson", + "abbrevName": "Wilson CAM", + "email": null, + "isCollectiveName": false, + "name": "Christian A M Wilson" + }, + { + "ForeName": "Joseph", + "LastName": "Hill", + "abbrevName": "Hill JA", + "email": null, + "isCollectiveName": false, + "name": "Joseph A Hill" + }, + { + "ForeName": "Sergio", + "LastName": "Lavandero", + "abbrevName": "Lavandero S", + "email": null, + "isCollectiveName": false, + "name": "Sergio Lavandero" + }, + { + "ForeName": "Alfredo", + "LastName": "Criollo", + "abbrevName": "Criollo A", + "email": null, + "isCollectiveName": false, + "name": "Alfredo Criollo" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2020.1782035", + "pmid": "32543276", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "PKD2/polycystin-2 induces autophagy by forming a complex with BECN1." + } + }, + { + "pmid": "30767700", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation. Abbreviations: ATG: autophagy-related; BafA1: bafilomycin A1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GFP: enhanced green fluorescent protein; KO: knockout; LDS: LIR docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62: sequestosome 1; VPS: Vacuolar protein sorting; ULK: unc-51 like autophagy activating kinase.", + "authors": { + "abbreviation": "Åsa Birna Birgisdottir, Stephane Mouilleron, Zambarlal Bhujabal, ..., Terje Johansen", + "authorList": [ + { + "ForeName": "Åsa", + "LastName": "Birgisdottir", + "abbrevName": "Birgisdottir ÅB", + "email": null, + "isCollectiveName": false, + "name": "Åsa Birna Birgisdottir" + }, + { + "ForeName": "Stephane", + "LastName": "Mouilleron", + "abbrevName": "Mouilleron S", + "email": null, + "isCollectiveName": false, + "name": "Stephane Mouilleron" + }, + { + "ForeName": "Zambarlal", + "LastName": "Bhujabal", + "abbrevName": "Bhujabal Z", + "email": null, + "isCollectiveName": false, + "name": "Zambarlal Bhujabal" + }, + { + "ForeName": "Martina", + "LastName": "Wirth", + "abbrevName": "Wirth M", + "email": null, + "isCollectiveName": false, + "name": "Martina Wirth" + }, + { + "ForeName": "Eva", + "LastName": "Sjøttem", + "abbrevName": "Sjøttem E", + "email": null, + "isCollectiveName": false, + "name": "Eva Sjøttem" + }, + { + "ForeName": "Gry", + "LastName": "Evjen", + "abbrevName": "Evjen G", + "email": null, + "isCollectiveName": false, + "name": "Gry Evjen" + }, + { + "ForeName": "Wenxin", + "LastName": "Zhang", + "abbrevName": "Zhang W", + "email": null, + "isCollectiveName": false, + "name": "Wenxin Zhang" + }, + { + "ForeName": "Rebecca", + "LastName": "Lee", + "abbrevName": "Lee R", + "email": null, + "isCollectiveName": false, + "name": "Rebecca Lee" + }, + { + "ForeName": "Nicola", + "LastName": "O'Reilly", + "abbrevName": "O'Reilly N", + "email": null, + "isCollectiveName": false, + "name": "Nicola O'Reilly" + }, + { + "ForeName": "Sharon", + "LastName": "Tooze", + "abbrevName": "Tooze SA", + "email": null, + "isCollectiveName": false, + "name": "Sharon A Tooze" + }, + { + "ForeName": "Trond", + "LastName": "Lamark", + "abbrevName": "Lamark T", + "email": null, + "isCollectiveName": false, + "name": "Trond Lamark" + }, + { + "ForeName": "Terje", + "LastName": "Johansen", + "abbrevName": "Johansen T", + "email": null, + "isCollectiveName": false, + "name": "Terje Johansen" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1581009", + "pmid": "30767700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs." + } + }, + { + "pmid": "31818185", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "CASP9 (caspase 9) is a well-known initiator caspase which triggers intrinsic apoptosis. Recent studies also suggest various non-apoptotic roles of CASP9, including macroautophagy/autophagy regulation. However, the involvement of CASP9 in autophagy and its molecular mechanisms are not well understood. Here we report the non-apoptotic function of CASP9 in positive regulation of autophagy through maintenance of mitochondrial homeostasis. Growth factor or amino acid deprivation-induced autophagy activated CASP9, but without apoptotic features. Pharmacological inhibition or genetic ablation of CASP9 decreased autophagy flux, while ectopic expression of CASP9 rescued autophagy defects. In CASP9 knockout (KO) cells, initiation and elongation of phagophore membranes were normal, but sealing of the membranes and autophagosome maturation were impaired, and the lifetime of autophagosomes was prolonged. Ablation of CASP9 caused an accumulation of inactive ATG3 and decreased lipidation of the Atg8-family members, most severely that of GABARAPL1. Moreover, it resulted in abnormal mitochondrial morphology with depolarization of the membrane potential, reduced reactive oxygen species production, and aberrant accumulation of mitochondrial fusion-fission proteins. CASP9 expression or exogenously added H2O2 in the CASP9 KO cells corrected the ATG3 level and lipidation status of Atg8-family members, and restored autophagy flux. Of note, only CASP9 expression but not H2O2 rescued mitochondrial defects, revealing regulation of mitochondrial homeostasis by CASP9. Our findings suggest a new regulatory link between mitochondria and autophagy through CASP9 activity, especially for the proper operation of the Atg8-family conjugation system and autophagosome closure and maturation. ABBREVIATIONS: AA: amino acid; ACD: autophagic cell death; ACTB: actin beta; ANXA5: annexin A5; APAF1: apoptotic peptidase activating factor 1; Atg: autophagy related; ATG16L1: autophagy related 16 like 1; BafA1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CARD: caspase recruitment domain containing; CASP: caspase; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; Δψm: mitochondrial membrane potential; DN: dominant-negative; DNM1L/DRP1: dynamin 1 like; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; HCN: hippocampal neural stem cells; IAM: inner autophagosome membrane; INS: insulin; KO: knockout; LEHD: Z-LEHD-fmk; MAP1LC3: microtubule associated protein 1 light chain 3; MFN1: mitofusin 1; MFN2: mitofusin 2; MTORC1: mechanistic target of rapamycin kinase complex 1; PARP1: poly(ADP-ribose) polymerase 1; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; ROS: reactive oxygen species; sgRNA: single guide RNA; SR-SIM: super-resolution structured illumination microscopy; SQSTM1: sequestosome 1; STS: staurosporine; STX17: syntaxin 17; TMRE: tetramethylrhodamine ethyl ester; TUBB: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Hyun-Kyu An, Kyung Min Chung, Hyunhee Park, ..., Seong-Woon Yu", + "authorList": [ + { + "ForeName": "Hyun-Kyu", + "LastName": "An", + "abbrevName": "An HK", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Kyu An" + }, + { + "ForeName": "Kyung", + "LastName": "Chung", + "abbrevName": "Chung KM", + "email": null, + "isCollectiveName": false, + "name": "Kyung Min Chung" + }, + { + "ForeName": "Hyunhee", + "LastName": "Park", + "abbrevName": "Park H", + "email": null, + "isCollectiveName": false, + "name": "Hyunhee Park" + }, + { + "ForeName": "Jihyun", + "LastName": "Hong", + "abbrevName": "Hong J", + "email": null, + "isCollectiveName": false, + "name": "Jihyun Hong" + }, + { + "ForeName": "Ji-Eun", + "LastName": "Gim", + "abbrevName": "Gim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Gim" + }, + { + "ForeName": "Hyosun", + "LastName": "Choi", + "abbrevName": "Choi H", + "email": null, + "isCollectiveName": false, + "name": "Hyosun Choi" + }, + { + "ForeName": "Ye", + "LastName": "Lee", + "abbrevName": "Lee YW", + "email": null, + "isCollectiveName": false, + "name": "Ye Won Lee" + }, + { + "ForeName": "Jieun", + "LastName": "Choi", + "abbrevName": "Choi J", + "email": null, + "isCollectiveName": false, + "name": "Jieun Choi" + }, + { + "ForeName": "Ji", + "LastName": "Mun", + "abbrevName": "Mun JY", + "email": null, + "isCollectiveName": false, + "name": "Ji Young Mun" + }, + { + "ForeName": "Seong-Woon", + "LastName": "Yu", + "abbrevName": "Yu SW", + "email": null, + "isCollectiveName": false, + "name": "Seong-Woon Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1695398", + "pmid": "31818185", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis." + } + }, + { + "pmid": "30767704", + "pubmed": { + "ISODate": "2019-08-01T00:00:00.000Z", + "abstract": "TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5, or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations: 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2W35,I38A, TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2W35,I38A[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.", + "authors": { + "abbreviation": "Zhiyuan You, Yinfeng Xu, Wei Wan, ..., Wei Liu", + "authorList": [ + { + "ForeName": "Zhiyuan", + "LastName": "You", + "abbrevName": "You Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyuan You" + }, + { + "ForeName": "Yinfeng", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yinfeng Xu" + }, + { + "ForeName": "Wei", + "LastName": "Wan", + "abbrevName": "Wan W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wan" + }, + { + "ForeName": "Li", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Li Zhou" + }, + { + "ForeName": "Jin", + "LastName": "Li", + "abbrevName": "Li J", + "email": null, + "isCollectiveName": false, + "name": "Jin Li" + }, + { + "ForeName": "Tianhua", + "LastName": "Zhou", + "abbrevName": "Zhou T", + "email": null, + "isCollectiveName": false, + "name": "Tianhua Zhou" + }, + { + "ForeName": "Yin", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yin Shi" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1580510", + "pmid": "30767704", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 15 2019", + "title": "TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction." + } + }, + { + "pmid": "31517566", + "pubmed": { + "ISODate": "2020-06-01T00:00:00.000Z", + "abstract": "Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. ABBREVIATIONS: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; ChoPL: choline phospholipid; CHKA: choline kinase alpha; CHPT1: choline phosphotransferase 1; CTCF: corrected total cell fluorescence; CTP: cytidine-5'-triphosphate; DCA: dichloroacetate; DMEM: dulbeccos modified Eagles medium; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; ER: endoplasmic reticulum; GDPD5: glycerophosphodiester phosphodiesterase domain containing 5; GFP: green fluorescent protein; GPC: glycerophosphorylcholine; HBSS: hanks balances salt solution; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; LysoPtdCho: lysophosphatidylcholine; MRS: magnetic resonance spectroscopy; MTORC1: mechanistic target of rapamycin kinase complex 1; PCho: phosphocholine; PCYT: choline phosphate cytidylyltransferase; PLA2: phospholipase A2; PLB: phospholipase B; PLC: phospholipase C; PLD: phospholipase D; PCYT1A: phosphate cytidylyltransferase 1, choline, alpha; PI3K: phosphoinositide-3-kinase; pMAFs: pancreatic mouse adult fibroblasts; PNPLA6: patatin like phospholipase domain containing 6; Pro-Cho: propargylcholine; Pro-ChoPLs: propargylcholine phospholipids; PtdCho: phosphatidylcholine; PtdEth: phosphatidylethanolamine; PtdIns3P: phosphatidylinositol-3-phosphate; RPS6: ribosomal protein S6; SCD: stearoyl-CoA desaturase; SEM: standard error of the mean; SM: sphingomyelin; SMPD1/SMase: sphingomyelin phosphodiesterase 1, acid lysosomal; SGMS: sphingomyelin synthase; WT: wild-type.", + "authors": { + "abbreviation": "Gabriela Andrejeva, Sharon Gowan, Gigin Lin, ..., Yuen-Li Chung", + "authorList": [ + { + "ForeName": "Gabriela", + "LastName": "Andrejeva", + "abbrevName": "Andrejeva G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Andrejeva" + }, + { + "ForeName": "Sharon", + "LastName": "Gowan", + "abbrevName": "Gowan S", + "email": null, + "isCollectiveName": false, + "name": "Sharon Gowan" + }, + { + "ForeName": "Gigin", + "LastName": "Lin", + "abbrevName": "Lin G", + "email": null, + "isCollectiveName": false, + "name": "Gigin Lin" + }, + { + "ForeName": "Anne-Christine", + "LastName": "Wong Te Fong", + "abbrevName": "Wong Te Fong AL", + "email": null, + "isCollectiveName": false, + "name": "Anne-Christine Lf Wong Te Fong" + }, + { + "ForeName": "Elham", + "LastName": "Shamsaei", + "abbrevName": "Shamsaei E", + "email": null, + "isCollectiveName": false, + "name": "Elham Shamsaei" + }, + { + "ForeName": "Harry", + "LastName": "Parkes", + "abbrevName": "Parkes HG", + "email": null, + "isCollectiveName": false, + "name": "Harry G Parkes" + }, + { + "ForeName": "James", + "LastName": "Mui", + "abbrevName": "Mui J", + "email": null, + "isCollectiveName": false, + "name": "James Mui" + }, + { + "ForeName": "Florence", + "LastName": "Raynaud", + "abbrevName": "Raynaud FI", + "email": null, + "isCollectiveName": false, + "name": "Florence I Raynaud" + }, + { + "ForeName": "Yasmin", + "LastName": "Asad", + "abbrevName": "Asad Y", + "email": null, + "isCollectiveName": false, + "name": "Yasmin Asad" + }, + { + "ForeName": "Gema", + "LastName": "Vizcay-Barrena", + "abbrevName": "Vizcay-Barrena G", + "email": null, + "isCollectiveName": false, + "name": "Gema Vizcay-Barrena" + }, + { + "ForeName": "Joanna", + "LastName": "Nikitorowicz-Buniak", + "abbrevName": "Nikitorowicz-Buniak J", + "email": null, + "isCollectiveName": false, + "name": "Joanna Nikitorowicz-Buniak" + }, + { + "ForeName": "Melanie", + "LastName": "Valenti", + "abbrevName": "Valenti M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Valenti" + }, + { + "ForeName": "Louise", + "LastName": "Howell", + "abbrevName": "Howell L", + "email": null, + "isCollectiveName": false, + "name": "Louise Howell" + }, + { + "ForeName": "Roland", + "LastName": "Fleck", + "abbrevName": "Fleck RA", + "email": null, + "isCollectiveName": false, + "name": "Roland A Fleck" + }, + { + "ForeName": "Lesley-Ann", + "LastName": "Martin", + "abbrevName": "Martin LA", + "email": null, + "isCollectiveName": false, + "name": "Lesley-Ann Martin" + }, + { + "ForeName": "Vladimir", + "LastName": "Kirkin", + "abbrevName": "Kirkin V", + "email": null, + "isCollectiveName": false, + "name": "Vladimir Kirkin" + }, + { + "ForeName": "Martin", + "LastName": "Leach", + "abbrevName": "Leach MO", + "email": null, + "isCollectiveName": false, + "name": "Martin O Leach" + }, + { + "ForeName": "Yuen-Li", + "LastName": "Chung", + "abbrevName": "Chung YL", + "email": null, + "isCollectiveName": false, + "name": "Yuen-Li Chung" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2019.1659608", + "pmid": "31517566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 16 2020", + "title": "De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy." + } + }, + { + "pmid": "33783314", + "pubmed": { + "ISODate": "2021-11-01T00:00:00.000Z", + "abstract": "MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12-ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation.Abbreviations: CQ: Chloroquine; EBSS: Earle's Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.", + "authors": { + "abbreviation": "Hao-Chun Chang, Ran N Tao, Chong Teik Tan, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "Hao-Chun", + "LastName": "Chang", + "abbrevName": "Chang HC", + "email": null, + "isCollectiveName": false, + "name": "Hao-Chun Chang" + }, + { + "ForeName": "Ran", + "LastName": "Tao", + "abbrevName": "Tao RN", + "email": null, + "isCollectiveName": false, + "name": "Ran N Tao" + }, + { + "ForeName": "Chong", + "LastName": "Tan", + "abbrevName": "Tan CT", + "email": null, + "isCollectiveName": false, + "name": "Chong Teik Tan" + }, + { + "ForeName": "Ya", + "LastName": "Wu", + "abbrevName": "Wu YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jun Wu" + }, + { + "ForeName": "Boon", + "LastName": "Bay", + "abbrevName": "Bay BH", + "email": null, + "isCollectiveName": false, + "name": "Boon Huat Bay" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1080/15548627.2021.1896157", + "pmid": "33783314", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Autophagy 17 2021", + "title": "The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore." + } + }, + { + "pmid": "19100260", + "pubmed": { + "ISODate": "2009-04-15T00:00:00.000Z", + "abstract": "Bax, a multi-domain pro-apoptotic Bcl-2 family member, is a key regulator for the release of apoptogenic factors from mitochondria. MOAP-1, which was first isolated from a screen for Bax-associating proteins, interacts with Bax upon apoptotic induction. MOAP-1 is a short-lived protein that is constitutively degraded by the ubiquitin-proteasome system. Apoptotic stimuli upregulate MOAP-1 rapidly through inhibition of its poly-ubiquitination process. However, cellular factors that regulate the stability of MOAP-1 have not yet been identified. In this study, we report the identification of TRIM39 as a MOAP-1-binding protein. TRIM39 belongs to a family of proteins characterized by a Tripartite Motif (TRIM), consisting of RING domain, B-box and coiled-coil domain. Several TRIM family members are known to demonstrate E3 ubiquitin ligase activity. Surprisingly, TRIM39 significantly extends the half-life of MOAP-1 by inhibiting its poly-ubiquitination process. In agreement with its effect on enhancing MOAP-1 stability, TRIM39 sensitizes cells to etoposide-induced apoptosis. Conversely, knockdown of TRIM39 reduces the sensitivity of cells to etoposide-stimulated apoptosis. Furthermore, TRIM39 elevates the level of MOAP-1 in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Together, these data suggest that TRIM39 can promote apoptosis signalling through stabilization of MOAP-1.", + "authors": { + "abbreviation": "San San Lee, Nai Yang Fu, Sunil K Sukumaran, ..., Victor C Yu", + "authorList": [ + { + "ForeName": "San", + "LastName": "Lee", + "abbrevName": "Lee SS", + "email": null, + "isCollectiveName": false, + "name": "San San Lee" + }, + { + "ForeName": "Nai", + "LastName": "Fu", + "abbrevName": "Fu NY", + "email": null, + "isCollectiveName": false, + "name": "Nai Yang Fu" + }, + { + "ForeName": "Sunil", + "LastName": "Sukumaran", + "abbrevName": "Sukumaran SK", + "email": null, + "isCollectiveName": false, + "name": "Sunil K Sukumaran" + }, + { + "ForeName": "Kah", + "LastName": "Wan", + "abbrevName": "Wan KF", + "email": null, + "isCollectiveName": false, + "name": "Kah Fei Wan" + }, + { + "ForeName": "Qian", + "LastName": "Wan", + "abbrevName": "Wan Q", + "email": null, + "isCollectiveName": false, + "name": "Qian Wan" + }, + { + "ForeName": "Victor", + "LastName": "Yu", + "abbrevName": "Yu VC", + "email": null, + "isCollectiveName": false, + "name": "Victor C Yu" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.11.021", + "pmid": "19100260", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 315 2009", + "title": "TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process." + } + } + ], + "secret": "read-only", + "type": "complex" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/doct_tests_1.json b/neo4j-test/document/doct_tests_1.json new file mode 100644 index 000000000..9d32863d1 --- /dev/null +++ b/neo4j-test/document/doct_tests_1.json @@ -0,0 +1,15119 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-02-13T11:20:08.504Z", + "_newestOpId": "788f515c-7082-48df-9607-8b2f4e54fd1b", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Kindler syndrome is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding t kindlin-1. Kindlin-1 localizes to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of Kindler syndrome show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective integrin activation, cell adhesion, and migration. However, roles for kindlin-1 beyond integrin activation remain poorly defined. In this study we show that skin and keratinocytes from Kindler syndrome patients have significantly reduced expression levels of the EGFR, resulting in defective EGF-dependent signaling and cell migration. Mechanistically, we show that kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner and that formation of this complex is required for EGF-dependent migration. We further show that kindlin-1 acts to protect EGFR from lysosomal-mediated degradation. This shows a new role for kindlin-1 that has implications for understanding Kindler syndrome disease pathology.", + "ArticleTitle": "Kindlin-1 Regulates Epidermal Growth Factor Receptor Signaling.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Magdalene", + "Identifier": [], + "Initials": "M", + "LastName": "Michael" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK; St. Johns Institute of Dermatology, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rumena", + "Identifier": [], + "Initials": "R", + "LastName": "Begum" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Grace K", + "Identifier": [], + "Initials": "GK", + "LastName": "Chan" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, Kent, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Austin J", + "Identifier": [], + "Initials": "AJ", + "LastName": "Whitewood" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Nikon Imaging Centre, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Daniel R", + "Identifier": [], + "Initials": "DR", + "LastName": "Matthews" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, Kent, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Benjamin T", + "Identifier": [], + "Initials": "BT", + "LastName": "Goult" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "John A", + "Identifier": [], + "Initials": "JA", + "LastName": "McGrath" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "St. Johns Institute of Dermatology, King's College London, Guy's Campus, London, UK; Nikon Imaging Centre, King's College London, Guy's Campus, London, UK. Electronic address: maddy.parsons@kcl.ac.uk.", + "email": [ + "maddy.parsons@kcl.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Maddy", + "Identifier": [], + "Initials": "M", + "LastName": "Parsons" + } + ], + "Journal": { + "ISOAbbreviation": "J Invest Dermatol", + "ISSN": { + "IssnType": "Electronic", + "value": "1523-1747" + }, + "JournalIssue": { + "Issue": "2", + "PubDate": { + "Day": null, + "Month": "Feb", + "Year": "2019" + }, + "Volume": "139" + }, + "Title": "The Journal of investigative dermatology" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "D066255", + "value": "EGF Family of Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "C475301", + "value": "FERMT1 protein, human" + }, + 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One of these is its capability to determine equilibrium constants in solution including complex biological matrices such as cell lysates. MST requires one binding partner to be fluorescent, which is typically achieved by labeling target proteins with a suitable fluorophore. Here, we present a near-native, site-specific in situ labeling strategy for MST experiments that enables reliable measurements in cell lysates and that has distinct advantages over routine covalent labeling techniques. To this end, we exploited the high-affinity interaction of tris-NTA with oligohistidine-tags, which are popular for purification, immobilization or detection of recombinant proteins. We used various DYE-tris-NTA conjugates to successfully label His-tagged proteins that were either purified or a component of cell lysate. The RED-tris-NTA was identified as the optimal dye conjugate with a high affinity towards oligohistidine-tags, a high fluorescence signal and an optimal signal-to-noise ratio in MST binding experiments. Owing to its emission in the red region of the spectrum, it also enables reliable measurements in complex biological matrices such as cell lysates allowing a more physiologically realistic assessment and eliminating the need for protein purification.", + "authors": { + "abbreviation": "Tanja Bartoschik, Stefanie Galinec, Christian Kleusch, ..., Nuska Tschammer", + "authorList": [ + { + "ForeName": "Tanja", + "LastName": "Bartoschik", + "abbrevName": "Bartoschik T", + "email": null, + "isCollectiveName": false, + "name": "Tanja Bartoschik" + }, + { + "ForeName": "Stefanie", + "LastName": "Galinec", + "abbrevName": "Galinec S", + "email": null, + "isCollectiveName": false, + "name": "Stefanie Galinec" + }, + { + "ForeName": "Christian", + "LastName": "Kleusch", + "abbrevName": "Kleusch C", + "email": null, + "isCollectiveName": false, + "name": "Christian Kleusch" + }, + { + "ForeName": "Katarzyna", + "LastName": "Walkiewicz", + "abbrevName": "Walkiewicz K", + "email": null, + "isCollectiveName": false, + "name": "Katarzyna Walkiewicz" + }, + { + "ForeName": "Dennis", + "LastName": "Breitsprecher", + "abbrevName": "Breitsprecher D", + "email": null, + "isCollectiveName": false, + "name": "Dennis Breitsprecher" + }, + { + "ForeName": "Sebastian", + "LastName": "Weigert", + "abbrevName": "Weigert S", + "email": null, + "isCollectiveName": false, + "name": "Sebastian Weigert" + }, + { + "ForeName": "Yves", + "LastName": "Muller", + "abbrevName": "Muller YA", + "email": null, + "isCollectiveName": false, + "name": "Yves A Muller" + }, + { + "ForeName": "Changjiang", + "LastName": "You", + "abbrevName": "You C", + "email": null, + "isCollectiveName": false, + "name": "Changjiang You" + }, + { + "ForeName": "Jacob", + "LastName": "Piehler", + "abbrevName": "Piehler J", + "email": null, + "isCollectiveName": false, + "name": "Jacob Piehler" + }, + { + "ForeName": "Thomas", + "LastName": "Vercruysse", + "abbrevName": "Vercruysse T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Vercruysse" + }, + { + "ForeName": "Dirk", + "LastName": "Daelemans", + "abbrevName": "Daelemans D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Daelemans" + }, + { + "ForeName": "Nuska", + "LastName": "Tschammer", + "abbrevName": "Tschammer N", + "email": "nuska.tschammer@nanotempertech.com", + "isCollectiveName": false, + "name": "Nuska Tschammer" + } + ], + "contacts": [ + { + "ForeName": "Nuska", + "LastName": "Tschammer", + "email": [ + "nuska.tschammer@nanotempertech.com" + ], + "name": "Nuska Tschammer" + } + ] + }, + "doi": "10.1038/s41598-018-23154-3", + "pmid": "29563556", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Sci Rep 8 2018", + "title": "Near-native, site-specific and purification-free protein labeling for quantitative protein interaction analysis by MicroScale Thermophoresis." + } + }, + { + "pmid": "29180516", + "pubmed": { + "ISODate": "2017-12-15T00:00:00.000Z", + "abstract": "When cell surface receptors engage their cognate ligands in the extracellular space, they become competent to transmit potent signals to the inside of the cell, thereby instigating growth, differentiation, motility and many other processes. In order to control these signals, activated receptors are endocytosed and thoroughly curated by the endosomal network of intracellular vesicles and proteolytic organelles. In this Review, we follow the epidermal growth factor (EGF) receptor (EGFR) from ligand engagement, through its voyage on endosomes and, ultimately, to its destruction in the lysosome. We focus on the spatial and temporal considerations underlying the molecular decisions that govern this complex journey and discuss how additional cellular organelles - particularly the ER - play active roles in the regulation of receptor lifespan. In summarizing the functions of relevant molecules on the endosomes and the ER, we cover the order of molecular events in receptor activation, trafficking and downregulation, and provide an overview of how signaling is controlled at the interface between these organelles.", + "authors": { + "abbreviation": "Jeroen Bakker, Menno Spits, Jacques Neefjes, Ilana Berlin", + "authorList": [ + { + "ForeName": "Jeroen", + "LastName": "Bakker", + "abbrevName": "Bakker J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Bakker" + }, + { + "ForeName": "Menno", + "LastName": "Spits", + "abbrevName": "Spits M", + "email": null, + "isCollectiveName": false, + "name": "Menno Spits" + }, + { + "ForeName": "Jacques", + "LastName": "Neefjes", + "abbrevName": "Neefjes J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Neefjes" + }, + { + "ForeName": "Ilana", + "LastName": "Berlin", + "abbrevName": "Berlin I", + "email": "I.Berlin@lumc.nl", + "isCollectiveName": false, + "name": "Ilana Berlin" + } + ], + "contacts": [ + { + "ForeName": "Ilana", + "LastName": "Berlin", + "email": [ + "I.Berlin@lumc.nl" + ], + "name": "Ilana Berlin" + } + ] + }, + "doi": "10.1242/jcs.209197", + "pmid": "29180516", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "The EGFR odyssey - from activation to destruction in space and time." + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "26729028", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation. Another hallmark of kindlins is their involvement in disease. Mutations in the KINDLIN-1 (also known as FERMT1) gene cause Kindler syndrome (KS)--in which mainly skin and intestine are affected, whereas mutations in the KINDLIN-3 (also known as FERMT3) gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by impaired extravasation of blood effector cells and severe, spontaneous bleedings. Also, aberrant expression of kindlins in various forms of cancer and in tissue fibrosis has been reported. Although the malfunctioning of integrins represent a major cause leading to kindlin-associated diseases, increasing evidence also point to integrin-independent functions of kindlins that play an important role in the pathogenesis of certain disease aspects. Furthermore, isoform-specific kindlin functions have been discovered, explaining, for example, why loss of kindlins differentially affects tissue stem cell homeostasis or tumor development. This Commentary focuses on new and isoform-specific kindlin functions in different tissues and discusses their potential role in disease development and progression.", + "authors": { + "abbreviation": "Emanuel Rognoni, Raphael Ruppert, Reinhard Fässler", + "authorList": [ + { + "ForeName": "Emanuel", + "LastName": "Rognoni", + "abbrevName": "Rognoni E", + "email": null, + "isCollectiveName": false, + "name": "Emanuel Rognoni" + }, + { + "ForeName": "Raphael", + "LastName": "Ruppert", + "abbrevName": "Ruppert R", + "email": null, + "isCollectiveName": false, + "name": "Raphael Ruppert" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": "faessler@biochem.mpg.de", + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [ + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "email": [ + "faessler@biochem.mpg.de" + ], + "name": "Reinhard Fässler" + } + ] + }, + "doi": "10.1242/jcs.161190", + "pmid": "26729028", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "The kindlin family: functions, signaling properties and implications for human disease." + } + }, + { + "pmid": "26037143", + "pubmed": { + "ISODate": "2015-07-08T00:00:00.000Z", + "abstract": "Kindlin-2 regulates external to internal cell signaling by interaction with integrins in a process that involves the tyrosine kinase, Src. However, the underlying mechanisms remain elusive. Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. These findings suggest that Src, Kindlin-2 and Migfilin together constitute a positive feedback loop that controls Src activity and regulates integrin-mediated cellular functions. ", + "authors": { + "abbreviation": "Zhaoli Liu, Danyu Lu, Xiang Wang, ..., Hongquan Zhang", + "authorList": [ + { + "ForeName": "Zhaoli", + "LastName": "Liu", + "abbrevName": "Liu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhaoli Liu" + }, + { + "ForeName": "Danyu", + "LastName": "Lu", + "abbrevName": "Lu D", + "email": null, + "isCollectiveName": false, + "name": "Danyu Lu" + }, + { + "ForeName": "Xiang", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiang Wang" + }, + { + "ForeName": "Junhu", + "LastName": "Wan", + "abbrevName": "Wan J", + "email": null, + "isCollectiveName": false, + "name": "Junhu Wan" + }, + { + "ForeName": "Chang", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Chang Liu" + }, + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": "Hongquan.Zhang@bjmu.edu.cn", + "isCollectiveName": false, + "name": "Hongquan Zhang" + } + ], + "contacts": [ + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "email": [ + "Hongquan.Zhang@bjmu.edu.cn" + ], + "name": "Hongquan Zhang" + } + ] + }, + "doi": "10.1016/j.febslet.2015.05.038", + "pmid": "26037143", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 589 2015", + "title": "Kindlin-2 phosphorylation by Src at Y193 enhances Src activity and is involved in Migfilin recruitment to the focal adhesions." + } + }, + { + "pmid": "25790908", + "pubmed": { + "ISODate": "2015-06-01T00:00:00.000Z", + "abstract": "Epidermal growth factor receptor (EGFR) mediates multiple signaling pathways that regulate cell proliferation, migration and tumor invasion. Kindlin-2 has been known as a focal adhesion molecule that binds to integrin to control cell migration and invasion. However, molecular mechanisms underlying the role of Kindlin-2 in breast cancer progression remain elusive. Here we report that Kindlin-2 interacts with EGFR and mediates EGF-induced breast cancer cell migration. We found that EGF treatment dramatically increases Kindlin-2 expression at both mRNA and protein levels in a variety of cancer cells. Inhibitors specific for EGFR or PI3K blocked Kindlin-2 induction by EGF. Importantly, Kindlin-2 interacted with EGFR kinase domain, which was independent of Kindlin-2 binding to integrin cytoplasmic domain. Intriguingly, Kindlin-2 stabilized EGFR protein by blocking its ubiquitination and degradation. Depletion of Kindlin-2 impaired EGF-induced cell migration. Our results demonstrated that Kindlin-2 participates in EGFR signaling and regulates breast cancer progression. ", + "authors": { + "abbreviation": "Baohui Guo, Jianchao Gao, Jun Zhan, Hongquan Zhang", + "authorList": [ + { + "ForeName": "Baohui", + "LastName": "Guo", + "abbrevName": "Guo B", + "email": null, + "isCollectiveName": false, + "name": "Baohui Guo" + }, + { + "ForeName": "Jianchao", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": null, + "isCollectiveName": false, + "name": "Jianchao Gao" + }, + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": "Hongquan.Zhang@bjmu.edu.cn", + "isCollectiveName": false, + "name": "Hongquan Zhang" + } + ], + "contacts": [ + { + "ForeName": "Hongquan", + "LastName": "Zhang", + "email": [ + "Hongquan.Zhang@bjmu.edu.cn" + ], + "name": "Hongquan Zhang" + } + ] + }, + "doi": "10.1016/j.canlet.2015.03.011", + "pmid": "25790908", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Lett 361 2015", + "title": "Kindlin-2 interacts with and stabilizes EGFR and is required for EGF-induced breast cancer cell migration." + } + }, + { + "pmid": "25237194", + "pubmed": { + "ISODate": "2014-11-07T00:00:00.000Z", + "abstract": "Integrin-mediated cell-extracellular matrix (ECM) adhesion is critical for control of intracellular signaling; however, the mechanisms underlying this \"outside-in\" signaling are incompletely understood. Here we show that depletion of kindlin-2 impairs integrin outside-in signaling. Kindlin-2 is tyrosine-phosphorylated upon cell-ECM adhesion. Furthermore, kindlin-2 binds Src in a cell-ECM adhesion-regulatable fashion. At the molecular level, the kindlin-2·Src interaction is mediated by the kindlin-2 F0 and the Src SH2 and SH3 domains. Src activation increases kindlin-2 tyrosine phosphorylation and the kindlin-2·Src interaction. Conversely, inhibition of Src reduces kindlin-2 tyrosine phosphorylation and diminishes the kindlin-2·Src interaction. Finally, disruption of the kindlin-2·Src interaction, unlike depletion of kindlin-2, impairs neither cell-ECM adhesion nor cell-ECM adhesion-induced focal adhesion kinase Tyr-397 phosphorylation. However, it markedly inhibits cell-ECM adhesion-induced paxillin tyrosine phosphorylation, cell migration, and proliferation. These results suggest that kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch downstream of focal adhesion kinase in the integrin outside-in signaling circuit, relaying signals from cell-ECM adhesion to paxillin that control cell migration and proliferation. ", + "authors": { + "abbreviation": "Hong Qu, Yizeng Tu, Jun-Lin Guan, ..., Chuanyue Wu", + "authorList": [ + { + "ForeName": "Hong", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Hong Qu" + }, + { + "ForeName": "Yizeng", + "LastName": "Tu", + "abbrevName": "Tu Y", + "email": null, + "isCollectiveName": false, + "name": "Yizeng Tu" + }, + { + "ForeName": "Jun-Lin", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "Jun-Lin Guan" + }, + { + "ForeName": "Guozhi", + "LastName": "Xiao", + "abbrevName": "Xiao G", + "email": null, + "isCollectiveName": false, + "name": "Guozhi Xiao" + }, + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": "carywu@pitt.edu", + "isCollectiveName": false, + "name": "Chuanyue Wu" + } + ], + "contacts": [ + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "email": [ + "carywu@pitt.edu" + ], + "name": "Chuanyue Wu" + } + ] + }, + "doi": "10.1074/jbc.M114.580811", + "pmid": "25237194", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "Kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch in the integrin outside-in signaling circuit." + } + }, + { + "pmid": "25086068", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Kindlins are essential FERM-domain-containing focal adhesion (FA) proteins required for proper integrin activation and signaling. Despite the widely accepted importance of each of the three mammalian kindlins in cell adhesion, the molecular basis for their function has yet to be fully elucidated, and the functional differences between isoforms have generally not been examined. Here, we report functional differences between kindlin-2 and -3 (also known as FERMT2 and FERMT3, respectively); GFP-tagged kindlin-2 localizes to FAs whereas kindlin-3 does not, and kindlin-2, but not kindlin-3, can rescue α5β1 integrin activation defects in kindlin-2-knockdown fibroblasts. Using chimeric kindlins, we show that the relatively uncharacterized kindlin-2 F2 subdomain drives FA targeting and integrin activation. We find that the integrin-linked kinase (ILK)-PINCH-parvin complex binds strongly to the kindlin-2 F2 subdomain but poorly to that of kindlin-3. Using a point-mutated kindlin-2, we establish that efficient kindlin-2-mediated integrin activation and FA targeting require binding to the ILK complex. Thus, ILK-complex binding is crucial for normal kindlin-2 function and differential ILK binding contributes to kindlin isoform specificity. ", + "authors": { + "abbreviation": "Clotilde Huet-Calderwood, Nina N Brahme, Nikit Kumar, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Clotilde", + "LastName": "Huet-Calderwood", + "abbrevName": "Huet-Calderwood C", + "email": null, + "isCollectiveName": false, + "name": "Clotilde Huet-Calderwood" + }, + { + "ForeName": "Nina", + "LastName": "Brahme", + "abbrevName": "Brahme NN", + "email": null, + "isCollectiveName": false, + "name": "Nina N Brahme" + }, + { + "ForeName": "Nikit", + "LastName": "Kumar", + "abbrevName": "Kumar N", + "email": null, + "isCollectiveName": false, + "name": "Nikit Kumar" + }, + { + "ForeName": "Amy", + "LastName": "Stiegler", + "abbrevName": "Stiegler AL", + "email": null, + "isCollectiveName": false, + "name": "Amy L Stiegler" + }, + { + "ForeName": "Srikala", + "LastName": "Raghavan", + "abbrevName": "Raghavan S", + "email": null, + "isCollectiveName": false, + "name": "Srikala Raghavan" + }, + { + "ForeName": "Titus", + "LastName": "Boggon", + "abbrevName": "Boggon TJ", + "email": null, + "isCollectiveName": false, + "name": "Titus J Boggon" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": "david.calderwood@yale.edu", + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Calderwood", + "email": [ + "david.calderwood@yale.edu" + ], + "name": "David A Calderwood" + } + ] + }, + "doi": "10.1242/jcs.155879", + "pmid": "25086068", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 127 2014", + "title": "Differences in binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation." + } + }, + { + "pmid": "24691054", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.", + "authors": { + "abbreviation": "Patrick Campbell, Penny E Morton, Takuya Takeichi, ..., John A McGrath", + "authorList": [ + { + "ForeName": "Patrick", + "LastName": "Campbell", + "abbrevName": "Campbell P", + "email": null, + "isCollectiveName": false, + "name": "Patrick Campbell" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Takuya", + "LastName": "Takeichi", + "abbrevName": "Takeichi T", + "email": null, + "isCollectiveName": false, + "name": "Takuya Takeichi" + }, + { + "ForeName": "Amr", + "LastName": "Salam", + "abbrevName": "Salam A", + "email": null, + "isCollectiveName": false, + "name": "Amr Salam" + }, + { + "ForeName": "Nerys", + "LastName": "Roberts", + "abbrevName": "Roberts N", + "email": null, + "isCollectiveName": false, + "name": "Nerys Roberts" + }, + { + "ForeName": "Laura", + "LastName": "Proudfoot", + "abbrevName": "Proudfoot LE", + "email": null, + "isCollectiveName": false, + "name": "Laura E Proudfoot" + }, + { + "ForeName": "Jemima", + "LastName": "Mellerio", + "abbrevName": "Mellerio JE", + "email": null, + "isCollectiveName": false, + "name": "Jemima E Mellerio" + }, + { + "ForeName": "Kingi", + "LastName": "Aminu", + "abbrevName": "Aminu K", + "email": null, + "isCollectiveName": false, + "name": "Kingi Aminu" + }, + { + "ForeName": "Cheryl", + "LastName": "Wellington", + "abbrevName": "Wellington C", + "email": null, + "isCollectiveName": false, + "name": "Cheryl Wellington" + }, + { + "ForeName": "Sachin", + "LastName": "Patil", + "abbrevName": "Patil SN", + "email": null, + "isCollectiveName": false, + "name": "Sachin N Patil" + }, + { + "ForeName": "Masashi", + "LastName": "Akiyama", + "abbrevName": "Akiyama M", + "email": null, + "isCollectiveName": false, + "name": "Masashi Akiyama" + }, + { + "ForeName": "Lu", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lu Liu" + }, + { + "ForeName": "James", + "LastName": "McMillan", + "abbrevName": "McMillan JR", + "email": null, + "isCollectiveName": false, + "name": "James R McMillan" + }, + { + "ForeName": "Sophia", + "LastName": "Aristodemou", + "abbrevName": "Aristodemou S", + "email": null, + "isCollectiveName": false, + "name": "Sophia Aristodemou" + }, + { + "ForeName": "Akemi", + "LastName": "Ishida-Yamamoto", + "abbrevName": "Ishida-Yamamoto A", + "email": null, + "isCollectiveName": false, + "name": "Akemi Ishida-Yamamoto" + }, + { + "ForeName": "Alya", + "LastName": "Abdul-Wahab", + "abbrevName": "Abdul-Wahab A", + "email": null, + "isCollectiveName": false, + "name": "Alya Abdul-Wahab" + }, + { + "ForeName": "Gabriela", + "LastName": "Petrof", + "abbrevName": "Petrof G", + "email": null, + "isCollectiveName": false, + "name": "Gabriela Petrof" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Sarawin", + "LastName": "Harnchoowong", + "abbrevName": "Harnchoowong S", + "email": null, + "isCollectiveName": false, + "name": "Sarawin Harnchoowong" + }, + { + "ForeName": "Kristina", + "LastName": "Stone", + "abbrevName": "Stone KL", + "email": null, + "isCollectiveName": false, + "name": "Kristina L Stone" + }, + { + "ForeName": "John", + "LastName": "Harper", + "abbrevName": "Harper JI", + "email": null, + "isCollectiveName": false, + "name": "John I Harper" + }, + { + "ForeName": "W", + "LastName": "Irwin McLean", + "abbrevName": "Irwin McLean WH", + "email": null, + "isCollectiveName": false, + "name": "W H Irwin McLean" + }, + { + "ForeName": "Michael", + "LastName": "Simpson", + "abbrevName": "Simpson MA", + "email": null, + "isCollectiveName": false, + "name": "Michael A Simpson" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": "john.mcgrath@kcl.ac.uk", + "isCollectiveName": false, + "name": "John A McGrath" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "McGrath", + "email": [ + "john.mcgrath@kcl.ac.uk" + ], + "name": "John A McGrath" + } + ] + }, + "doi": "10.1038/jid.2014.164", + "pmid": "24691054", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 134 2014", + "title": "Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR." + } + }, + { + "pmid": "24525752", + "pubmed": { + "ISODate": "2014-03-01T00:00:00.000Z", + "abstract": "Detection and quantification of fluorescently labeled molecules in subcellular compartments is a key step in the analysis of many cell biological processes. Pixel-wise colocalization analyses, however, are not always suitable, because they do not provide object-specific information, and they are vulnerable to noise and background fluorescence. Here we present a versatile protocol for a method named 'Squassh' (segmentation and quantification of subcellular shapes), which is used for detecting, delineating and quantifying subcellular structures in fluorescence microscopy images. The workflow is implemented in freely available, user-friendly software. It works on both 2D and 3D images, accounts for the microscope optics and for uneven image background, computes cell masks and provides subpixel accuracy. The Squassh software enables both colocalization and shape analyses. The protocol can be applied in batch, on desktop computers or computer clusters, and it usually requires <1 min and <5 min for 2D and 3D images, respectively. Basic computer-user skills and some experience with fluorescence microscopy are recommended to successfully use the protocol. ", + "authors": { + "abbreviation": "Aurélien Rizk, Grégory Paul, Pietro Incardona, ..., Ivo F Sbalzarini", + "authorList": [ + { + "ForeName": "Aurélien", + "LastName": "Rizk", + "abbrevName": "Rizk A", + "email": null, + "isCollectiveName": false, + "name": "Aurélien Rizk" + }, + { + "ForeName": "Grégory", + "LastName": "Paul", + "abbrevName": "Paul G", + "email": null, + "isCollectiveName": false, + "name": "Grégory Paul" + }, + { + "ForeName": "Pietro", + "LastName": "Incardona", + "abbrevName": "Incardona P", + "email": null, + "isCollectiveName": false, + "name": "Pietro Incardona" + }, + { + "ForeName": "Milica", + "LastName": "Bugarski", + "abbrevName": "Bugarski M", + "email": null, + "isCollectiveName": false, + "name": "Milica Bugarski" + }, + { + "ForeName": "Maysam", + "LastName": "Mansouri", + "abbrevName": "Mansouri M", + "email": null, + "isCollectiveName": false, + "name": "Maysam Mansouri" + }, + { + "ForeName": "Axel", + "LastName": "Niemann", + "abbrevName": "Niemann A", + "email": null, + "isCollectiveName": false, + "name": "Axel Niemann" + }, + { + "ForeName": "Urs", + "LastName": "Ziegler", + "abbrevName": "Ziegler U", + "email": null, + "isCollectiveName": false, + "name": "Urs Ziegler" + }, + { + "ForeName": "Philipp", + "LastName": "Berger", + "abbrevName": "Berger P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Berger" + }, + { + "ForeName": "Ivo", + "LastName": "Sbalzarini", + "abbrevName": "Sbalzarini IF", + "email": null, + "isCollectiveName": false, + "name": "Ivo F Sbalzarini" + } + ], + "contacts": [] + }, + "doi": "10.1038/nprot.2014.037", + "pmid": "24525752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Protoc 9 2014", + "title": "Segmentation and quantification of subcellular structures in fluorescence microscopy images using Squassh." + } + }, + { + "pmid": "24215440", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "A largely unilamellar epithelial layer lines body cavities and organ ducts such as the digestive tract and kidney tubules. This polarized epithelium is composed of biochemically and functionally separate apical and basolateral surfaces. The epidermal growth factor receptor (EGFR) signaling pathway is a critical regulator of epithelial homeostasis and is perturbed in a number of epithelial disorders. It is underappreciated that in vivo EGFR signaling is most often initiated by cell-surface delivery and processing of one of seven transmembrane ligands, resulting in release of the soluble form that binds EGFR. In polarized epithelial cells, EGFR is restricted largely to the basolateral surface, and apical or basolateral ligand delivery therefore has important biological consequences. In vitro approaches have been used to study the biosynthesis, cell-surface delivery, proteolytic processing, and release of soluble EGFR ligands in polarized epithelial cells. We review these results, discuss their relevance to normal physiology, and demonstrate the pathophysiological consequences of aberrant trafficking. These studies have uncovered a rich diversity of apico-basolateral trafficking mechanisms among the EGFR ligands, provided insights into the pathogenesis of an inherited magnesium-wasting disorder of the kidney (isolated renal hypomagnesemia), and identified a new mode of EGFR ligand signaling via exosomes. ", + "authors": { + "abbreviation": "Bhuminder Singh, Robert J Coffey", + "authorList": [ + { + "ForeName": "Bhuminder", + "LastName": "Singh", + "abbrevName": "Singh B", + "email": "robert.coffey@vanderbilt.edu", + "isCollectiveName": false, + "name": "Bhuminder Singh" + }, + { + "ForeName": "Robert", + "LastName": "Coffey", + "abbrevName": "Coffey RJ", + "email": null, + "isCollectiveName": false, + "name": "Robert J Coffey" + } + ], + "contacts": [ + { + "ForeName": "Bhuminder", + "LastName": "Singh", + "email": [ + "robert.coffey@vanderbilt.edu", + "bhuminder.singh@vanderbilt.edu" + ], + "name": "Bhuminder Singh" + } + ] + }, + "doi": "10.1146/annurev-physiol-021113-170406", + "pmid": "24215440", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Annu Rev Physiol 76 2014", + "title": "Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells." + } + }, + { + "pmid": "24165133", + "pubmed": { + "ISODate": "2013-12-06T00:00:00.000Z", + "abstract": "Focal adhesions (FAs), sites of tight adhesion to the extracellular matrix, are composed of clusters of transmembrane integrin adhesion receptors and intracellular proteins that link integrins to the actin cytoskeleton and signaling pathways. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. Migfilin, originally identified in a yeast two-hybrid screen for kindlin-2-interacting proteins, is a LIM domain-containing adaptor protein found in FAs and implicated in control of cell adhesion, spreading, and migration. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. Here, using a combination of kindlin knockdown, biochemical pulldown assays, fluorescence microscopy, fluorescence resonance energy transfer (FRET), and fluorescence recovery after photobleaching (FRAP), we have established that the C-terminal LIM domains of migfilin dictate its FA localization, shown that these domains mediate an interaction with kindlin in vitro and in cells, and demonstrated that kindlin is important for normal migfilin dynamics in cells. We also show that when the C-terminal LIM domain region is deleted, then the N-terminal filamin-binding region of the protein, which is capable of targeting migfilin to actin-rich stress fibers, is the predominant driver of migfilin localization. Our work details a correlation between migfilin domains that drive kindlin binding and those that drive FA localization as well as a kindlin dependence on migfilin FA recruitment and mobility. We therefore suggest that the kindlin interaction with migfilin LIM domains drives migfilin FA recruitment, localization, and mobility. ", + "authors": { + "abbreviation": "Nina N Brahme, David S Harburger, Karl Kemp-O'Brien, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Brahme", + "abbrevName": "Brahme NN", + "email": null, + "isCollectiveName": false, + "name": "Nina N Brahme" + }, + { + "ForeName": "David", + "LastName": "Harburger", + "abbrevName": "Harburger DS", + "email": null, + "isCollectiveName": false, + "name": "David S Harburger" + }, + { + "ForeName": "Karl", + "LastName": "Kemp-O'Brien", + "abbrevName": "Kemp-O'Brien K", + "email": null, + "isCollectiveName": false, + "name": "Karl Kemp-O'Brien" + }, + { + "ForeName": "Rachel", + "LastName": "Stewart", + "abbrevName": "Stewart R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Stewart" + }, + { + "ForeName": "Srikala", + "LastName": "Raghavan", + "abbrevName": "Raghavan S", + "email": null, + "isCollectiveName": false, + "name": "Srikala Raghavan" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M113.483016", + "pmid": "24165133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics." + } + }, + { + "pmid": "23747363", + "pubmed": { + "ISODate": "2014-02-01T00:00:00.000Z", + "abstract": "Proteins of the 4.1 family are characteristic of eumetazoan organisms. Invertebrates contain single 4.1 genes and the Drosophila model suggests that 4.1 is essential for animal life. Vertebrates have four paralogues, known as 4.1R, 4.1N, 4.1G and 4.1B, which are additionally duplicated in the ray-finned fish. Protein 4.1R was the first to be discovered: it is a major mammalian erythrocyte cytoskeletal protein, essential to the mechanochemical properties of red cell membranes because it promotes the interaction between spectrin and actin in the membrane cytoskeleton. 4.1R also binds certain phospholipids and is required for the stable cell surface accumulation of a number of erythrocyte transmembrane proteins that span multiple functional classes; these include cell adhesion molecules, transporters and a chemokine receptor. The vertebrate 4.1 proteins are expressed in most tissues, and they are required for the correct cell surface accumulation of a very wide variety of membrane proteins including G-Protein coupled receptors, voltage-gated and ligand-gated channels, as well as the classes identified in erythrocytes. Indeed, such large numbers of protein interactions have been mapped for mammalian 4.1 proteins, most especially 4.1R, that it appears that they can act as hubs for membrane protein organization. The range of critical interactions of 4.1 proteins is reflected in disease relationships that include hereditary anaemias, tumour suppression, control of heartbeat and nervous system function. The 4.1 proteins are defined by their domain structure: apart from the spectrin/actin-binding domain they have FERM and FERM-adjacent domains and a unique C-terminal domain. Both the FERM and C-terminal domains can bind transmembrane proteins, thus they have the potential to be cross-linkers for membrane proteins. The activity of the FERM domain is subject to multiple modes of regulation via binding of regulatory ligands, phosphorylation of the FERM associated domain and differential mRNA splicing. Finally, the spectrum of interactions of the 4.1 proteins overlaps with that of another membrane-cytoskeleton linker, ankyrin. Both ankyrin and 4.1 link to the actin cytoskeleton via spectrin, and we hypothesize that differential regulation of 4.1 proteins and ankyrins allows highly selective control of cell surface protein accumulation and, hence, function. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé ", + "authors": { + "abbreviation": "Anthony J Baines, Hui-Chun Lu, Pauline M Bennett", + "authorList": [ + { + "ForeName": "Anthony", + "LastName": "Baines", + "abbrevName": "Baines AJ", + "email": null, + "isCollectiveName": false, + "name": "Anthony J Baines" + }, + { + "ForeName": "Hui-Chun", + "LastName": "Lu", + "abbrevName": "Lu HC", + "email": null, + "isCollectiveName": false, + "name": "Hui-Chun Lu" + }, + { + "ForeName": "Pauline", + "LastName": "Bennett", + "abbrevName": "Bennett PM", + "email": "pauline.bennett@kcl.ac.uk", + "isCollectiveName": false, + "name": "Pauline M Bennett" + } + ], + "contacts": [ + { + "ForeName": "Pauline", + "LastName": "Bennett", + "email": [ + "pauline.bennett@kcl.ac.uk" + ], + "name": "Pauline M Bennett" + } + ] + }, + "doi": "10.1016/j.bbamem.2013.05.030", + "pmid": "23747363", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochim Biophys Acta 1838 2014", + "title": "The Protein 4.1 family: hub proteins in animals for organizing membrane proteins." + } + }, + { + "pmid": "22974990", + "pubmed": { + "ISODate": "2012-09-11T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Paolo Maiuri, Emmanuel Terriac, Perrine Paul-Gilloteaux, ..., Manuel Théry", + "authorList": [ + { + "ForeName": "Paolo", + "LastName": "Maiuri", + "abbrevName": "Maiuri P", + "email": null, + "isCollectiveName": false, + "name": "Paolo Maiuri" + }, + { + "ForeName": "Emmanuel", + "LastName": "Terriac", + "abbrevName": "Terriac E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuel Terriac" + }, + { + "ForeName": "Perrine", + "LastName": "Paul-Gilloteaux", + "abbrevName": "Paul-Gilloteaux P", + "email": null, + "isCollectiveName": false, + "name": "Perrine Paul-Gilloteaux" + }, + { + "ForeName": "Timothée", + "LastName": "Vignaud", + "abbrevName": "Vignaud T", + "email": null, + "isCollectiveName": false, + "name": "Timothée Vignaud" + }, + { + "ForeName": "Krista", + "LastName": "McNally", + "abbrevName": "McNally K", + "email": null, + "isCollectiveName": false, + "name": "Krista McNally" + }, + { + "ForeName": "James", + "LastName": "Onuffer", + "abbrevName": "Onuffer J", + "email": null, + "isCollectiveName": false, + "name": "James Onuffer" + }, + { + "ForeName": "Kurt", + "LastName": "Thorn", + "abbrevName": "Thorn K", + "email": null, + "isCollectiveName": false, + "name": "Kurt Thorn" + }, + { + "ForeName": "Phuong", + "LastName": "Nguyen", + "abbrevName": "Nguyen PA", + "email": null, + "isCollectiveName": false, + "name": "Phuong A Nguyen" + }, + { + "ForeName": "Nefeli", + "LastName": "Georgoulia", + "abbrevName": "Georgoulia N", + "email": null, + "isCollectiveName": false, + "name": "Nefeli Georgoulia" + }, + { + "ForeName": "Daniel", + "LastName": "Soong", + "abbrevName": "Soong D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Soong" + }, + { + "ForeName": "Asier", + "LastName": "Jayo", + "abbrevName": "Jayo A", + "email": null, + "isCollectiveName": false, + "name": "Asier Jayo" + }, + { + "ForeName": "Nina", + "LastName": "Beil", + "abbrevName": "Beil N", + "email": null, + "isCollectiveName": false, + "name": "Nina Beil" + }, + { + "ForeName": "Jürgen", + "LastName": "Beneke", + "abbrevName": "Beneke J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Beneke" + }, + { + "ForeName": "Joleen", + "LastName": "Lim", + "abbrevName": "Lim JC", + "email": null, + "isCollectiveName": false, + "name": "Joleen Chooi Hong Lim" + }, + { + "ForeName": "Chloe", + "LastName": "Sim", + "abbrevName": "Sim CP", + "email": null, + "isCollectiveName": false, + "name": "Chloe Pei-Ying Sim" + }, + { + "ForeName": "Yeh-Shiu", + "LastName": "Chu", + "abbrevName": "Chu YS", + "email": null, + "isCollectiveName": false, + "name": "Yeh-Shiu Chu" + }, + { + "ForeName": null, + "LastName": null, + "abbrevName": "WCR participants", + "email": null, + "isCollectiveName": true, + "name": "WCR participants" + }, + { + "ForeName": "Andrea", + "LastName": "Jiménez-Dalmaroni", + "abbrevName": "Jiménez-Dalmaroni A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Jiménez-Dalmaroni" + }, + { + "ForeName": "Jean-François", + "LastName": "Joanny", + "abbrevName": "Joanny JF", + "email": null, + "isCollectiveName": false, + "name": "Jean-François Joanny" + }, + { + "ForeName": "Jean-Paul", + "LastName": "Thiery", + "abbrevName": "Thiery JP", + "email": null, + "isCollectiveName": false, + "name": "Jean-Paul Thiery" + }, + { + "ForeName": "Holger", + "LastName": "Erfle", + "abbrevName": "Erfle H", + "email": null, + "isCollectiveName": false, + "name": "Holger Erfle" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Timothy", + "LastName": "Mitchison", + "abbrevName": "Mitchison TJ", + "email": null, + "isCollectiveName": false, + "name": "Timothy J Mitchison" + }, + { + "ForeName": "Wendell", + "LastName": "Lim", + "abbrevName": "Lim WA", + "email": null, + "isCollectiveName": false, + "name": "Wendell A Lim" + }, + { + "ForeName": "Ana-Maria", + "LastName": "Lennon-Duménil", + "abbrevName": "Lennon-Duménil AM", + "email": null, + "isCollectiveName": false, + "name": "Ana-Maria Lennon-Duménil" + }, + { + "ForeName": "Matthieu", + "LastName": "Piel", + "abbrevName": "Piel M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Piel" + }, + { + "ForeName": "Manuel", + "LastName": "Théry", + "abbrevName": "Théry M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Théry" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2012.07.052", + "pmid": "22974990", + "pubTypes": [ + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 22 2012", + "title": "The first World Cell Race." + } + }, + { + "pmid": "22718763", + "pubmed": { + "ISODate": "2012-08-10T00:00:00.000Z", + "abstract": "Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways.", + "authors": { + "abbreviation": "Jong Hyun Kim, Aibing Wang, Mary Anne Conti, Robert S Adelstein", + "authorList": [ + { + "ForeName": "Jong", + "LastName": "Kim", + "abbrevName": "Kim JH", + "email": "nr.kimjohn@gmail.com", + "isCollectiveName": false, + "name": "Jong Hyun Kim" + }, + { + "ForeName": "Aibing", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aibing Wang" + }, + { + "ForeName": "Mary", + "LastName": "Conti", + "abbrevName": "Conti MA", + "email": null, + "isCollectiveName": false, + "name": "Mary Anne Conti" + }, + { + "ForeName": "Robert", + "LastName": "Adelstein", + "abbrevName": "Adelstein RS", + "email": null, + "isCollectiveName": false, + "name": "Robert S Adelstein" + } + ], + "contacts": [ + { + "ForeName": "Jong", + "LastName": "Kim", + "email": [ + "nr.kimjohn@gmail.com" + ], + "name": "Jong Hyun Kim" + } + ] + }, + "doi": "10.1074/jbc.M111.304824", + "pmid": "22718763", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Nonmuscle myosin II is required for internalization of the epidermal growth factor receptor and modulation of downstream signaling." + } + }, + { + "pmid": "22564415", + "pubmed": { + "ISODate": "2012-05-14T00:00:00.000Z", + "abstract": "Fascin is an evolutionarily conserved actin-binding protein that plays a key role in forming filopodia. It is widely thought that this function involves fascin directly bundling actin filaments, which is controlled by an N-terminal regulatory serine residue. In this paper, by studying cellular processes in Drosophila melanogaster that require fascin activity, we identify a regulatory residue within the C-terminal region of the protein (S289). Unexpectedly, although mutation (S289A) of this residue disrupted the actin-bundling capacity of fascin, fascin S289A fully rescued filopodia formation in fascin mutant flies. Live imaging of migrating macrophages in vivo revealed that this mutation restricted the localization of fascin to the distal ends of filopodia. The corresponding mutation of human fascin (S274) similarly affected its interaction with actin and altered filopodia dynamics within carcinoma cells. These data reveal an evolutionarily conserved role for this regulatory region and unveil a function for fascin, uncoupled from actin bundling, at the distal end of filopodia.", + "authors": { + "abbreviation": "Jennifer Zanet, Asier Jayo, Serge Plaza, ..., Brian Stramer", + "authorList": [ + { + "ForeName": "Jennifer", + "LastName": "Zanet", + "abbrevName": "Zanet J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Zanet" + }, + { + "ForeName": "Asier", + "LastName": "Jayo", + "abbrevName": "Jayo A", + "email": null, + "isCollectiveName": false, + "name": "Asier Jayo" + }, + { + "ForeName": "Serge", + "LastName": "Plaza", + "abbrevName": "Plaza S", + "email": null, + "isCollectiveName": false, + "name": "Serge Plaza" + }, + { + "ForeName": "Tom", + "LastName": "Millard", + "abbrevName": "Millard T", + "email": null, + "isCollectiveName": false, + "name": "Tom Millard" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Brian", + "LastName": "Stramer", + "abbrevName": "Stramer B", + "email": null, + "isCollectiveName": false, + "name": "Brian Stramer" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201110135", + "pmid": "22564415", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 197 2012", + "title": "Fascin promotes filopodia formation independent of its role in actin bundling." + } + }, + { + "pmid": "22418300", + "pubmed": { + "ISODate": "2012-02-27T00:00:00.000Z", + "abstract": "We present a novel approach for three-dimensional localization of single molecules using adaptive optics. A 52-actuator deformable mirror is used to both correct aberrations and induce two-dimensional astigmatism in the point-spread-function. The dependence of the z-localization precision on the degree of astigmatism is discussed. We achieve a z-localization precision of 40 nm for fluorescent proteins and 20 nm for fluorescent dyes, over an axial depth of ~800 nm. We illustrate the capabilities of our approach for three-dimensional high-resolution microscopy with super-resolution images of actin filaments in fixed cells and single-molecule tracking of quantum-dot labeled transmembrane proteins in live HeLa cells.", + "authors": { + "abbreviation": "Ignacio Izeddin, Mohamed El Beheiry, Jordi Andilla, ..., Maxime Dahan", + "authorList": [ + { + "ForeName": "Ignacio", + "LastName": "Izeddin", + "abbrevName": "Izeddin I", + "email": null, + "isCollectiveName": false, + "name": "Ignacio Izeddin" + }, + { + "ForeName": "Mohamed", + "LastName": "El Beheiry", + "abbrevName": "El Beheiry M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed El Beheiry" + }, + { + "ForeName": "Jordi", + "LastName": "Andilla", + "abbrevName": "Andilla J", + "email": null, + "isCollectiveName": false, + "name": "Jordi Andilla" + }, + { + "ForeName": "Daniel", + "LastName": "Ciepielewski", + "abbrevName": "Ciepielewski D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Ciepielewski" + }, + { + "ForeName": "Xavier", + "LastName": "Darzacq", + "abbrevName": "Darzacq X", + "email": null, + "isCollectiveName": false, + "name": "Xavier Darzacq" + }, + { + "ForeName": "Maxime", + "LastName": "Dahan", + "abbrevName": "Dahan M", + "email": null, + "isCollectiveName": false, + "name": "Maxime Dahan" + } + ], + "contacts": [] + }, + "doi": "10.1364/OE.20.004957", + "pmid": "22418300", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Opt Express 20 2012", + "title": "PSF shaping using adaptive optics for three-dimensional single-molecule super-resolution imaging and tracking." + } + }, + { + "pmid": "22351767", + "pubmed": { + "ISODate": "2012-04-20T00:00:00.000Z", + "abstract": "Talin, which is composed of head (THD) and rod domains, plays an important role in cell adhesion events in diverse species including most metazoans and Dictyostelium discoideum. Talin is abundant in the cytosol; however, it mediates adhesion by associating with integrins in the plasma membrane where it forms a primary link between integrins and the actin cytoskeleton. Cells modulate the partitioning of talin between the plasma membrane and the cytosol to control cell adhesion. Here, we combine nuclear magnetic resonance spectroscopy (NMR) with subcellular fractionation to characterize two distinct THD-rod domain interactions that control the interaction of talin with the actin cytoskeleton or its localization to the plasma membrane. An interaction between a discrete vinculin-binding region of the rod (VBS1/2a; Tln1(482-787)), and the THD restrains talin from interacting with the plasma membrane. Furthermore, we show that vinculin binding to VBS1/2a results in talin recruitment to the plasma membrane. Thus, we have structurally defined specific inter-domain interactions between THD and the talin rod domain that regulate the subcellular localization of talin.", + "authors": { + "abbreviation": "Asoka Banno, Benjamin T Goult, HoSup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Asoka", + "LastName": "Banno", + "abbrevName": "Banno A", + "email": null, + "isCollectiveName": false, + "name": "Asoka Banno" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "HoSup", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "HoSup Lee" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.341214", + "pmid": "22351767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Subcellular localization of talin is regulated by inter-domain interactions." + } + }, + { + "pmid": "22328497", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Integrin-β1-null keratinocytes can adhere to fibronectin through integrin αvβ6, but form large peripheral focal adhesions and exhibit defective cell spreading. Here we report that, in addition to the reduced avidity of αvβ6 integrin binding to fibronectin, the inability of integrin β6 to efficiently bind and recruit kindlin-2 to focal adhesions directly contributes to these phenotypes. Kindlins regulate integrins through direct interactions with the integrin-β cytoplasmic tail and keratinocytes express kindlin-1 and kindlin-2. Notably, although both kindlins localize to focal adhesions in wild-type cells, only kindlin-1 localizes to the integrin-β6-rich adhesions of integrin-β1-null cells. Rescue of these cells with wild-type and chimeric integrin constructs revealed a correlation between kindlin-2 recruitment and cell spreading. Furthermore, despite the presence of kindlin-1, knockdown of kindlin-2 in wild-type keratinocytes impaired cell spreading. Our data reveal unexpected functional consequences of differences in the association of two homologous kindlin isoforms with two closely related integrins, and suggest that despite their similarities, different kindlins are likely to have unique functions.", + "authors": { + "abbreviation": "Aditi Bandyopadhyay, Gerson Rothschild, Sean Kim, ..., Srikala Raghavan", + "authorList": [ + { + "ForeName": "Aditi", + "LastName": "Bandyopadhyay", + "abbrevName": "Bandyopadhyay A", + "email": null, + "isCollectiveName": false, + "name": "Aditi Bandyopadhyay" + }, + { + "ForeName": "Gerson", + "LastName": "Rothschild", + "abbrevName": "Rothschild G", + "email": null, + "isCollectiveName": false, + "name": "Gerson Rothschild" + }, + { + "ForeName": "Sean", + "LastName": "Kim", + "abbrevName": "Kim S", + "email": null, + "isCollectiveName": false, + "name": "Sean Kim" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Srikala", + "LastName": "Raghavan", + "abbrevName": "Raghavan S", + "email": null, + "isCollectiveName": false, + "name": "Srikala Raghavan" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.096214", + "pmid": "22328497", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 125 2012", + "title": "Functional differences between kindlin-1 and kindlin-2 in keratinocytes." + } + }, + { + "pmid": "22235127", + "pubmed": { + "ISODate": "2012-03-02T00:00:00.000Z", + "abstract": "The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin β subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin β tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin β subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in αIIbβ3 integrin activation, but not for kindlin binding to integrin β tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well β-integrin tails contribute to the ability of kindlins to activate integrins.", + "authors": { + "abbreviation": "Mohamed Bouaouina, Benjamin T Goult, Clotilde Huet-Calderwood, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Clotilde", + "LastName": "Huet-Calderwood", + "abbrevName": "Huet-Calderwood C", + "email": null, + "isCollectiveName": false, + "name": "Clotilde Huet-Calderwood" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Nina", + "LastName": "Brahme", + "abbrevName": "Brahme NN", + "email": null, + "isCollectiveName": false, + "name": "Nina N Brahme" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M111.330845", + "pmid": "22235127", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "20378539", + "pubmed": { + "ISODate": "2010-06-11T00:00:00.000Z", + "abstract": "Integrin activation is crucial for numerous cellular responses, including cell adhesion, migration, and survival. Recent studies in mice have specifically emphasized the vital role of kindlin-3 in integrin activation. Kindlin-3 deficiency in humans also has now been documented and includes symptoms of bleeding, frequent infections, and osteopetrosis, which are consequences of an inability to activate beta1, beta2, and beta3 integrins. To date, kindlin-3 was thought to be restricted to hematopoietic cells. In this article, we demonstrate that kindlin-3 is present in human endothelial cells derived from various anatomical origins. The mRNA and protein for KINDLIN-3 was detected in endothelial cells by reverse transcription-PCR and Western blots. When subjected to sequencing by mass spectrometry, the protein was identified as authentic kindlin-3 and unequivocally distinguished from KINDLIN-1 and KINDLIN-2 or any other known protein. By quantitative real time PCR, the level of kindlin-3 in endothelial cells was 20-50% of that of kindlin-2. Using knockdown approaches, we show that kindlin-3 plays a role in integrin-mediated adhesion of endothelial cells. This function depends upon the integrin and substrate and is distinct from that of kindlin-2. Formation of tube-like structures in Matrigel also was impaired by kindlin-3 knockdown. Mechanistically, the distinct functions of the kindlins can be traced to differences in their subcellular localization in integrin-containing adhesion structures. Thus, the prevailing view that individual kindlins exert their functions in a cell type-specific manner must now be modified to consider distinct functions of the different family members within the same cell type.", + "authors": { + "abbreviation": "Katarzyna Bialkowska, Yan-Qing Ma, Kamila Bledzka, ..., Edward F Plow", + "authorList": [ + { + "ForeName": "Katarzyna", + "LastName": "Bialkowska", + "abbrevName": "Bialkowska K", + "email": null, + "isCollectiveName": false, + "name": "Katarzyna Bialkowska" + }, + { + "ForeName": "Yan-Qing", + "LastName": "Ma", + "abbrevName": "Ma YQ", + "email": null, + "isCollectiveName": false, + "name": "Yan-Qing Ma" + }, + { + "ForeName": "Kamila", + "LastName": "Bledzka", + "abbrevName": "Bledzka K", + "email": null, + "isCollectiveName": false, + "name": "Kamila Bledzka" + }, + { + "ForeName": "Khalid", + "LastName": "Sossey-Alaoui", + "abbrevName": "Sossey-Alaoui K", + "email": null, + "isCollectiveName": false, + "name": "Khalid Sossey-Alaoui" + }, + { + "ForeName": "Lahoucine", + "LastName": "Izem", + "abbrevName": "Izem L", + "email": null, + "isCollectiveName": false, + "name": "Lahoucine Izem" + }, + { + "ForeName": "Xiaoxia", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoxia Zhang" + }, + { + "ForeName": "Nikolay", + "LastName": "Malinin", + "abbrevName": "Malinin N", + "email": null, + "isCollectiveName": false, + "name": "Nikolay Malinin" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.085746", + "pmid": "20378539", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "The integrin co-activator Kindlin-3 is expressed and functional in a non-hematopoietic cell, the endothelial cell." + } + }, + { + "pmid": "19804783", + "pubmed": { + "ISODate": "2009-12-18T00:00:00.000Z", + "abstract": "The integrin family of heterodimeric cell adhesion molecules exists in both low- and high-affinity states, and integrin activation requires binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to membrane-proximal sequences in the beta-integrin cytoplasmic domain. However, it has recently become apparent that the kindlin family of FERM domain proteins is also essential for talin-induced integrin activation. FERM domains are typically composed of F1, F2, and F3 domains, but the talin FERM domain is atypical in that it contains a large insert in F1 and is preceded by a previously unrecognized domain, F0. Initial sequence alignments showed that the kindlin FERM domain was most similar to the talin FERM domain, but the homology appeared to be restricted to the F2 and F3 domains. Based on a detailed characterization of the talin FERM domain, we have reinvestigated the sequence relationship with kindlins and now show that kindlins do indeed contain the same domain structure as the talin FERM domain. However, the kindlin F1 domain contains an even larger insert than that in talin F1 that disrupts the sequence alignment. The insert, which varies in length between different kindlins, is not conserved and, as in talin, is largely unstructured. We have determined the structure of the kindlin-1 F0 domain by NMR, which shows that it adopts the same ubiquitin-like fold as the talin F0 and F1 domains. Comparison of the kindlin-1 and talin F0 domains identifies the probable interface with the kindlin-1 F1 domain. Potential sites of interaction of kindlin F0 with other proteins are discussed, including sites that differ between kindlin-1, kindlin-2, and kindlin-3. We also demonstrate that F0 is required for the ability of kindlin-1 to support talin-induced alphaIIbbeta3 integrin activation and for the localization of kindlin-1 to focal adhesions.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, David S Harburger, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "David", + "LastName": "Harburger", + "abbrevName": "Harburger DS", + "email": null, + "isCollectiveName": false, + "name": "David S Harburger" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Nicholas", + "LastName": "Anthis", + "abbrevName": "Anthis NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicholas J Anthis" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2009.09.061", + "pmid": "19804783", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 394 2009", + "title": "The structure of the N-terminus of kindlin-1: a domain important for alphaiibbeta3 integrin activation." + } + }, + { + "pmid": "19766491", + "pubmed": { + "ISODate": "2009-10-01T00:00:00.000Z", + "abstract": "Kindlins are a group of proteins that have recently attracted attention for their ability to bind and activate integrins. Moreover, they have also been linked to inherited and acquired human diseases including Kindler syndrome, leukocyte adhesion deficiency, and cancer. Although most studies have focused on kindlins as key regulatory components of cell-extracellular matrix junctions such as focal adhesions, preliminary data suggest the involvement of additional cellular compartments in mediating their functions, particularly at cell-cell contacts and the nucleus. Investigating the many roles of kindlins is likely to expand and sharpen our view on the versatility of integrin-mediated cell adhesion, the nuclear function of focal adhesion proteins, and the crosstalk between cell-cell and cell-matrix adhesions in health and disease.", + "authors": { + "abbreviation": "Alexander Meves, Christopher Stremmel, Kay Gottschalk, Reinhard Fässler", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Meves", + "abbrevName": "Meves A", + "email": "meves.alexander@mayo.edu", + "isCollectiveName": false, + "name": "Alexander Meves" + }, + { + "ForeName": "Christopher", + "LastName": "Stremmel", + "abbrevName": "Stremmel C", + "email": null, + "isCollectiveName": false, + "name": "Christopher Stremmel" + }, + { + "ForeName": "Kay", + "LastName": "Gottschalk", + "abbrevName": "Gottschalk K", + "email": null, + "isCollectiveName": false, + "name": "Kay Gottschalk" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [ + { + "ForeName": "Alexander", + "LastName": "Meves", + "email": [ + "meves.alexander@mayo.edu" + ], + "name": "Alexander Meves" + } + ] + }, + "doi": "10.1016/j.tcb.2009.07.006", + "pmid": "19766491", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Trends Cell Biol 19 2009", + "title": "The Kindlin protein family: new members to the club of focal adhesion proteins." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "18997731", + "pubmed": { + "ISODate": "2008-12-01T00:00:00.000Z", + "abstract": "Integrin-mediated cell-ECM (extracellular matrix) adhesion is a fundamental process that controls cell behaviour. For correct cell-ECM adhesion, both the ligand-binding affinity and the spatial organization of integrins must be precisely controlled; how integrins are regulated, however, is not completely understood. Kindlins constitute a family of evolutionarily conserved cytoplasmic components of cell-ECM adhesions that bind to beta-integrin cytoplasmic tails directly and cooperate with talin in integrin activation. In addition, kindlins interact with many components of cell-ECM adhesions--such as migfilin and integrin-linked kinase--to promote cytoskeletal reorganization. Loss of kindlins causes severe defects in integrin signalling, cell-ECM adhesion and cytoskeletal organization, resulting in early embryonic lethality (kindlin-2), postnatal lethality (kindlin-3) and Kindler syndrome (kindlin-1). It is therefore clear that kindlins, together with several other integrin-proximal proteins, are essential for integrin signalling and cell-ECM adhesion regulation.", + "authors": { + "abbreviation": "Hannu Larjava, Edward F Plow, Chuanyue Wu", + "authorList": [ + { + "ForeName": "Hannu", + "LastName": "Larjava", + "abbrevName": "Larjava H", + "email": null, + "isCollectiveName": false, + "name": "Hannu Larjava" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": null, + "isCollectiveName": false, + "name": "Chuanyue Wu" + } + ], + "contacts": [] + }, + "doi": "10.1038/embor.2008.202", + "pmid": "18997731", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "EMBO Rep 9 2008", + "title": "Kindlins: essential regulators of integrin signalling and cell-matrix adhesion." + } + }, + { + "pmid": "18652585", + "pubmed": { + "ISODate": "2008-11-01T00:00:00.000Z", + "abstract": "BACKGROUND: The Kindler syndrome (KS) protein kindlin-1 is a member of a protein complex that links cortical actin to integrins on the surface of basal keratinocytes. Loss of kindlin-1 leads to abnormalities of cell adhesion and motility, and to skin blistering and progressive poikiloderma as clinical symptoms. OBJECTIVES: Here we investigated a severely affected patient, disclosed the mutation that caused the disease and delineated its biological consequences. METHODS: Mutation screening of the kindlin-1 gene, KIND1 (now called FERMT1), was performed with polymerase chain reaction (PCR) amplification of all exons and sequencing. Mutated kindlin-1 was characterized by reverse transcriptase (RT)-PCR and immunoblotting, and genotype-phenotype correlations were analysed using immunohistochemical staining of skin biopsies and keratinocytes from the patient's skin. Cell adhesion and motility were assessed with functional tests. RESULTS: We disclosed a splice site mutation in the first position of intron 13 of the FERMT1 gene, which caused skipping of exon 13. The short transcript partially escaped nonsense-mediated mRNA decay and was translated into a truncated protein. CONCLUSION: A C-terminally truncated kindlin-1 in keratinocytes could not function correctly even if it were expressed.", + "authors": { + "abbreviation": "C Has, R J Ludwig, C Herz, ..., L Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Ludwig", + "abbrevName": "Ludwig RJ", + "email": null, + "isCollectiveName": false, + "name": "R J Ludwig" + }, + { + "ForeName": "C", + "LastName": "Herz", + "abbrevName": "Herz C", + "email": null, + "isCollectiveName": false, + "name": "C Herz" + }, + { + "ForeName": "J", + "LastName": "Kern", + "abbrevName": "Kern JS", + "email": null, + "isCollectiveName": false, + "name": "J S Kern" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "F", + "LastName": "Ochsendorf", + "abbrevName": "Ochsendorf FR", + "email": null, + "isCollectiveName": false, + "name": "F R Ochsendorf" + }, + { + "ForeName": "R", + "LastName": "Kaufmann", + "abbrevName": "Kaufmann R", + "email": null, + "isCollectiveName": false, + "name": "R Kaufmann" + }, + { + "ForeName": "H", + "LastName": "Schumann", + "abbrevName": "Schumann H", + "email": null, + "isCollectiveName": false, + "name": "H Schumann" + }, + { + "ForeName": "J", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "J Kohlhase" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08760.x", + "pmid": "18652585", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 159 2008", + "title": "C-terminally truncated kindlin-1 leads to abnormal adhesion and migration of keratinocytes." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "18454678", + "pubmed": { + "ISODate": "2008-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: The association of aggressive periodontitis with Kindler syndrome was based on a single case in 1996 and later confirmed with a larger population. Since then, significant research has greatly increased our understanding of the molecular pathology of this disorder. We review recent advances in the molecular mechanisms of the syndrome and present a maintenance case report of a patient who has been followed in our clinic. METHODS: A female patient who was diagnosed with Kindler syndrome and aggressive periodontitis at the age of 16 years has been followed and treated in our clinic for 12 years. Her main treatment has been maintenance therapy following her initial treatment and restorative work previously documented. Gingival biopsies obtained during the recent extraction of hopeless maxillary molars were used for histologic assessment of gingival tissue attachment apparatus and to isolate gingival fibroblasts. Reverse transcription-polymerase chain reaction (RT-PCR) was performed using these cells to confirm the lack of expression of kindlin-1. RESULTS: RT-PCR showed the total loss of kindlin-1 mRNA in cultured gingival fibroblasts, supporting the clinical diagnosis of Kindler syndrome. Tissue biopsies revealed atypical pocket epithelium. Maintenance therapy has been moderately successful. Teeth that were recently lost had a poor prognosis at the initial assessment. The patient's gingiva and oral mucosa continue to be fragile with episodes of sloughing and inflammation. CONCLUSIONS: Periodontitis in Kindler syndrome responds to maintenance therapy, but the gingiva and oral mucosa continue to display an abnormal appearance with white patches. Histologic findings suggest that the junctional epithelium in Kindler syndrome may be abnormal and could explain why these patients have periodontal disease. Attachment loss progressed around teeth with an initial guarded or poor prognosis. Teeth that started with a good or fair prognosis continue to have a fair prognosis. Limited dental implant treatment is being considered.", + "authors": { + "abbreviation": "Colin B Wiebe, Giorgio Petricca, Lari Häkkinen, ..., Hannu S Larjava", + "authorList": [ + { + "ForeName": "Colin", + "LastName": "Wiebe", + "abbrevName": "Wiebe CB", + "email": null, + "isCollectiveName": false, + "name": "Colin B Wiebe" + }, + { + "ForeName": "Giorgio", + "LastName": "Petricca", + "abbrevName": "Petricca G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Petricca" + }, + { + "ForeName": "Lari", + "LastName": "Häkkinen", + "abbrevName": "Häkkinen L", + "email": null, + "isCollectiveName": false, + "name": "Lari Häkkinen" + }, + { + "ForeName": "Guoqiao", + "LastName": "Jiang", + "abbrevName": "Jiang G", + "email": null, + "isCollectiveName": false, + "name": "Guoqiao Jiang" + }, + { + "ForeName": "Chuanyue", + "LastName": "Wu", + "abbrevName": "Wu C", + "email": null, + "isCollectiveName": false, + "name": "Chuanyue Wu" + }, + { + "ForeName": "Hannu", + "LastName": "Larjava", + "abbrevName": "Larjava HS", + "email": null, + "isCollectiveName": false, + "name": "Hannu S Larjava" + } + ], + "contacts": [] + }, + "doi": "10.1902/jop.2008.070167", + "pmid": "18454678", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Periodontol 79 2008", + "title": "Kindler syndrome and periodontal disease: review of the literature and a 12-year follow-up case." + } + }, + { + "pmid": "17925226", + "pubmed": { + "ISODate": "2007-10-01T00:00:00.000Z", + "abstract": "Here, we report a direct interaction between the beta1 integrin cytoplasmic tail and Rab25, a GTPase that has been linked to tumor aggressiveness and metastasis. Rab25 promotes a mode of migration on 3D matrices that is characterized by the extension of long pseudopodia, and the association of the GTPase with alpha5beta1 promotes localization of vesicles that deliver integrin to the plasma membrane at pseudopodial tips as well as the retention of a pool of cycling alpha5beta1 at the cell front. Furthermore, Rab25-driven tumor-cell invasion into a 3D extracellular matrix environment is strongly dependent on ligation of fibronectin by alpha5beta1 integrin and the capacity of Rab25 to interact with beta1 integrin. These data indicate that Rab25 contributes to tumor progression by directing the localization of integrin-recycling vesicles and thereby enhancing the ability of tumor cells to invade the extracellular matrix.", + "authors": { + "abbreviation": "Patrick T Caswell, Heather J Spence, Maddy Parsons, ..., Jim C Norman", + "authorList": [ + { + "ForeName": "Patrick", + "LastName": "Caswell", + "abbrevName": "Caswell PT", + "email": null, + "isCollectiveName": false, + "name": "Patrick T Caswell" + }, + { + "ForeName": "Heather", + "LastName": "Spence", + "abbrevName": "Spence HJ", + "email": null, + "isCollectiveName": false, + "name": "Heather J Spence" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Dominic", + "LastName": "White", + "abbrevName": "White DP", + "email": null, + "isCollectiveName": false, + "name": "Dominic P White" + }, + { + "ForeName": "Katherine", + "LastName": "Clark", + "abbrevName": "Clark K", + "email": null, + "isCollectiveName": false, + "name": "Katherine Clark" + }, + { + "ForeName": "Kwai", + "LastName": "Cheng", + "abbrevName": "Cheng KW", + "email": null, + "isCollectiveName": false, + "name": "Kwai Wa Cheng" + }, + { + "ForeName": "Gordon", + "LastName": "Mills", + "abbrevName": "Mills GB", + "email": null, + "isCollectiveName": false, + "name": "Gordon B Mills" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Anthea", + "LastName": "Messent", + "abbrevName": "Messent AJ", + "email": null, + "isCollectiveName": false, + "name": "Anthea J Messent" + }, + { + "ForeName": "Kurt", + "LastName": "Anderson", + "abbrevName": "Anderson KI", + "email": null, + "isCollectiveName": false, + "name": "Kurt I Anderson" + }, + { + "ForeName": "Mary", + "LastName": "McCaffrey", + "abbrevName": "McCaffrey MW", + "email": null, + "isCollectiveName": false, + "name": "Mary W McCaffrey" + }, + { + "ForeName": "Bradford", + "LastName": "Ozanne", + "abbrevName": "Ozanne BW", + "email": null, + "isCollectiveName": false, + "name": "Bradford W Ozanne" + }, + { + "ForeName": "Jim", + "LastName": "Norman", + "abbrevName": "Norman JC", + "email": null, + "isCollectiveName": false, + "name": "Jim C Norman" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2007.08.012", + "pmid": "17925226", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 13 2007", + "title": "Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments." + } + }, + { + "pmid": "17460733", + "pubmed": { + "ISODate": "2007-09-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Joey E Lai-Cheong, Lu Liu, Gomathy Sethuraman, ..., John A McGrath", + "authorList": [ + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "Lu", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "Lu Liu" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Rajesh", + "LastName": "Kumar", + "abbrevName": "Kumar R", + "email": null, + "isCollectiveName": false, + "name": "Rajesh Kumar" + }, + { + "ForeName": "Vinod", + "LastName": "Sharma", + "abbrevName": "Sharma VK", + "email": null, + "isCollectiveName": false, + "name": "Vinod K Sharma" + }, + { + "ForeName": "Siva", + "LastName": "Reddy", + "abbrevName": "Reddy SR", + "email": null, + "isCollectiveName": false, + "name": "Siva R Reddy" + }, + { + "ForeName": "Anders", + "LastName": "Vahlquist", + "abbrevName": "Vahlquist A", + "email": null, + "isCollectiveName": false, + "name": "Anders Vahlquist" + }, + { + "ForeName": "Sandra", + "LastName": "Pather", + "abbrevName": "Pather S", + "email": null, + "isCollectiveName": false, + "name": "Sandra Pather" + }, + { + "ForeName": "Ken", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "Ken Arita" + }, + { + "ForeName": "Vesarat", + "LastName": "Wessagowit", + "abbrevName": "Wessagowit V", + "email": null, + "isCollectiveName": false, + "name": "Vesarat Wessagowit" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.jid.5700830", + "pmid": "17460733", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016420", + "value": "Comment" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 127 2007", + "title": "Five new homozygous mutations in the KIND1 gene in Kindler syndrome." + } + }, + { + "pmid": "17012746", + "pubmed": { + "ISODate": "2006-11-24T00:00:00.000Z", + "abstract": "A novel family of focal adhesion proteins, the kindlins, is involved in attachment of the actin cytoskeleton to the plasma membrane and in integrin-mediated cellular processes. Deficiency of kindlin-1, as a result of loss-of-function mutations in the KIND1 gene, causes Kindler syndrome, an autosomal recessive genodermatosis characterized by skin blistering, progressive skin atrophy, photosensitivity and, occasionally, carcinogenesis. Here we characterized authentic and recombinantly expressed kindlin-1 and show that it is localized in basal epidermal keratinocytes in a polar fashion, close to the cell surface facing the basement membrane, in the areas between the hemidesmosomes. We identified two forms of kindlin-1 in keratinocytes, with apparent molecular masses of 78 and 74 kDa, corresponding to phosphorylated and desphosphorylated forms of the protein. In kindlin-1-deficient skin, basal keratinocytes show multiple abnormalities: cell polarity is lost, proliferation is strongly reduced, and several cells undergo apoptosis. In vitro, deficiency of kindlin-1 in keratinocytes leads to strongly reduced cell proliferation, decreased adhesion, undirected motility, and intense protrusion activity of the plasma membrane. Taken together, these results show that kindlin-1 plays a role in keratinocyte adhesion, polarization, proliferation, and migration. It is involved in organization and anchorage of the actin cytoskeleton to integrin-associated signaling platforms.", + "authors": { + "abbreviation": "Corinna Herz, Monique Aumailley, Carsten Schulte, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Corinna", + "LastName": "Herz", + "abbrevName": "Herz C", + "email": null, + "isCollectiveName": false, + "name": "Corinna Herz" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + }, + { + "ForeName": "Carsten", + "LastName": "Schulte", + "abbrevName": "Schulte C", + "email": null, + "isCollectiveName": false, + "name": "Carsten Schulte" + }, + { + "ForeName": "Ursula", + "LastName": "Schlötzer-Schrehardt", + "abbrevName": "Schlötzer-Schrehardt U", + "email": null, + "isCollectiveName": false, + "name": "Ursula Schlötzer-Schrehardt" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M606259200", + "pmid": "17012746", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 281 2006", + "title": "Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "12789646", + "pubmed": { + "ISODate": "2003-07-01T00:00:00.000Z", + "abstract": "Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed \"KIND1\" [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.", + "authors": { + "abbreviation": "Dawn H Siegel, Gabrielle H S Ashton, Homero G Penagos, ..., Ervin H Epstein", + "authorList": [ + { + "ForeName": "Dawn", + "LastName": "Siegel", + "abbrevName": "Siegel DH", + "email": null, + "isCollectiveName": false, + "name": "Dawn H Siegel" + }, + { + "ForeName": "Gabrielle", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": null, + "isCollectiveName": false, + "name": "Gabrielle H S Ashton" + }, + { + "ForeName": "Homero", + "LastName": "Penagos", + "abbrevName": "Penagos HG", + "email": null, + "isCollectiveName": false, + "name": "Homero G Penagos" + }, + { + "ForeName": "James", + "LastName": "Lee", + "abbrevName": "Lee JV", + "email": null, + "isCollectiveName": false, + "name": "James V Lee" + }, + { + "ForeName": "Heidi", + "LastName": "Feiler", + "abbrevName": "Feiler HS", + "email": null, + "isCollectiveName": false, + "name": "Heidi S Feiler" + }, + { + "ForeName": "Kirk", + "LastName": "Wilhelmsen", + "abbrevName": "Wilhelmsen KC", + "email": null, + "isCollectiveName": false, + "name": "Kirk C Wilhelmsen" + }, + { + "ForeName": "Andrew", + "LastName": "South", + "abbrevName": "South AP", + "email": null, + "isCollectiveName": false, + "name": "Andrew P South" + }, + { + "ForeName": "Frances", + "LastName": "Smith", + "abbrevName": "Smith FJ", + "email": null, + "isCollectiveName": false, + "name": "Frances J D Smith" + }, + { + "ForeName": "Alan", + "LastName": "Prescott", + "abbrevName": "Prescott AR", + "email": null, + "isCollectiveName": false, + "name": "Alan R Prescott" + }, + { + "ForeName": "Vesarat", + "LastName": "Wessagowit", + "abbrevName": "Wessagowit V", + "email": null, + "isCollectiveName": false, + "name": "Vesarat Wessagowit" + }, + { + "ForeName": "Noritaka", + "LastName": "Oyama", + "abbrevName": "Oyama N", + "email": null, + "isCollectiveName": false, + "name": "Noritaka Oyama" + }, + { + "ForeName": "Masashi", + "LastName": "Akiyama", + "abbrevName": "Akiyama M", + "email": null, + "isCollectiveName": false, + "name": "Masashi Akiyama" + }, + { + "ForeName": "Daifullah", + "LastName": "Al Aboud", + "abbrevName": "Al Aboud D", + "email": null, + "isCollectiveName": false, + "name": "Daifullah Al Aboud" + }, + { + "ForeName": "Khalid", + "LastName": "Al Aboud", + "abbrevName": "Al Aboud K", + "email": null, + "isCollectiveName": false, + "name": "Khalid Al Aboud" + }, + { + "ForeName": "Ahmad", + "LastName": "Al Githami", + "abbrevName": "Al Githami A", + "email": null, + "isCollectiveName": false, + "name": "Ahmad Al Githami" + }, + { + "ForeName": "Khalid", + "LastName": "Al Hawsawi", + "abbrevName": "Al Hawsawi K", + "email": null, + "isCollectiveName": false, + "name": "Khalid Al Hawsawi" + }, + { + "ForeName": "Abla", + "LastName": "Al Ismaily", + "abbrevName": "Al Ismaily A", + "email": null, + "isCollectiveName": false, + "name": "Abla Al Ismaily" + }, + { + "ForeName": "Raouf", + "LastName": "Al-Suwaid", + "abbrevName": "Al-Suwaid R", + "email": null, + "isCollectiveName": false, + "name": "Raouf Al-Suwaid" + }, + { + "ForeName": "David", + "LastName": "Atherton", + "abbrevName": "Atherton DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Atherton" + }, + { + "ForeName": "Ruggero", + "LastName": "Caputo", + "abbrevName": "Caputo R", + "email": null, + "isCollectiveName": false, + "name": "Ruggero Caputo" + }, + { + "ForeName": "Jo-David", + "LastName": "Fine", + "abbrevName": "Fine JD", + "email": null, + "isCollectiveName": false, + "name": "Jo-David Fine" + }, + { + "ForeName": "Ilona", + "LastName": "Frieden", + "abbrevName": "Frieden IJ", + "email": null, + "isCollectiveName": false, + "name": "Ilona J Frieden" + }, + { + "ForeName": "Elaine", + "LastName": "Fuchs", + "abbrevName": "Fuchs E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Fuchs" + }, + { + "ForeName": "Richard", + "LastName": "Haber", + "abbrevName": "Haber RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Haber" + }, + { + "ForeName": "Takashi", + "LastName": "Harada", + "abbrevName": "Harada T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Harada" + }, + { + "ForeName": "Yasuo", + "LastName": "Kitajima", + "abbrevName": "Kitajima Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuo Kitajima" + }, + { + "ForeName": "Susan", + "LastName": "Mallory", + "abbrevName": "Mallory SB", + "email": null, + "isCollectiveName": false, + "name": "Susan B Mallory" + }, + { + "ForeName": "Hideoki", + "LastName": "Ogawa", + "abbrevName": "Ogawa H", + "email": null, + "isCollectiveName": false, + "name": "Hideoki Ogawa" + }, + { + "ForeName": "Sedef", + "LastName": "Sahin", + "abbrevName": "Sahin S", + "email": null, + "isCollectiveName": false, + "name": "Sedef Sahin" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + }, + { + "ForeName": "Yasushi", + "LastName": "Suga", + "abbrevName": "Suga Y", + "email": null, + "isCollectiveName": false, + "name": "Yasushi Suga" + }, + { + "ForeName": "Gianluca", + "LastName": "Tadini", + "abbrevName": "Tadini G", + "email": null, + "isCollectiveName": false, + "name": "Gianluca Tadini" + }, + { + "ForeName": "Kikuo", + "LastName": "Tsuchiya", + "abbrevName": "Tsuchiya K", + "email": null, + "isCollectiveName": false, + "name": "Kikuo Tsuchiya" + }, + { + "ForeName": "Colin", + "LastName": "Wiebe", + "abbrevName": "Wiebe CB", + "email": null, + "isCollectiveName": false, + "name": "Colin B Wiebe" + }, + { + "ForeName": "Fenella", + "LastName": "Wojnarowska", + "abbrevName": "Wojnarowska F", + "email": null, + "isCollectiveName": false, + "name": "Fenella Wojnarowska" + }, + { + "ForeName": "Adel", + "LastName": "Zaghloul", + "abbrevName": "Zaghloul AB", + "email": null, + "isCollectiveName": false, + "name": "Adel B Zaghloul" + }, + { + "ForeName": "Takahiro", + "LastName": "Hamada", + "abbrevName": "Hamada T", + "email": null, + "isCollectiveName": false, + "name": "Takahiro Hamada" + }, + { + "ForeName": "Rajeev", + "LastName": "Mallipeddi", + "abbrevName": "Mallipeddi R", + "email": null, + "isCollectiveName": false, + "name": "Rajeev Mallipeddi" + }, + { + "ForeName": "Robin", + "LastName": "Eady", + "abbrevName": "Eady RA", + "email": null, + "isCollectiveName": false, + "name": "Robin A J Eady" + }, + { + "ForeName": "W", + "LastName": "McLean", + "abbrevName": "McLean WH", + "email": null, + "isCollectiveName": false, + "name": "W H Irwin McLean" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Ervin", + "LastName": "Epstein", + "abbrevName": "Epstein EH", + "email": null, + "isCollectiveName": false, + "name": "Ervin H Epstein" + } + ], + "contacts": [] + }, + "doi": "10.1086/376609", + "pmid": "12789646", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Am J Hum Genet 73 2003", + "title": "Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome." + } + }, + { + "pmid": "12754251", + "pubmed": { + "ISODate": "2003-08-01T00:00:00.000Z", + "abstract": "Ligand-induced down-regulation controls the signaling potency of the epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation. However, the role of endogenous Cbl in EGFR down-regulation and the precise step in the endocytic pathway regulated by Cbl remain unclear. Using Cbl-/- mouse embryonic fibroblast cell lines, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and efficient degradation of EGFR. Further analyses using Chinese hamster ovary cells with a temperature-sensitive defect in ubiquitinylation confirm a crucial role of the ubiquitin machinery in Cbl-mediated EGFR degradation. However, internalization into early endosomes did not require Cbl function or an intact ubiquitin pathway. Confocal immunolocalization studies indicated that Cbl-dependent ubiquitinylation plays a critical role at the early endosome to late endosome/lysosome sorting step of EGFR down-regulation. These findings establish Cbl as the major endogenous ubiquitin ligase responsible for EGFR degradation, and show that the critical role of Cbl-mediated ubiquitinylation is at the level of endosomal sorting, rather than at the level of internalization.", + "authors": { + "abbreviation": "Lei Duan, Yuko Miura, Manjari Dimri, ..., Hamid Band", + "authorList": [ + { + "ForeName": "Lei", + "LastName": "Duan", + "abbrevName": "Duan L", + "email": null, + "isCollectiveName": false, + "name": "Lei Duan" + }, + { + "ForeName": "Yuko", + "LastName": "Miura", + "abbrevName": "Miura Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Miura" + }, + { + "ForeName": "Manjari", + "LastName": "Dimri", + "abbrevName": "Dimri M", + "email": null, + "isCollectiveName": false, + "name": "Manjari Dimri" + }, + { + "ForeName": "Biswanath", + "LastName": "Majumder", + "abbrevName": "Majumder B", + "email": null, + "isCollectiveName": false, + "name": "Biswanath Majumder" + }, + { + "ForeName": "Ingrid", + "LastName": "Dodge", + "abbrevName": "Dodge IL", + "email": null, + "isCollectiveName": false, + "name": "Ingrid L Dodge" + }, + { + "ForeName": "Alagarsamy", + "LastName": "Reddi", + "abbrevName": "Reddi AL", + "email": null, + "isCollectiveName": false, + "name": "Alagarsamy L Reddi" + }, + { + "ForeName": "Amiya", + "LastName": "Ghosh", + "abbrevName": "Ghosh A", + "email": null, + "isCollectiveName": false, + "name": "Amiya Ghosh" + }, + { + "ForeName": "Norvin", + "LastName": "Fernandes", + "abbrevName": "Fernandes N", + "email": null, + "isCollectiveName": false, + "name": "Norvin Fernandes" + }, + { + "ForeName": "Pengcheng", + "LastName": "Zhou", + "abbrevName": "Zhou P", + "email": null, + "isCollectiveName": false, + "name": "Pengcheng Zhou" + }, + { + "ForeName": "Karen", + "LastName": "Mullane-Robinson", + "abbrevName": "Mullane-Robinson K", + "email": null, + "isCollectiveName": false, + "name": "Karen Mullane-Robinson" + }, + { + "ForeName": "Navin", + "LastName": "Rao", + "abbrevName": "Rao N", + "email": null, + "isCollectiveName": false, + "name": "Navin Rao" + }, + { + "ForeName": "Stephen", + "LastName": "Donoghue", + "abbrevName": "Donoghue S", + "email": null, + "isCollectiveName": false, + "name": "Stephen Donoghue" + }, + { + "ForeName": "Rick", + "LastName": "Rogers", + "abbrevName": "Rogers RA", + "email": null, + "isCollectiveName": false, + "name": "Rick A Rogers" + }, + { + "ForeName": "David", + "LastName": "Bowtell", + "abbrevName": "Bowtell D", + "email": null, + "isCollectiveName": false, + "name": "David Bowtell" + }, + { + "ForeName": "Mayumi", + "LastName": "Naramura", + "abbrevName": "Naramura M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Naramura" + }, + { + "ForeName": "Hua", + "LastName": "Gu", + "abbrevName": "Gu H", + "email": null, + "isCollectiveName": false, + "name": "Hua Gu" + }, + { + "ForeName": "Vimla", + "LastName": "Band", + "abbrevName": "Band V", + "email": null, + "isCollectiveName": false, + "name": "Vimla Band" + }, + { + "ForeName": "Hamid", + "LastName": "Band", + "abbrevName": "Band H", + "email": null, + "isCollectiveName": false, + "name": "Hamid Band" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M304474200", + "pmid": "12754251", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 278 2003", + "title": "Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis." + } + }, + { + "pmid": "12717446", + "pubmed": { + "ISODate": "2003-05-01T00:00:00.000Z", + "abstract": "The epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase (RTK) superfamily and is involved in regulating cell proliferation, differentiation and motility. Growth factor binding induces receptor oligomerization at the plasma membrane, which leads to activation of the intrinsic RTK activity and trans-phosphorylation of tyrosine residues in the intracellular part of the receptor. These residues are docking sites for proteins containing Src homology domain 2 and phosphotyrosine-binding domains that relay the signal inside the cell. In response to EGF attached to beads, lateral propagation of EGFR phosphorylation occurs at the plasma membrane, representing an early amplification step in EGFR signalling. Here we have investigated an underlying reaction network that couples RTK activity to protein tyrosine phosphatase (PTP) inhibition by reactive oxygen species. Mathematical analysis of the chemical kinetic equations of the minimal reaction network detects general properties of this system that can be observed experimentally by imaging EGFR phosphorylation in cells. The existence of a bistable state in this reaction network explains a threshold response and how a high proportion of phosphorylated receptors can be maintained in plasma membrane regions that are not exposed to ligand.", + "authors": { + "abbreviation": "Andrew R Reynolds, Christian Tischer, Peter J Verveer, ..., Philippe I H Bastiaens", + "authorList": [ + { + "ForeName": "Andrew", + "LastName": "Reynolds", + "abbrevName": "Reynolds AR", + "email": null, + "isCollectiveName": false, + "name": "Andrew R Reynolds" + }, + { + "ForeName": "Christian", + "LastName": "Tischer", + "abbrevName": "Tischer C", + "email": null, + "isCollectiveName": false, + "name": "Christian Tischer" + }, + { + "ForeName": "Peter", + "LastName": "Verveer", + "abbrevName": "Verveer PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Verveer" + }, + { + "ForeName": "Oliver", + "LastName": "Rocks", + "abbrevName": "Rocks O", + "email": null, + "isCollectiveName": false, + "name": "Oliver Rocks" + }, + { + "ForeName": "Philippe", + "LastName": "Bastiaens", + "abbrevName": "Bastiaens PI", + "email": null, + "isCollectiveName": false, + "name": "Philippe I H Bastiaens" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb981", + "pmid": "12717446", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 5 2003", + "title": "EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation." + } + }, + { + "pmid": "12668616", + "pubmed": { + "ISODate": "2003-04-15T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare autosomal-recessive genodermatosis characterized by bullous poikiloderma with photosensitivity. We report the localization to chromosome 20p12.3 by homozygosity mapping and the identification of a new gene, which we propose to name kindlerin. We found four different homozygous mutations in four consanguineous families from North Africa and Senegal; three are expected to lead to premature stop codons and truncated proteins and the fourth involves a splice site. We were unable to identify a mutation in kindlerin in a fifth consanguineous family from Algeria with a similar phenotype and in which the patient was homozygous for the markers in the 20p12.3 interval. The kindlerin protein contains several domains which are shared by a diverse group of peripheral membrane proteins that function as membrane-cytoskeleton linkers: two regions homologous to band 4.1 domain of which one includes a FERM domain with a NPKY sequence motif, and a third region with a PH or pleckstrin homology domain. Kindlerin might be involved in the bidirectional signaling between integrin molecules in the membrane and the cytoskeleton, and could be involved in cell adhesion processes via integrin signaling.", + "authors": { + "abbreviation": "Florence Jobard, Bakar Bouadjar, Frédéric Caux, ..., Judith Fischer", + "authorList": [ + { + "ForeName": "Florence", + "LastName": "Jobard", + "abbrevName": "Jobard F", + "email": null, + "isCollectiveName": false, + "name": "Florence Jobard" + }, + { + "ForeName": "Bakar", + "LastName": "Bouadjar", + "abbrevName": "Bouadjar B", + "email": null, + "isCollectiveName": false, + "name": "Bakar Bouadjar" + }, + { + "ForeName": "Frédéric", + "LastName": "Caux", + "abbrevName": "Caux F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Caux" + }, + { + "ForeName": "Smail", + "LastName": "Hadj-Rabia", + "abbrevName": "Hadj-Rabia S", + "email": null, + "isCollectiveName": false, + "name": "Smail Hadj-Rabia" + }, + { + "ForeName": "Christina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Christina Has" + }, + { + "ForeName": "Fumi", + "LastName": "Matsuda", + "abbrevName": "Matsuda F", + "email": null, + "isCollectiveName": false, + "name": "Fumi Matsuda" + }, + { + "ForeName": "Jean", + "LastName": "Weissenbach", + "abbrevName": "Weissenbach J", + "email": null, + "isCollectiveName": false, + "name": "Jean Weissenbach" + }, + { + "ForeName": "Mark", + "LastName": "Lathrop", + "abbrevName": "Lathrop M", + "email": null, + "isCollectiveName": false, + "name": "Mark Lathrop" + }, + { + "ForeName": "Jean-François", + "LastName": "Prud'homme", + "abbrevName": "Prud'homme JF", + "email": null, + "isCollectiveName": false, + "name": "Jean-François Prud'homme" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddg097", + "pmid": "12668616", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mol Genet 12 2003", + "title": "Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome." + } + } + ], + "relatedPapers": [ + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2022-02-13T11:20:18.247Z", + "_newestOpId": "100998dd-3d29-4b28-8e63-02e1349340d5", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "607900" + }, + { + "db": "HGNC", + "id": "HGNC:15889" + }, + { + "db": "Ensembl", + "id": "ENSG00000101311" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.754701, + "id": "55612", + "name": "FERMT1", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200100, + "shortSynonyms": [ + "FERMT1", + "C20orf42", + "DTGCU2", + "KIND1", + "UNC112A", + "URP1", + "kindlin 1", + "kindlerin", + "kindlin syndrome protein", + "FERM domain containing kindlin 1", + "unc-112-related protein 1" + ], + "synonyms": [ + "C20orf42", + "DTGCU2", + "KIND1", + "UNC112A", + "URP1", + "fermitin family homolog 1", + "UNC112 related protein 1", + "fermitin family member 1", + "kindlerin", + "kindlin 1", + "kindlin syndrome protein", + "unc-112-related protein 1", + "FERM domain containing kindlin 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "1df25530-cd6f-45b9-8e4a-246651c639e3", + "liveId": "8f17b1de-eb8f-4df1-a52f-f37f1ba64ba7", + "lock": null, + "locked": false, + "name": "Kindlin-1", + "position": { + "x": 164.0506329113924, + "y": 100.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + }, + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-13T11:20:36.940Z", + "_newestOpId": "4ba689a9-b813-4399-ba3b-ee46ffd10070", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "1df25530-cd6f-45b9-8e4a-246651c639e3" + }, + { + "group": "unsigned", + "id": "95c4cbb1-bdff-473e-9203-8ebca2d44747" + } + ], + "id": "f4b557ff-2219-45a8-bffb-5b7691e6b6bd", + "liveId": "d3295da6-d497-4e45-8e1c-88ef00cd0322", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-13T11:20:27.354Z", + "_newestOpId": "5270a386-72a2-46a4-931d-a3d5a297cb50", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "131550" + }, + { + "db": "HGNC", + "id": "HGNC:3236" + }, + { + "db": "Ensembl", + "id": "ENSG00000146648" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.857173, + "formulae": null, + "id": "1956", + "inchi": null, + "inchiKey": null, + "mass": null, + "monoisotopicMass": null, + "name": "EGFR", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "ERBB", + "ERBB1", + "ERRP", + "HER1", + "NISBD2", + "EGFR vIII", + "cell proliferation-inducing protein 61", + "epidermal growth factor receptor", + "PIG61", + "proto-oncogene c-ErbB-1" + ], + "summary": null, + "synonyms": [ + "ERBB", + "ERBB1", + "ERRP", + "HER1", + "NISBD2", + "PIG61", + "mENA", + "epidermal growth factor receptor", + "EGFR vIII", + "avian erythroblastic leukemia viral (v-erb-b) oncogene homolog", + "cell growth inhibiting protein 40", + "cell proliferation-inducing protein 61", + "epidermal growth factor receptor tyrosine kinase domain", + "erb-b2 receptor tyrosine kinase 1", + "proto-oncogene c-ErbB-1", + "receptor tyrosine-protein kinase erbB-1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "95c4cbb1-bdff-473e-9203-8ebca2d44747", + "liveId": "aac0431d-6675-4130-9a22-d637502f0320", + "lock": null, + "locked": false, + "name": "EGFR", + "position": { + "x": 250.126582278481, + "y": 127.59493670886076 + }, + "relatedPapers": [ + { + "pmid": "21146372", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. OBJECTIVE: To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. METHODS: Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. RESULTS: Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. CONCLUSION: This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive.", + "authors": { + "abbreviation": "Ken Natsuga, Wataru Nishie, Satoru Shinkuma, ..., Hiroshi Shimizu", + "authorList": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "abbrevName": "Natsuga K", + "email": "natsuga@med.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ken Natsuga" + }, + { + "ForeName": "Wataru", + "LastName": "Nishie", + "abbrevName": "Nishie W", + "email": null, + "isCollectiveName": false, + "name": "Wataru Nishie" + }, + { + "ForeName": "Satoru", + "LastName": "Shinkuma", + "abbrevName": "Shinkuma S", + "email": null, + "isCollectiveName": false, + "name": "Satoru Shinkuma" + }, + { + "ForeName": "Hideki", + "LastName": "Nakamura", + "abbrevName": "Nakamura H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Nakamura" + }, + { + "ForeName": "Yoichiro", + "LastName": "Matsushima", + "abbrevName": "Matsushima Y", + "email": null, + "isCollectiveName": false, + "name": "Yoichiro Matsushima" + }, + { + "ForeName": "Aya", + "LastName": "Tatsuta", + "abbrevName": "Tatsuta A", + "email": null, + "isCollectiveName": false, + "name": "Aya Tatsuta" + }, + { + "ForeName": "Mayumi", + "LastName": "Komine", + "abbrevName": "Komine M", + "email": null, + "isCollectiveName": false, + "name": "Mayumi Komine" + }, + { + "ForeName": "Hiroshi", + "LastName": "Shimizu", + "abbrevName": "Shimizu H", + "email": null, + "isCollectiveName": false, + "name": "Hiroshi Shimizu" + } + ], + "contacts": [ + { + "ForeName": "Ken", + "LastName": "Natsuga", + "email": [ + "natsuga@med.hokudai.ac.jp" + ], + "name": "Ken Natsuga" + } + ] + }, + "doi": "10.1016/j.jdermsci.2010.11.008", + "pmid": "21146372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol Sci 61 2011", + "title": "Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome." + } + }, + { + "pmid": "25156791", + "pubmed": { + "ISODate": "2015-09-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity. ", + "authors": { + "abbreviation": "C Has, N Chmel, L Levati, ..., D Castiglia", + "authorList": [ + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "N", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "N Chmel" + }, + { + "ForeName": "L", + "LastName": "Levati", + "abbrevName": "Levati L", + "email": null, + "isCollectiveName": false, + "name": "L Levati" + }, + { + "ForeName": "I", + "LastName": "Neri", + "abbrevName": "Neri I", + "email": null, + "isCollectiveName": false, + "name": "I Neri" + }, + { + "ForeName": "T", + "LastName": "Sonnenwald", + "abbrevName": "Sonnenwald T", + "email": null, + "isCollectiveName": false, + "name": "T Sonnenwald" + }, + { + "ForeName": "M", + "LastName": "Pigors", + "abbrevName": "Pigors M", + "email": null, + "isCollectiveName": false, + "name": "M Pigors" + }, + { + "ForeName": "K", + "LastName": "Godbole", + "abbrevName": "Godbole K", + "email": null, + "isCollectiveName": false, + "name": "K Godbole" + }, + { + "ForeName": "A", + "LastName": "Dudhbhate", + "abbrevName": "Dudhbhate A", + "email": null, + "isCollectiveName": false, + "name": "A Dudhbhate" + }, + { + "ForeName": "L", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "L Bruckner-Tuderman" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/cge.12490", + "pmid": "25156791", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Clin Genet 88 2015", + "title": "FERMT1 promoter mutations in patients with Kindler syndrome." + } + }, + { + "pmid": "29384271", + "pubmed": { + "ISODate": "2018-03-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Mina Saleva, Cristina Has, Yinghong He, ..., Lubka Miteva", + "authorList": [ + { + "ForeName": "Mina", + "LastName": "Saleva", + "abbrevName": "Saleva M", + "email": null, + "isCollectiveName": false, + "name": "Mina Saleva" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Snejina", + "LastName": "Vassileva", + "abbrevName": "Vassileva S", + "email": null, + "isCollectiveName": false, + "name": "Snejina Vassileva" + }, + { + "ForeName": "Maria", + "LastName": "Balabanova", + "abbrevName": "Balabanova M", + "email": null, + "isCollectiveName": false, + "name": "Maria Balabanova" + }, + { + "ForeName": "Lubka", + "LastName": "Miteva", + "abbrevName": "Miteva L", + "email": null, + "isCollectiveName": false, + "name": "Lubka Miteva" + } + ], + "contacts": [] + }, + "doi": "10.1111/ddg.13435", + "pmid": "29384271", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Dtsch Dermatol Ges 16 2018", + "title": "Natural history of Kindler syndrome and propensity for skin cancer - case report and literature review." + } + }, + { + "pmid": "26375235", + "pubmed": { + "ISODate": null, + "abstract": "A typical feature of Kindler Syndrome is skin fragility; this condition in currently classified as a form of epidermolysis bullosa. We describe a rarely reported feature of two cases, one sporadic and one familial; both patients noticed acquired adermatoglyphia. The loss of dermatoglyphics could be an additional feature of this syndrome. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Fernanda Mendes Goetze, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Fernanda", + "LastName": "Goetze", + "abbrevName": "Goetze FM", + "email": null, + "isCollectiveName": false, + "name": "Fernanda Mendes Goetze" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20153501", + "pmid": "26375235", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 90", + "title": "Is adermatoglyphia an additional feature of Kindler Syndrome?" + } + }, + { + "pmid": "24346923", + "pubmed": { + "ISODate": null, + "abstract": "We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. ", + "authors": { + "abbreviation": "Hiram Larangeira de Almeida, Gláucia Thomas Heckler, Kenneth Fong, ..., John McGrath", + "authorList": [ + { + "ForeName": "Hiram", + "LastName": "Almeida", + "abbrevName": "Almeida HL", + "email": null, + "isCollectiveName": false, + "name": "Hiram Larangeira de Almeida" + }, + { + "ForeName": "Gláucia", + "LastName": "Heckler", + "abbrevName": "Heckler GT", + "email": null, + "isCollectiveName": false, + "name": "Gláucia Thomas Heckler" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong J", + "email": null, + "isCollectiveName": false, + "name": "Joey Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath J", + "email": null, + "isCollectiveName": false, + "name": "John McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1590/abd1806-4841.20132173", + "pmid": "24346923", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "An Bras Dermatol 88", + "title": "Sporadic Kindler syndrome with a novel mutation." + } + }, + { + "pmid": "25865288", + "pubmed": { + "ISODate": "2016-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "D Kartal, M Borlu, C Has, R Fölster-Holst", + "authorList": [ + { + "ForeName": "D", + "LastName": "Kartal", + "abbrevName": "Kartal D", + "email": null, + "isCollectiveName": false, + "name": "D Kartal" + }, + { + "ForeName": "M", + "LastName": "Borlu", + "abbrevName": "Borlu M", + "email": null, + "isCollectiveName": false, + "name": "M Borlu" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "R", + "LastName": "Fölster-Holst", + "abbrevName": "Fölster-Holst R", + "email": null, + "isCollectiveName": false, + "name": "R Fölster-Holst" + } + ], + "contacts": [] + }, + "doi": "10.1111/jdv.13163", + "pmid": "25865288", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Eur Acad Dermatol Venereol 30 2016", + "title": "A novel mutation in the FERMT1 gene in Turkish siblings with Kindler syndrome." + } + }, + { + "pmid": "21309038", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS.", + "authors": { + "abbreviation": "Anja Heinemann, Yinghong He, Elena Zimina, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Elena", + "LastName": "Zimina", + "abbrevName": "Zimina E", + "email": null, + "isCollectiveName": false, + "name": "Elena Zimina" + }, + { + "ForeName": "Melanie", + "LastName": "Boerries", + "abbrevName": "Boerries M", + "email": null, + "isCollectiveName": false, + "name": "Melanie Boerries" + }, + { + "ForeName": "Hauke", + "LastName": "Busch", + "abbrevName": "Busch H", + "email": null, + "isCollectiveName": false, + "name": "Hauke Busch" + }, + { + "ForeName": "Nadja", + "LastName": "Chmel", + "abbrevName": "Chmel N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Chmel" + }, + { + "ForeName": "Thorsten", + "LastName": "Kurz", + "abbrevName": "Kurz T", + "email": null, + "isCollectiveName": false, + "name": "Thorsten Kurz" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21449", + "pmid": "21309038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Induction of phenotype modifying cytokines by FERMT1 mutations." + } + }, + { + "pmid": "31957900", + "pubmed": { + "ISODate": "2020-03-01T00:00:00.000Z", + "abstract": "BACKGROUND: Kindler syndrome is a rare genodermatosis. Major clinical criteria include acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. METHODS: FERMT1 gene was sequenced in 5 patients with a clinical diagnosis of Kindler syndrome. RESULTS: We report a novel pathogenic variant detected in four unrelated families of Paraguayan origin, where one nucleotide deletion in FERMT1 gene (c.450delG) is predicted to cause a frameshift mutation leading to loss of function. Haplotype analysis revealed the propagation of an ancestral allele through this population. CONCLUSIONS: The identification of this recurrent pathogenic variant enables optimization of molecular detection strategies in our patients, reducing the cost of diagnosis.", + "authors": { + "abbreviation": "Laura Elena Valinotto, Mónica Inés Natale, Silvina Beatriz Lusso, ..., Graciela Beatriz Manzur", + "authorList": [ + { + "ForeName": "Laura", + "LastName": "Valinotto", + "abbrevName": "Valinotto LE", + "email": null, + "isCollectiveName": false, + "name": "Laura Elena Valinotto" + }, + { + "ForeName": "Mónica", + "LastName": "Natale", + "abbrevName": "Natale MI", + "email": null, + "isCollectiveName": false, + "name": "Mónica Inés Natale" + }, + { + "ForeName": "Silvina", + "LastName": "Lusso", + "abbrevName": "Lusso SB", + "email": null, + "isCollectiveName": false, + "name": "Silvina Beatriz Lusso" + }, + { + "ForeName": "Eliana", + "LastName": "Cella", + "abbrevName": "Cella E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Cella" + }, + { + "ForeName": "Olga", + "LastName": "Gutiérrez", + "abbrevName": "Gutiérrez O", + "email": null, + "isCollectiveName": false, + "name": "Olga Gutiérrez" + }, + { + "ForeName": "Fernando", + "LastName": "Sebastiani", + "abbrevName": "Sebastiani F", + "email": null, + "isCollectiveName": false, + "name": "Fernando Sebastiani" + }, + { + "ForeName": "Graciela", + "LastName": "Manzur", + "abbrevName": "Manzur GB", + "email": null, + "isCollectiveName": false, + "name": "Graciela Beatriz Manzur" + } + ], + "contacts": [] + }, + "doi": "10.1111/pde.14076", + "pmid": "31957900", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Pediatr Dermatol 37 2020", + "title": "A novel pathogenic FERMT1 variant in four families with Kindler syndrome in Argentina." + } + }, + { + "pmid": "22220914", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Pakeeza A Shaiq, Alfred Klausegger, Fawad Muzaffar, ..., Ghazala K Raja", + "authorList": [ + { + "ForeName": "Pakeeza", + "LastName": "Shaiq", + "abbrevName": "Shaiq PA", + "email": null, + "isCollectiveName": false, + "name": "Pakeeza A Shaiq" + }, + { + "ForeName": "Alfred", + "LastName": "Klausegger", + "abbrevName": "Klausegger A", + "email": null, + "isCollectiveName": false, + "name": "Alfred Klausegger" + }, + { + "ForeName": "Fawad", + "LastName": "Muzaffar", + "abbrevName": "Muzaffar F", + "email": null, + "isCollectiveName": false, + "name": "Fawad Muzaffar" + }, + { + "ForeName": "Johann", + "LastName": "Bauer", + "abbrevName": "Bauer JW", + "email": null, + "isCollectiveName": false, + "name": "Johann W Bauer" + }, + { + "ForeName": "Muhammad", + "LastName": "Khan", + "abbrevName": "Khan MI", + "email": null, + "isCollectiveName": false, + "name": "Muhammad I Khan" + }, + { + "ForeName": "Azra", + "LastName": "Khanum", + "abbrevName": "Khanum A", + "email": null, + "isCollectiveName": false, + "name": "Azra Khanum" + }, + { + "ForeName": "Raheel", + "LastName": "Qamar", + "abbrevName": "Qamar R", + "email": null, + "isCollectiveName": false, + "name": "Raheel Qamar" + }, + { + "ForeName": "Ghazala", + "LastName": "Raja", + "abbrevName": "Raja GK", + "email": null, + "isCollectiveName": false, + "name": "Ghazala K Raja" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2011.01464.x", + "pmid": "22220914", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Founder mutation c.676insC in three unrelated Kindler syndrome families belonging to a particular clan from Pakistan." + } + }, + { + "pmid": "22672060", + "pubmed": { + "ISODate": "2012-12-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Makoto Wada, Koji Masuda, Daisuke Tsuruta, ..., Norito Katoh", + "authorList": [ + { + "ForeName": "Makoto", + "LastName": "Wada", + "abbrevName": "Wada M", + "email": null, + "isCollectiveName": false, + "name": "Makoto Wada" + }, + { + "ForeName": "Koji", + "LastName": "Masuda", + "abbrevName": "Masuda K", + "email": null, + "isCollectiveName": false, + "name": "Koji Masuda" + }, + { + "ForeName": "Daisuke", + "LastName": "Tsuruta", + "abbrevName": "Tsuruta D", + "email": null, + "isCollectiveName": false, + "name": "Daisuke Tsuruta" + }, + { + "ForeName": "Katsuto", + "LastName": "Tamai", + "abbrevName": "Tamai K", + "email": null, + "isCollectiveName": false, + "name": "Katsuto Tamai" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Norito", + "LastName": "Katoh", + "abbrevName": "Katoh N", + "email": null, + "isCollectiveName": false, + "name": "Norito Katoh" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1346-8138.2012.01598.x", + "pmid": "22672060", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "J Dermatol 39 2012", + "title": "Case of Kindler syndrome resulting from mutation in the FERMT1 gene." + } + }, + { + "pmid": "21936020", + "pubmed": { + "ISODate": "2011-11-01T00:00:00.000Z", + "abstract": "Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.", + "authors": { + "abbreviation": "Cristina Has, Daniele Castiglia, Marcela del Rio, ..., Leena Bruckner-Tuderman", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Daniele", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "Daniele Castiglia" + }, + { + "ForeName": "Marcela", + "LastName": "del Rio", + "abbrevName": "del Rio M", + "email": null, + "isCollectiveName": false, + "name": "Marcela del Rio" + }, + { + "ForeName": "Marta", + "LastName": "Diez", + "abbrevName": "Diez MG", + "email": null, + "isCollectiveName": false, + "name": "Marta Garcia Diez" + }, + { + "ForeName": "Eugenia", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Piccinni" + }, + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Peter", + "LastName": "Itin", + "abbrevName": "Itin P", + "email": null, + "isCollectiveName": false, + "name": "Peter Itin" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Judith", + "LastName": "Fischer", + "abbrevName": "Fischer J", + "email": null, + "isCollectiveName": false, + "name": "Judith Fischer" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + } + ], + "contacts": [] + }, + "doi": "10.1002/humu.21576", + "pmid": "21936020", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Hum Mutat 32 2011", + "title": "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history." + } + }, + { + "pmid": "30414177", + "pubmed": { + "ISODate": "2019-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Ruri Fukushi, Ryoji Tsuboi, Tatsuo Maeda, ..., Kazutoshi Harada", + "authorList": [ + { + "ForeName": "Ruri", + "LastName": "Fukushi", + "abbrevName": "Fukushi R", + "email": null, + "isCollectiveName": false, + "name": "Ruri Fukushi" + }, + { + "ForeName": "Ryoji", + "LastName": "Tsuboi", + "abbrevName": "Tsuboi R", + "email": null, + "isCollectiveName": false, + "name": "Ryoji Tsuboi" + }, + { + "ForeName": "Tatsuo", + "LastName": "Maeda", + "abbrevName": "Maeda T", + "email": null, + "isCollectiveName": false, + "name": "Tatsuo Maeda" + }, + { + "ForeName": "Yasuhiro", + "LastName": "Kanda", + "abbrevName": "Kanda Y", + "email": null, + "isCollectiveName": false, + "name": "Yasuhiro Kanda" + }, + { + "ForeName": "Noriyasu", + "LastName": "Sakai", + "abbrevName": "Sakai N", + "email": null, + "isCollectiveName": false, + "name": "Noriyasu Sakai" + }, + { + "ForeName": "Shinji", + "LastName": "Suzuki", + "abbrevName": "Suzuki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Suzuki" + }, + { + "ForeName": "Kazutoshi", + "LastName": "Harada", + "abbrevName": "Harada K", + "email": null, + "isCollectiveName": false, + "name": "Kazutoshi Harada" + } + ], + "contacts": [] + }, + "doi": "10.1111/ijd.14288", + "pmid": "30414177", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Int J Dermatol 58 2019", + "title": "A case of Kindler syndrome in a young Indian female with exon deletion." + } + }, + { + "pmid": "28501563", + "pubmed": { + "ISODate": "2017-07-01T00:00:00.000Z", + "abstract": "Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to β-integrin subunits and is required for integrin activation. Loss of function mutations in the FERMT1 gene which encodes Kindlin-1 leads to the development of Kindler Syndrome (KS) an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, and predisposition to aggressive squamous cell carcinoma (SCC). Here we show that loss of Kindlin-1 sensitizes both SCC cells and keratinocytes to oxidative stress: Kindlin-1 deficient cells have higher levels of reactive oxygen species, decreased viability and increased DNA damage after treatment with either hydrogen peroxide (H2O2) or irradiation with UVA. We show that Kindlin-1 is required to fully activate ERK signalling after oxidative damage, and that activation of ERK protects cells from DNA damage following oxidative stress: inhibition of ERK activation sensitizes Kindlin-1 expressing cells, but not Kindlin-1 deficient cells to oxidative stress. Finally we demonstrate that the Kindlin-1 dependent activation of ERK and protection from DNA damage following oxidative stress depends on the ability of Kindlin-1 to bind integrins. Thus loss of Kindlin-1 leads to an imbalance in the cellular oxidative state, which renders Kindlin-1 deficient cells more prone to the effects of ROS generated in response to oxidative stress. We propose that Kindlin-1 dependent activation of ERK signalling is a key molecular mechanism that renders KS keratinocytes more sensitive to oxidative damage and contributes to the increased photosensitivity in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Hitesh Patel, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Hitesh", + "LastName": "Patel", + "abbrevName": "Patel H", + "email": null, + "isCollectiveName": false, + "name": "Hitesh Patel" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": "v.brunton@ed.ac.uk", + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [ + { + "ForeName": "Valerie", + "LastName": "Brunton", + "email": [ + "v.brunton@ed.ac.uk" + ], + "name": "Valerie G Brunton" + } + ] + }, + "doi": "10.1016/j.freeradbiomed.2017.05.013", + "pmid": "28501563", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Free Radic Biol Med 108 2017", + "title": "Kindlin-1 protects cells from oxidative damage through activation of ERK signalling." + } + }, + { + "pmid": "28690212", + "pubmed": { + "ISODate": "2017-06-01T00:00:00.000Z", + "abstract": "Focal adhesions are large multiprotein cell-matrix adhesion complexes, which regulate multiple cellular functions, such as adhesion and migration. Their biological significance in skin is underscored by two genetic disorders, the Kindler syndrome and the interstitial lung disease, nephrotic syndrome and epidermolysis bullosa, in which mutations affect focal adhesion proteins, kindlin-1 and the integrin α3 subunit, respectively. Here we provide an overview of what we learned from the study of the molecular mechanisms of these diseases. Emphasis is put on the point of view of the clinician dermatologist.", + "authors": { + "abbreviation": "Cristina Has, Yinghong He", + "authorList": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + } + ], + "contacts": [] + }, + "doi": "10.1684/ejd.2017.3039", + "pmid": "28690212", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Eur J Dermatol 27 2017", + "title": "Focal adhesions in the skin: lessons learned from skin fragility disorders." + } + }, + { + "pmid": "18528435", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.", + "authors": { + "abbreviation": "J E Lai-Cheong, S Ussar, K Arita, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "S", + "LastName": "Ussar", + "abbrevName": "Ussar S", + "email": null, + "isCollectiveName": false, + "name": "S Ussar" + }, + { + "ForeName": "K", + "LastName": "Arita", + "abbrevName": "Arita K", + "email": null, + "isCollectiveName": false, + "name": "K Arita" + }, + { + "ForeName": "I", + "LastName": "Hart", + "abbrevName": "Hart IR", + "email": null, + "isCollectiveName": false, + "name": "I R Hart" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1038/jid.2008.58", + "pmid": "18528435", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 128 2008", + "title": "Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome." + } + }, + { + "pmid": "31260568", + "pubmed": { + "ISODate": "2019-09-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering and photosensitivity. KS is caused by loss of function mutations in FERMT1, which encodes Kindlin-1. Kindlin-1 is a FERM domain containing adaptor protein that is found predominantly at cell-extracellular matrix adhesions where it binds to integrin β subunits and is required for efficient integrin activation. Using keratinocytes derived from a patient with KS, into which wild-type Kindlin-1 (Kin1WT) has been expressed, we show that Kindlin-1 binds to cyclin-dependent kinase (CDK)1 and CDK2. CDK1 and CDK2 are key regulators of cell cycle progression, however, cell cycle analysis showed only small differences between the KS and KS-Kin1WT keratinocytes. In contrast, G2/M cell cycle arrest in response to oxidative stress induced by hydrogen peroxide (H2 O2 ) was enhanced in KS keratinocytes but not KS-Kin1WT cells, following inhibition of CDK activity. Furthermore, KS keratinocytes were more sensitive to DNA damage in response to H2 O2 and this was exacerbated by treatment with the CDK inhibitor roscovitine. Thus, in Kindlin-1 deficient keratinocytes, CDK activity can further regulate oxidative damage induced cell cycle arrest and DNA damage. This provides further insight into the key pathways that control sensitivity to oxidative stress in KS patients.", + "authors": { + "abbreviation": "Hila Emmert, Jayne Culley, Valerie G Brunton", + "authorList": [ + { + "ForeName": "Hila", + "LastName": "Emmert", + "abbrevName": "Emmert H", + "email": null, + "isCollectiveName": false, + "name": "Hila Emmert" + }, + { + "ForeName": "Jayne", + "LastName": "Culley", + "abbrevName": "Culley J", + "email": null, + "isCollectiveName": false, + "name": "Jayne Culley" + }, + { + "ForeName": "Valerie", + "LastName": "Brunton", + "abbrevName": "Brunton VG", + "email": null, + "isCollectiveName": false, + "name": "Valerie G Brunton" + } + ], + "contacts": [] + }, + "doi": "10.1111/exd.14000", + "pmid": "31260568", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Dermatol 28 2019", + "title": "Inhibition of cyclin-dependent kinase activity exacerbates H2 O2 -induced DNA damage in Kindler syndrome keratinocytes." + } + }, + { + "pmid": "26827766", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Philipp R Esser, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Kerstin", + "LastName": "Thriene", + "abbrevName": "Thriene K", + "email": null, + "isCollectiveName": false, + "name": "Kerstin Thriene" + }, + { + "ForeName": "Daniela", + "LastName": "Sarca", + "abbrevName": "Sarca D", + "email": null, + "isCollectiveName": false, + "name": "Daniela Sarca" + }, + { + "ForeName": "Jürgen", + "LastName": "Kohlhase", + "abbrevName": "Kohlhase J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Kohlhase" + }, + { + "ForeName": "Jörn", + "LastName": "Dengjel", + "abbrevName": "Dengjel J", + "email": null, + "isCollectiveName": false, + "name": "Jörn Dengjel" + }, + { + "ForeName": "Ludovic", + "LastName": "Martin", + "abbrevName": "Martin L", + "email": null, + "isCollectiveName": false, + "name": "Ludovic Martin" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": "cristina.has@uniklinik-freiburg.de", + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [ + { + "ForeName": "Cristina", + "LastName": "Has", + "email": [ + "cristina.has@uniklinik-freiburg.de" + ], + "name": "Cristina Has" + } + ] + }, + "doi": "10.1016/j.jid.2015.12.039", + "pmid": "26827766", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment." + } + }, + { + "pmid": "22326752", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.", + "authors": { + "abbreviation": "Haiyan Qu, Tingting Wen, Monika Pesch, Monique Aumailley", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Qu", + "abbrevName": "Qu H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Qu" + }, + { + "ForeName": "Tingting", + "LastName": "Wen", + "abbrevName": "Wen T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Wen" + }, + { + "ForeName": "Monika", + "LastName": "Pesch", + "abbrevName": "Pesch M", + "email": null, + "isCollectiveName": false, + "name": "Monika Pesch" + }, + { + "ForeName": "Monique", + "LastName": "Aumailley", + "abbrevName": "Aumailley M", + "email": null, + "isCollectiveName": false, + "name": "Monique Aumailley" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2012.01.005", + "pmid": "22326752", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 180 2012", + "title": "Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes." + } + }, + { + "pmid": "25591451", + "pubmed": { + "ISODate": "2015-05-01T00:00:00.000Z", + "abstract": "Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues. ", + "authors": { + "abbreviation": "Jun Zhan, Mei Yang, Jing Zhang, ..., HongQuan Zhang", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Zhan", + "abbrevName": "Zhan J", + "email": null, + "isCollectiveName": false, + "name": "Jun Zhan" + }, + { + "ForeName": "Mei", + "LastName": "Yang", + "abbrevName": "Yang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Yang" + }, + { + "ForeName": "Jing", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Zhang" + }, + { + "ForeName": "YongQing", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "YongQing Guo" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "HongQuan", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "HongQuan Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1007/s11427-014-4775-2", + "pmid": "25591451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci China Life Sci 58 2015", + "title": "Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm." + } + }, + { + "pmid": "14987263", + "pubmed": { + "ISODate": "2004-03-01T00:00:00.000Z", + "abstract": "Kindler syndrome is a rare, autosomal recessive skin fragility disorder characterized by blistering in infancy, followed by photosensitivity and progressive poikiloderma. Ultrastructural examination reveals marked basement membrane reduplication and variable levels of cleavage at the dermal-epidermal junction. The molecular pathology underlying Kindler syndrome has recently been shown to involve loss-of-function mutations in a novel gene, KIND1, encoding kindlin-1. Immunofluorescence, gene expression and cell biology studies have shown that kindlin-1 is expressed mainly in basal keratinocytes and plays a role in the attachment of the actin cytoskeleton via focal contacts to the extracellular matrix. Thus, Kindler syndrome is the first genodermatosis caused by a defect in actin-extracellular matrix linkage rather than the classic keratin-extracellular matrix linkage underlying the pathology of other inherited skin fragility disorders such as epidermolysis bullosa. This article reviews the clinical features as well as the molecular and cellular pathology of Kindler syndrome and highlights the importance of the new protein, kindlin-1, in cell-matrix adhesion and its intriguing link to photosensitivity.", + "authors": { + "abbreviation": "G H S Ashton", + "authorList": [ + { + "ForeName": "G", + "LastName": "Ashton", + "abbrevName": "Ashton GH", + "email": "gabrielle.ashton@kcl.ac.uk", + "isCollectiveName": false, + "name": "G H S Ashton" + } + ], + "contacts": [ + { + "ForeName": "G", + "LastName": "Ashton", + "email": [ + "gabrielle.ashton@kcl.ac.uk" + ], + "name": "G H S Ashton" + } + ] + }, + "doi": "10.1111/j.1365-2230.2004.01465.x", + "pmid": "14987263", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Clin Exp Dermatol 29 2004", + "title": "Kindler syndrome." + } + }, + { + "pmid": "21356350", + "pubmed": { + "ISODate": "2011-03-01T00:00:00.000Z", + "abstract": "Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of β(1) integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.", + "authors": { + "abbreviation": "Yinghong He, Philipp Esser, Anja Heinemann, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Esser" + }, + { + "ForeName": "Anja", + "LastName": "Heinemann", + "abbrevName": "Heinemann A", + "email": null, + "isCollectiveName": false, + "name": "Anja Heinemann" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ajpath.2010.11.053", + "pmid": "21356350", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Am J Pathol 178 2011", + "title": "Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification." + } + }, + { + "pmid": "23278235", + "pubmed": { + "ISODate": "2013-05-01T00:00:00.000Z", + "abstract": "BACKGROUND: Individuals with Kindler syndrome (KS) have loss-of-function mutations in the FERMT1 gene that encodes the focal adhesion component kindlin-1. The major clinical manifestation of KS is epidermal atrophy (premature skin ageing). This phenotypic feature is thought to be related to the decreased proliferation rate of KS keratinocytes; nevertheless, molecular mediators of such abnormal behaviour have not been fully elucidated. OBJECTIVES: To investigate how kindlin-1 deficiency affects the proliferative potential of primary human keratinocytes. METHODS: We serially cultivated nine primary KS keratinocyte strains until senescence and determined their lifespan and colony-forming efficiency (CFE) at each serial passage. The expression of molecular markers of stemness and cellular senescence were investigated by immunoblotting using cell extracts of primary keratinocyte cultures from patients with KS and healthy donors. In another set of experiments, kindlin-1 downregulation in normal keratinocytes was obtained by small interfering RNA (siRNA) technology. RESULTS: We found that KS keratinocytes exhibited a precocious senescence and strongly reduced clonogenic potential. Moreover, KS cultures showed a strikingly increased percentage of aborted colonies (paraclones) already at early passages indicating an early depletion of stem cells. Immunoblotting analysis of KS keratinocyte extracts showed reduced levels of the stemness markers p63 and Bmi-1, upregulation of p16 and scant amounts of hypophosphorylated Rb protein, which indicated cell cycle-arrested status. Treatment of normal human primary keratinocytes with siRNA targeting kindlin-1 proved that its deficiency was directly responsible for p63, Bmi-1 and pRb downregulation and p16 induction. CONCLUSIONS: Our data directly implicate kindlin-1 in preventing premature senescence of keratinocytes.", + "authors": { + "abbreviation": "E Piccinni, G Di Zenzo, R Maurelli, ..., D Castiglia", + "authorList": [ + { + "ForeName": "E", + "LastName": "Piccinni", + "abbrevName": "Piccinni E", + "email": null, + "isCollectiveName": false, + "name": "E Piccinni" + }, + { + "ForeName": "G", + "LastName": "Di Zenzo", + "abbrevName": "Di Zenzo G", + "email": null, + "isCollectiveName": false, + "name": "G Di Zenzo" + }, + { + "ForeName": "R", + "LastName": "Maurelli", + "abbrevName": "Maurelli R", + "email": null, + "isCollectiveName": false, + "name": "R Maurelli" + }, + { + "ForeName": "E", + "LastName": "Dellambra", + "abbrevName": "Dellambra E", + "email": null, + "isCollectiveName": false, + "name": "E Dellambra" + }, + { + "ForeName": "M", + "LastName": "Teson", + "abbrevName": "Teson M", + "email": null, + "isCollectiveName": false, + "name": "M Teson" + }, + { + "ForeName": "C", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "C Has" + }, + { + "ForeName": "G", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "G Zambruno" + }, + { + "ForeName": "D", + "LastName": "Castiglia", + "abbrevName": "Castiglia D", + "email": null, + "isCollectiveName": false, + "name": "D Castiglia" + } + ], + "contacts": [] + }, + "doi": "10.1111/bjd.12184", + "pmid": "23278235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Br J Dermatol 168 2013", + "title": "Induction of senescence pathways in Kindler syndrome primary keratinocytes." + } + }, + { + "pmid": "19120339", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.", + "authors": { + "abbreviation": "J E Lai-Cheong, A Tanaka, G Hawche, ..., J A McGrath", + "authorList": [ + { + "ForeName": "J", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "J E Lai-Cheong" + }, + { + "ForeName": "A", + "LastName": "Tanaka", + "abbrevName": "Tanaka A", + "email": null, + "isCollectiveName": false, + "name": "A Tanaka" + }, + { + "ForeName": "G", + "LastName": "Hawche", + "abbrevName": "Hawche G", + "email": null, + "isCollectiveName": false, + "name": "G Hawche" + }, + { + "ForeName": "P", + "LastName": "Emanuel", + "abbrevName": "Emanuel P", + "email": null, + "isCollectiveName": false, + "name": "P Emanuel" + }, + { + "ForeName": "C", + "LastName": "Maari", + "abbrevName": "Maari C", + "email": null, + "isCollectiveName": false, + "name": "C Maari" + }, + { + "ForeName": "M", + "LastName": "Taskesen", + "abbrevName": "Taskesen M", + "email": null, + "isCollectiveName": false, + "name": "M Taskesen" + }, + { + "ForeName": "S", + "LastName": "Akdeniz", + "abbrevName": "Akdeniz S", + "email": null, + "isCollectiveName": false, + "name": "S Akdeniz" + }, + { + "ForeName": "L", + "LastName": "Liu", + "abbrevName": "Liu L", + "email": null, + "isCollectiveName": false, + "name": "L Liu" + }, + { + "ForeName": "J", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "J A McGrath" + } + ], + "contacts": [] + }, + "doi": "10.1111/j.1365-2133.2008.08976.x", + "pmid": "19120339", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Br J Dermatol 160 2009", + "title": "Kindler syndrome: a focal adhesion genodermatosis." + } + }, + { + "pmid": "22466645", + "pubmed": { + "ISODate": "2012-05-01T00:00:00.000Z", + "abstract": "Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.", + "authors": { + "abbreviation": "Dimitra Kiritsi, Yinghong He, Anna M G Pasmooij, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Dimitra", + "LastName": "Kiritsi", + "abbrevName": "Kiritsi D", + "email": null, + "isCollectiveName": false, + "name": "Dimitra Kiritsi" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Anna", + "LastName": "Pasmooij", + "abbrevName": "Pasmooij AM", + "email": null, + "isCollectiveName": false, + "name": "Anna M G Pasmooij" + }, + { + "ForeName": "Meltem", + "LastName": "Onder", + "abbrevName": "Onder M", + "email": null, + "isCollectiveName": false, + "name": "Meltem Onder" + }, + { + "ForeName": "Rudolf", + "LastName": "Happle", + "abbrevName": "Happle R", + "email": null, + "isCollectiveName": false, + "name": "Rudolf Happle" + }, + { + "ForeName": "Marcel", + "LastName": "Jonkman", + "abbrevName": "Jonkman MF", + "email": null, + "isCollectiveName": false, + "name": "Marcel F Jonkman" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61976", + "pmid": "22466645", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination." + } + }, + { + "pmid": "27862150", + "pubmed": { + "ISODate": "2017-01-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "P Kantheti, A Kubba, A Prabhu, ..., R Hiremagalore", + "authorList": [ + { + "ForeName": "P", + "LastName": "Kantheti", + "abbrevName": "Kantheti P", + "email": null, + "isCollectiveName": false, + "name": "P Kantheti" + }, + { + "ForeName": "A", + "LastName": "Kubba", + "abbrevName": "Kubba A", + "email": null, + "isCollectiveName": false, + "name": "A Kubba" + }, + { + "ForeName": "A", + "LastName": "Prabhu", + "abbrevName": "Prabhu A", + "email": null, + "isCollectiveName": false, + "name": "A Prabhu" + }, + { + "ForeName": "M", + "LastName": "Batrani", + "abbrevName": "Batrani M", + "email": null, + "isCollectiveName": false, + "name": "M Batrani" + }, + { + "ForeName": "R", + "LastName": "Hiremagalore", + "abbrevName": "Hiremagalore R", + "email": null, + "isCollectiveName": false, + "name": "R Hiremagalore" + } + ], + "contacts": [] + }, + "doi": "10.1111/ced.12946", + "pmid": "27862150", + "pubTypes": [ + { + "UI": "D002363", + "value": "Case Reports" + }, + { + "UI": "D016422", + "value": "Letter" + } + ], + "reference": "Clin Exp Dermatol 42 2017", + "title": "Two novel mutations in KIND1 in Indian patients with Kindler syndrome." + } + }, + { + "pmid": "23776470", + "pubmed": { + "ISODate": "2013-01-01T00:00:00.000Z", + "abstract": "Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.", + "authors": { + "abbreviation": "Coert Margadant, Maaike Kreft, Giovanna Zambruno, Arnoud Sonnenberg", + "authorList": [ + { + "ForeName": "Coert", + "LastName": "Margadant", + "abbrevName": "Margadant C", + "email": null, + "isCollectiveName": false, + "name": "Coert Margadant" + }, + { + "ForeName": "Maaike", + "LastName": "Kreft", + "abbrevName": "Kreft M", + "email": null, + "isCollectiveName": false, + "name": "Maaike Kreft" + }, + { + "ForeName": "Giovanna", + "LastName": "Zambruno", + "abbrevName": "Zambruno G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Zambruno" + }, + { + "ForeName": "Arnoud", + "LastName": "Sonnenberg", + "abbrevName": "Sonnenberg A", + "email": null, + "isCollectiveName": false, + "name": "Arnoud Sonnenberg" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0065341", + "pmid": "23776470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Kindlin-1 regulates integrin dynamics and adhesion turnover." + } + }, + { + "pmid": "27427485", + "pubmed": { + "ISODate": "2016-11-01T00:00:00.000Z", + "abstract": "Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.", + "authors": { + "abbreviation": "Gaofeng Zhang, Yu Gu, Rumena Begum, ..., Bing Song", + "authorList": [ + { + "ForeName": "Gaofeng", + "LastName": "Zhang", + "abbrevName": "Zhang G", + "email": null, + "isCollectiveName": false, + "name": "Gaofeng Zhang" + }, + { + "ForeName": "Yu", + "LastName": "Gu", + "abbrevName": "Gu Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Gu" + }, + { + "ForeName": "Rumena", + "LastName": "Begum", + "abbrevName": "Begum R", + "email": null, + "isCollectiveName": false, + "name": "Rumena Begum" + }, + { + "ForeName": "Hongduo", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hongduo Chen" + }, + { + "ForeName": "Xinghua", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xinghua Gao" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": "maddy.parsons@kcl.ac.uk", + "isCollectiveName": false, + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "abbrevName": "Song B", + "email": "SongB3@cardiff.ac.uk", + "isCollectiveName": false, + "name": "Bing Song" + } + ], + "contacts": [ + { + "ForeName": "Maddy", + "LastName": "Parsons", + "email": [ + "maddy.parsons@kcl.ac.uk" + ], + "name": "Maddy Parsons" + }, + { + "ForeName": "Bing", + "LastName": "Song", + "email": [ + "SongB3@cardiff.ac.uk" + ], + "name": "Bing Song" + } + ] + }, + "doi": "10.1016/j.jid.2016.05.129", + "pmid": "27427485", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Invest Dermatol 136 2016", + "title": "Kindlin-1 Regulates Keratinocyte Electrotaxis." + } + }, + { + "pmid": "31614010", + "pubmed": { + "ISODate": "2020-02-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Zlatko Kopecki, Cristina Has, Gink Yang, ..., Allison Cowin", + "authorList": [ + { + "ForeName": "Zlatko", + "LastName": "Kopecki", + "abbrevName": "Kopecki Z", + "email": null, + "isCollectiveName": false, + "name": "Zlatko Kopecki" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + }, + { + "ForeName": "Gink", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Gink Yang" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Allison", + "LastName": "Cowin", + "abbrevName": "Cowin A", + "email": null, + "isCollectiveName": false, + "name": "Allison Cowin" + } + ], + "contacts": [] + }, + "doi": "10.1111/cup.13597", + "pmid": "31614010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cutan Pathol 47 2020", + "title": "Flightless I, a contributing factor to skin blistering in Kindler syndrome patients?" + } + }, + { + "pmid": "21336475", + "pubmed": { + "ISODate": "2011-05-01T00:00:00.000Z", + "abstract": "Kindler syndrome (OMIM 173650) is an autosomal recessive condition characterized by skin blistering, skin atrophy, photosensitivity, colonic inflammation and mucosal stenosis. Fewer than 100 cases have been described in the literature. First reported in 1954, the molecular basis of Kindler syndrome was elucidated in 2003 with the discovery of FERMT1 (KIND1) loss-of-function mutations in affected individuals. The FERMT1 gene encodes kindlin-1 (also known as fermitin family homologue 1), a 77 kDa protein that localizes at focal adhesions, where it plays an important role in integrin signalling. In the current study, we describe five novel and three recurrent loss-of-function FERMT1 mutations in eight individuals with Kindler syndrome, and provide an overview of genotype-phenotype correlation in this disorder.", + "authors": { + "abbreviation": "Tanasit Techanukul, Gomathy Sethuraman, Abraham Zlotogorski, ..., Joey E Lai-Cheong", + "authorList": [ + { + "ForeName": "Tanasit", + "LastName": "Techanukul", + "abbrevName": "Techanukul T", + "email": null, + "isCollectiveName": false, + "name": "Tanasit Techanukul" + }, + { + "ForeName": "Gomathy", + "LastName": "Sethuraman", + "abbrevName": "Sethuraman G", + "email": null, + "isCollectiveName": false, + "name": "Gomathy Sethuraman" + }, + { + "ForeName": "Abraham", + "LastName": "Zlotogorski", + "abbrevName": "Zlotogorski A", + "email": null, + "isCollectiveName": false, + "name": "Abraham Zlotogorski" + }, + { + "ForeName": "Liran", + "LastName": "Horev", + "abbrevName": "Horev L", + "email": null, + "isCollectiveName": false, + "name": "Liran Horev" + }, + { + "ForeName": "Michal", + "LastName": "Macarov", + "abbrevName": "Macarov M", + "email": null, + "isCollectiveName": false, + "name": "Michal Macarov" + }, + { + "ForeName": "Alison", + "LastName": "Trainer", + "abbrevName": "Trainer A", + "email": null, + "isCollectiveName": false, + "name": "Alison Trainer" + }, + { + "ForeName": "Kenneth", + "LastName": "Fong", + "abbrevName": "Fong K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Fong" + }, + { + "ForeName": "Marko", + "LastName": "Lens", + "abbrevName": "Lens M", + "email": null, + "isCollectiveName": false, + "name": "Marko Lens" + }, + { + "ForeName": "Ljiljana", + "LastName": "Medenica", + "abbrevName": "Medenica L", + "email": null, + "isCollectiveName": false, + "name": "Ljiljana Medenica" + }, + { + "ForeName": "Venkatesh", + "LastName": "Ramesh", + "abbrevName": "Ramesh V", + "email": null, + "isCollectiveName": false, + "name": "Venkatesh Ramesh" + }, + { + "ForeName": "John", + "LastName": "McGrath", + "abbrevName": "McGrath JA", + "email": null, + "isCollectiveName": false, + "name": "John A McGrath" + }, + { + "ForeName": "Joey", + "LastName": "Lai-Cheong", + "abbrevName": "Lai-Cheong JE", + "email": null, + "isCollectiveName": false, + "name": "Joey E Lai-Cheong" + } + ], + "contacts": [] + }, + "doi": "10.2340/00015555-1063", + "pmid": "21336475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016448", + "value": "Multicenter Study" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Derm Venereol 91 2011", + "title": "Novel and recurrent FERMT1 gene mutations in Kindler syndrome." + } + }, + { + "pmid": "27798104", + "pubmed": { + "ISODate": "2016-12-15T00:00:00.000Z", + "abstract": "Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.", + "authors": { + "abbreviation": "Kristin Maier, Yinghong He, Ute Wölfle, ..., Cristina Has", + "authorList": [ + { + "ForeName": "Kristin", + "LastName": "Maier", + "abbrevName": "Maier K", + "email": null, + "isCollectiveName": false, + "name": "Kristin Maier" + }, + { + "ForeName": "Yinghong", + "LastName": "He", + "abbrevName": "He Y", + "email": null, + "isCollectiveName": false, + "name": "Yinghong He" + }, + { + "ForeName": "Ute", + "LastName": "Wölfle", + "abbrevName": "Wölfle U", + "email": null, + "isCollectiveName": false, + "name": "Ute Wölfle" + }, + { + "ForeName": "Philipp", + "LastName": "Esser", + "abbrevName": "Esser PR", + "email": null, + "isCollectiveName": false, + "name": "Philipp R Esser" + }, + { + "ForeName": "Tilman", + "LastName": "Brummer", + "abbrevName": "Brummer T", + "email": null, + "isCollectiveName": false, + "name": "Tilman Brummer" + }, + { + "ForeName": "Christoph", + "LastName": "Schempp", + "abbrevName": "Schempp C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Schempp" + }, + { + "ForeName": "Leena", + "LastName": "Bruckner-Tuderman", + "abbrevName": "Bruckner-Tuderman L", + "email": null, + "isCollectiveName": false, + "name": "Leena Bruckner-Tuderman" + }, + { + "ForeName": "Cristina", + "LastName": "Has", + "abbrevName": "Has C", + "email": null, + "isCollectiveName": false, + "name": "Cristina Has" + } + ], + "contacts": [] + }, + "doi": "10.1093/hmg/ddw350", + "pmid": "27798104", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Hum Mol Genet 25 2016", + "title": "UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome." + } + } + ], + "secret": "read-only", + "type": "protein" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/doct_tests_2.json b/neo4j-test/document/doct_tests_2.json new file mode 100644 index 000000000..01c1b3f72 --- /dev/null +++ b/neo4j-test/document/doct_tests_2.json @@ -0,0 +1,19768 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-02-02T21:50:08.370Z", + "_newestOpId": "d0c866f0-6ee4-4024-9672-528dc5ced785", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "ArticleTitle": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Integrative Biology, University of Liverpool, BioSciences Building, Crown Street, Liverpool L69 7ZB, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Thomas", + "Identifier": [], + "Initials": "T", + "LastName": "Zacharchenko" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Xiaolan", + "Identifier": [], + "Initials": "X", + "LastName": "Qian" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Kent, Canterbury, CT2 7NJ, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Benjamin T", + "Identifier": [], + "Initials": "BT", + "LastName": "Goult" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Devina", + "Identifier": [], + "Initials": "D", + "LastName": "Jethwa" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Integrative Biology, University of Liverpool, BioSciences Building, Crown Street, Liverpool L69 7ZB, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Teresa B", + "Identifier": [], + "Initials": "TB", + "LastName": "Almeida" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Christoph", + "Identifier": [], + "Initials": "C", + "LastName": "Ballestrem" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "David R", + "Identifier": [], + "Initials": "DR", + "LastName": "Critchley" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Douglas R", + "Identifier": [], + "Initials": "DR", + "LastName": "Lowy" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Institute of Integrative Biology, University of Liverpool, BioSciences Building, Crown Street, Liverpool L69 7ZB, UK. Electronic address: igb2@liv.ac.uk.", + "email": [ + "igb2@liv.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Igor L", + "Identifier": [], + "Initials": "IL", + "LastName": "Barsukov" + } + ], + "Journal": { + "ISOAbbreviation": "Structure", + "ISSN": { + "IssnType": "Electronic", + "value": "1878-4186" + }, + "JournalIssue": { + "Issue": "7", + "PubDate": { + "Day": "06", + "Month": "Jul", + "Year": "2016" + }, + "Volume": "24" + }, + "Title": "Structure (London, England : 1993)" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "C430864", + "value": "DLC-1 (deleted in liver cancer) protein, mouse" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D020690", + "value": "GTPase-Activating Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D016608", + "value": "Talin" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D025521", + "value": "Tumor Suppressor Proteins" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "C496077", + "value": "talin protein, mouse" + }, + "RegistryNumber": "0" + } + ], + "InvestigatorList": [], + "KeywordList": [], + "MeshheadingList": [ + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D000818", + "value": "Animals" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D001665", + "value": "Binding Sites" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D045744", + "value": "Cell Line, Tumor" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D020690", + "value": "GTPase-Activating Proteins" + }, + "QualifierName": [ + { + "MajorTopicYN": "Y", + "UI": "Q000737", + "value": "chemistry" + }, + { + "MajorTopicYN": "N", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D057809", + "value": "HEK293 Cells" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D006801", + "value": "Humans" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D051379", + "value": "Mice" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "Y", + "UI": "D062105", + "value": "Molecular Docking Simulation" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D011485", + "value": "Protein Binding" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D016608", + "value": "Talin" + }, + "QualifierName": [ + { + "MajorTopicYN": "Y", + "UI": "Q000737", + "value": "chemistry" + }, + { + "MajorTopicYN": "N", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D025521", + "value": "Tumor Suppressor Proteins" + }, + "QualifierName": [ + { + "MajorTopicYN": "Y", + "UI": "Q000737", + "value": "chemistry" + }, + { + "MajorTopicYN": "N", + "UI": "Q000378", + "value": "metabolism" + } + ] + } + ] + }, + "PubmedData": { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "27265849" + }, + { + "IdType": "pmc", + "id": "PMC4938799" + }, + { + "IdType": "doi", + "id": "10.1016/j.str.2016.04.016" + }, + { + "IdType": "pii", + "id": "S0969-2126(16)30077-6" + } + ], + "History": [ + { + "PubMedPubDate": { + "Day": "4", + "Month": "11", + "Year": "2015" + }, + "PubStatus": "received" + }, + { + "PubMedPubDate": { + "Day": "4", + "Month": "4", + "Year": "2016" + }, + "PubStatus": "revised" + }, + { + "PubMedPubDate": { + "Day": "5", + "Month": "4", + "Year": "2016" + }, + "PubStatus": "accepted" + }, + { + "PubMedPubDate": { + "Day": "7", + "Month": "6", + "Year": "2016" + }, + "PubStatus": "entrez" + }, + { + "PubMedPubDate": { + "Day": "7", + "Month": "6", + "Year": "2016" + }, + "PubStatus": "pubmed" + }, + { + "PubMedPubDate": { + "Day": "3", + "Month": "10", + "Year": "2017" + }, + "PubStatus": "medline" + } + ], + "ReferenceList": [ + { + "Reference": [ + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "24870021" + } + ], + "Citation": "Alam T., Alazmi M., Gao X., Arold S.T. 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Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J. Cell Biol. 2012;199:331–345." + }, + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "22819514" + } + ], + "Citation": "Wehrle-Haller B. Assembly and disassembly of cell matrix adhesions. Curr. Opin. Cell Biol. 2012;24:569–581." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC4432866" + }, + { + "IdType": "pubmed", + "id": "25520155" + } + ], + "Citation": "Yang J., Zhu L., Zhang H., Hirbawi J., Fukuda K., Dwivedi P., Liu J., Byzova T., Plow E.F., Wu J. Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion. Nat. Commun. 2014;5:5880." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC3980218" + }, + { + "IdType": "pubmed", + "id": "24714394" + } + ], + "Citation": "Yao M., Goult B.T., Chen H., Cong P., Sheetz M.P., Yan J. Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Sci. Rep. 2014;4:4610." + }, + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC2746969" + }, + { + "IdType": "pubmed", + "id": "19160486" + } + ], + "Citation": "Zhang X., Jiang G., Cai Y., Monkley S.J., Critchley D.R., Sheetz M.P. Talin depletion reveals independence of initial cell spreading from integrin activation and traction. Nat. Cell Biol. 2008;10:1062–1068." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko", + "orcid": null + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult", + "orcid": "0000-0002-3438-2807" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa", + "orcid": null + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida", + "orcid": null + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem", + "orcid": "0000-0002-5375-7985" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley", + "orcid": null + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy", + "orcid": null + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov", + "orcid": null + } + ], + "caption": "Cell adhesion, cell migration", + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1643838608, + "entries": [ + { + "id": "63eb9fac-573b-4bb2-8ac9-22b7da2ac361" + }, + { + "id": "5c0d65ae-a038-436c-99e5-78a6e58a773d" + }, + { + "id": "028e7366-9779-4466-96ea-18a45bfe3f38" + }, + { + "id": "7df04752-5ce5-4d50-9acb-5ea0f54e11e9" + }, + { + "id": "80a4d403-8bc1-4ddb-a4f9-5227e87ef6fa" + } + ], + "id": "de1b09bf-0104-4d9e-a862-a3bb91d6aade", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1643838691, + "liveId": "d67f7dc8-4dd8-4272-b17e-40085d0b7992", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "26238352", + "pubmed": { + "ISODate": "2015-08-03T00:00:00.000Z", + "abstract": "SUMMARY: Stimuli that promote cell migration, such as chemokines, cytokines, and growth factors in metazoans and cyclic AMP in Dictyostelium, activate signaling pathways that control organization of the actin cytoskeleton and adhesion complexes. The Rho-family GTPases are a key convergence point of these pathways. Their effectors include actin regulators such as formins, members of the WASP/WAVE family and the Arp2/3 complex, and the myosin II motor protein. Pathways that link to the Rho GTPases include Ras GTPases, TorC2, and PI3K. Many of the molecules involved form gradients within cells, which define the front and rear of migrating cells, and are also established in related cellular behaviors such as neuronal growth cone extension and cytokinesis. The signaling molecules that regulate migration can be integrated to provide a model of network function. The network displays biochemical excitability seen as spontaneous waves of activation that propagate along the cell cortex. These events coordinate cell movement and can be biased by external cues to bring about directed migration.", + "authors": { + "abbreviation": "Peter Devreotes, Alan Rick Horwitz", + "authorList": [ + { + "ForeName": "Peter", + "LastName": "Devreotes", + "abbrevName": "Devreotes P", + "email": null, + "isCollectiveName": false, + "name": "Peter Devreotes" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AR", + "email": null, + "isCollectiveName": false, + "name": "Alan Rick Horwitz" + } + ], + "contacts": [] + }, + "doi": "10.1101/cshperspect.a005959", + "pmid": "26238352", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cold Spring Harb Perspect Biol 7 2015", + "title": "Signaling networks that regulate cell migration." + } + }, + { + "pmid": "25572304", + "pubmed": { + "ISODate": "2015-04-01T00:00:00.000Z", + "abstract": "Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype. ", + "authors": { + "abbreviation": "Laetitia Seguin, Jay S Desgrosellier, Sara M Weis, David A Cheresh", + "authorList": [ + { + "ForeName": "Laetitia", + "LastName": "Seguin", + "abbrevName": "Seguin L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Seguin" + }, + { + "ForeName": "Jay", + "LastName": "Desgrosellier", + "abbrevName": "Desgrosellier JS", + "email": null, + "isCollectiveName": false, + "name": "Jay S Desgrosellier" + }, + { + "ForeName": "Sara", + "LastName": "Weis", + "abbrevName": "Weis SM", + "email": null, + "isCollectiveName": false, + "name": "Sara M Weis" + }, + { + "ForeName": "David", + "LastName": "Cheresh", + "abbrevName": "Cheresh DA", + "email": "cheresh@scripps.edu", + "isCollectiveName": false, + "name": "David A Cheresh" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Cheresh", + "email": [ + "cheresh@scripps.edu" + ], + "name": "David A Cheresh" + } + ] + }, + "doi": "10.1016/j.tcb.2014.12.006", + "pmid": "25572304", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Trends Cell Biol 25 2015", + "title": "Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "24870021", + "pubmed": { + "ISODate": "2014-06-15T00:00:00.000Z", + "abstract": "LD motifs (leucine-aspartic acid motifs) are short helical protein-protein interaction motifs that have emerged as key players in connecting cell adhesion with cell motility and survival. LD motifs are required for embryogenesis, wound healing and the evolution of multicellularity. LD motifs also play roles in disease, such as in cancer metastasis or viral infection. First described in the paxillin family of scaffolding proteins, LD motifs and similar acidic LXXLL interaction motifs have been discovered in several other proteins, whereas 16 proteins have been reported to contain LDBDs (LD motif-binding domains). Collectively, structural and functional analyses have revealed a surprising multivalency in LD motif interactions and a wide diversity in LDBD architectures. In the present review, we summarize the molecular basis for function, regulation and selectivity of LD motif interactions that has emerged from more than a decade of research. This overview highlights the intricate multi-level regulation and the inherently noisy and heterogeneous nature of signalling through short protein-protein interaction motifs.", + "authors": { + "abbreviation": "Tanvir Alam, Meshari Alazmi, Xin Gao, Stefan T Arold", + "authorList": [ + { + "ForeName": "Tanvir", + "LastName": "Alam", + "abbrevName": "Alam T", + "email": null, + "isCollectiveName": false, + "name": "Tanvir Alam" + }, + { + "ForeName": "Meshari", + "LastName": "Alazmi", + "abbrevName": "Alazmi M", + "email": null, + "isCollectiveName": false, + "name": "Meshari Alazmi" + }, + { + "ForeName": "Xin", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xin Gao" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + } + ], + "contacts": [] + }, + "doi": "10.1042/BJ20140298", + "pmid": "24870021", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochem J 460 2014", + "title": "How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs." + } + }, + { + "pmid": "24714394", + "pubmed": { + "ISODate": "2014-04-09T00:00:00.000Z", + "abstract": "The force-dependent interaction between talin and vinculin plays a crucial role in the initiation and growth of focal adhesions. Here we use magnetic tweezers to characterise the mechano-sensitive compact N-terminal region of the talin rod, and show that the three helical bundles R1-R3 in this region unfold in three distinct steps consistent with the domains unfolding independently. Mechanical stretching of talin R1-R3 enhances its binding to vinculin and vinculin binding inhibits talin refolding after force is released. Mutations that stabilize R3 identify it as the initial mechano-sensing domain in talin, unfolding at ∼5 pN, suggesting that 5 pN is the force threshold for vinculin binding and adhesion progression. ", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Hu Chen, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Hu", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hu Chen" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep04610", + "pmid": "24714394", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 4 2014", + "title": "Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation." + } + }, + { + "pmid": "24607953", + "pubmed": { + "ISODate": "2014-01-01T00:00:00.000Z", + "abstract": "Rho GTPases play an essential role in regulating cell spreading, adhesion, and migration downstream of integrin engagement with the extracellular matrix. In this review, we focus on RhoA and Rac1--2 Rho GTPases that are required for efficient adhesion and migration--and describe how specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate the extensive crosstalk that exists between them. In particular, we assess the role of GEFs and GAPs in light of recent, unexpected evidence concerning the spatiotemporal relationship between RhoA and Rac1 at the leading edge of migrating cells. Force is increasingly recognized as a key regulator of cell adhesion and we highlight the role of GEFs and GAPs in mechanotransduction, before debating the controversial role of tension in focal adhesion maturation.", + "authors": { + "abbreviation": "Campbell D Lawson, Keith Burridge", + "authorList": [ + { + "ForeName": "Campbell", + "LastName": "Lawson", + "abbrevName": "Lawson CD", + "email": null, + "isCollectiveName": false, + "name": "Campbell D Lawson" + }, + { + "ForeName": "Keith", + "LastName": "Burridge", + "abbrevName": "Burridge K", + "email": null, + "isCollectiveName": false, + "name": "Keith Burridge" + } + ], + "contacts": [] + }, + "doi": "10.4161/sgtp.27958", + "pmid": "24607953", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Small GTPases 5 2014", + "title": "The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration." + } + }, + { + "pmid": "23860236", + "pubmed": { + "ISODate": "2013-08-01T00:00:00.000Z", + "abstract": "Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling. ", + "authors": { + "abbreviation": "David A Calderwood, Iain D Campbell, David R Critchley", + "authorList": [ + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm3624", + "pmid": "23860236", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 14 2013", + "title": "Talins and kindlins: partners in integrin-mediated adhesion." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "23375895", + "pubmed": { + "ISODate": "2013-02-18T00:00:00.000Z", + "abstract": "BACKGROUND: Cells sense the extracellular environment using adhesion receptors (integrins) linked to the intracellular actin cytoskeleton through a complex network of regulatory proteins that, all together, form focal adhesions (FAs). The molecular basis of how these sensing units are regulated, how they are implicated in transducing mechanical stimuli, and how this leads to a spatiotemporal coordination of FAs is unclear. RESULTS: Here we show that vinculin, through its links to the talin-integrin complex and F-actin, regulates the transmission of mechanical signals from the extracellular matrix to the actomyosin machinery. We demonstrate that the vinculin interaction with the talin-integrin complex drives the recruitment and release of core FA components. The activation state of vinculin is itself regulated by force, as underscored by our observation that vinculin localization to FAs is dependent on actomyosin contraction. Using a variety of vinculin mutants, we establish which components of the cell-matrix adhesion network are coordinated through direct and indirect associations with vinculin. Moreover, using cyclic stretching, we demonstrate that vinculin plays a key role in the transmission of extracellular mechanical stimuli leading to the reorganization of cell polarity. Of particular importance is the actin-binding tail region of vinculin, without which the cell's ability to repolarize in response to cyclic stretching is perturbed. CONCLUSIONS: Overall our data promote a model whereby vinculin controls the transmission of intracellular and extracellular mechanical cues that are important for the spatiotemporal assembly, disassembly, and reorganization of FAs to coordinate polarized cell motility.", + "authors": { + "abbreviation": "Alex Carisey, Ricky Tsang, Alexandra M Greiner, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Alex", + "LastName": "Carisey", + "abbrevName": "Carisey A", + "email": null, + "isCollectiveName": false, + "name": "Alex Carisey" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Alexandra", + "LastName": "Greiner", + "abbrevName": "Greiner AM", + "email": null, + "isCollectiveName": false, + "name": "Alexandra M Greiner" + }, + { + "ForeName": "Nadja", + "LastName": "Nijenhuis", + "abbrevName": "Nijenhuis N", + "email": null, + "isCollectiveName": false, + "name": "Nadja Nijenhuis" + }, + { + "ForeName": "Nikki", + "LastName": "Heath", + "abbrevName": "Heath N", + "email": null, + "isCollectiveName": false, + "name": "Nikki Heath" + }, + { + "ForeName": "Alicja", + "LastName": "Nazgiewicz", + "abbrevName": "Nazgiewicz A", + "email": null, + "isCollectiveName": false, + "name": "Alicja Nazgiewicz" + }, + { + "ForeName": "Ralf", + "LastName": "Kemkemer", + "abbrevName": "Kemkemer R", + "email": null, + "isCollectiveName": false, + "name": "Ralf Kemkemer" + }, + { + "ForeName": "Brian", + "LastName": "Derby", + "abbrevName": "Derby B", + "email": null, + "isCollectiveName": false, + "name": "Brian Derby" + }, + { + "ForeName": "Joachim", + "LastName": "Spatz", + "abbrevName": "Spatz J", + "email": null, + "isCollectiveName": false, + "name": "Joachim Spatz" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2013.01.009", + "pmid": "23375895", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 23 2013", + "title": "Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner." + } + }, + { + "pmid": "23071154", + "pubmed": { + "ISODate": "2012-10-15T00:00:00.000Z", + "abstract": "Migrating cells acquire front-rear polarity with a leading edge and a trailing tail for directional movement. The Rac exchange factor Tiam1 participates in polarized cell migration with the PAR complex of PAR3, PAR6, and atypical protein kinase C. However, it remains largely unknown how Tiam1 is regulated and contributes to the establishment of polarity in migrating cells. We show here that Tiam1 interacts directly with talin, which binds and activates integrins to mediate their signaling. Tiam1 accumulated at adhesions in a manner dependent on talin and the PAR complex. The interactions of talin with Tiam1 and the PAR complex were required for adhesion-induced Rac1 activation, cell spreading, and migration toward integrin substrates. Furthermore, Tiam1 acted with talin to regulate adhesion turnover. Thus, we propose that Tiam1, with the PAR complex, binds to integrins through talin and, together with the PAR complex, thereby regulates Rac1 activity and adhesion turnover for polarized migration.", + "authors": { + "abbreviation": "Shujie Wang, Takashi Watanabe, Kenji Matsuzawa, ..., Kozo Kaibuchi", + "authorList": [ + { + "ForeName": "Shujie", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shujie Wang" + }, + { + "ForeName": "Takashi", + "LastName": "Watanabe", + "abbrevName": "Watanabe T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Watanabe" + }, + { + "ForeName": "Kenji", + "LastName": "Matsuzawa", + "abbrevName": "Matsuzawa K", + "email": null, + "isCollectiveName": false, + "name": "Kenji Matsuzawa" + }, + { + "ForeName": "Akira", + "LastName": "Katsumi", + "abbrevName": "Katsumi A", + "email": null, + "isCollectiveName": false, + "name": "Akira Katsumi" + }, + { + "ForeName": "Mai", + "LastName": "Kakeno", + "abbrevName": "Kakeno M", + "email": null, + "isCollectiveName": false, + "name": "Mai Kakeno" + }, + { + "ForeName": "Toshinori", + "LastName": "Matsui", + "abbrevName": "Matsui T", + "email": null, + "isCollectiveName": false, + "name": "Toshinori Matsui" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Kazuhide", + "LastName": "Sato", + "abbrevName": "Sato K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhide Sato" + }, + { + "ForeName": "Kiyoko", + "LastName": "Murase", + "abbrevName": "Murase K", + "email": null, + "isCollectiveName": false, + "name": "Kiyoko Murase" + }, + { + "ForeName": "Ikuko", + "LastName": "Sugiyama", + "abbrevName": "Sugiyama I", + "email": null, + "isCollectiveName": false, + "name": "Ikuko Sugiyama" + }, + { + "ForeName": "Kazushi", + "LastName": "Kimura", + "abbrevName": "Kimura K", + "email": null, + "isCollectiveName": false, + "name": "Kazushi Kimura" + }, + { + "ForeName": "Akira", + "LastName": "Mizoguchi", + "abbrevName": "Mizoguchi A", + "email": null, + "isCollectiveName": false, + "name": "Akira Mizoguchi" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + }, + { + "ForeName": "John", + "LastName": "Collard", + "abbrevName": "Collard JG", + "email": null, + "isCollectiveName": false, + "name": "John G Collard" + }, + { + "ForeName": "Kozo", + "LastName": "Kaibuchi", + "abbrevName": "Kaibuchi K", + "email": null, + "isCollectiveName": false, + "name": "Kozo Kaibuchi" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201202041", + "pmid": "23071154", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 199 2012", + "title": "Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration." + } + }, + { + "pmid": "22983197", + "pubmed": { + "ISODate": null, + "abstract": "Cell migration requires the coordination of adhesion site assembly and turnover. Canonical models for nascent adhesion formation postulate that integrin binding to extracellular matrix (ECM) proteins results in the rapid recruitment of cytoskeletal proteins such as talin and paxillin to integrin cytoplasmic domains. It is thought that integrin-talin clusters recruit and activate tyrosine kinases such as focal adhesion kinase (FAK). However, the molecular connections of this linkage remain unresolved. Our recent findings support an alternative model whereby FAK recruits talin to new sites of β1 integrin-mediated adhesion in mouse embryonic fibroblasts and human ovarian carcinoma cells. This is dependent on a direct binding interaction between FAK and talin and occurs independently of direct talin binding to β1 integrin. Herein, we discuss differences between nascent and mature adhesions, interactions between FAK, talin and paxillin, possible mechanisms of FAK activation and how this FAK-talin complex may function to promote cell motility through increased adhesion turnover.", + "authors": { + "abbreviation": "Christine Lawson, David D Schlaepfer", + "authorList": [ + { + "ForeName": "Christine", + "LastName": "Lawson", + "abbrevName": "Lawson C", + "email": null, + "isCollectiveName": false, + "name": "Christine Lawson" + }, + { + "ForeName": "David", + "LastName": "Schlaepfer", + "abbrevName": "Schlaepfer DD", + "email": null, + "isCollectiveName": false, + "name": "David D Schlaepfer" + } + ], + "contacts": [] + }, + "doi": "10.4161/cam.20488", + "pmid": "22983197", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Adh Migr 6", + "title": "Integrin adhesions: who's on first? What's on second? Connections between FAK and talin." + } + }, + { + "pmid": "22819514", + "pubmed": { + "ISODate": "2012-10-01T00:00:00.000Z", + "abstract": "The formation of tissues and organs requires cells to adhere to each other and/or to migrate and polarize in contact with components of the extracellular matrix. The connection between the cytoskeleton and the extracellular environment is provided by heterodimeric transmembrane receptors of the integrin family. In response to extracellular ligand binding, integrins undergo a conformational switch that permits the recruitment of cytoplasmic adapter proteins, eventually linking the integrin receptors to the actin cytoskeleton, progressively forming highly complex cell-matrix adhesions. A major challenge in the field consists in identifying the regulatory mechanisms, which drive the assembly of cell-matrix adhesions as they are based on posttranslational modifications as well as allosteric conformational changes caused by protein-protein as well as protein-lipid interactions. In response to mechanical tension, generated either by intra-cellular acto-myosin contraction, shear stress or mechanical strain on the extracellular scaffold, the composition and signaling of cell-matrix adhesion changes, leading either to increased anchorage or controlled disassembly of cell matrix adhesions, both processes critically involved in cell migration. The aim of this review is to provide insight into the mechanisms leading to the progressive assembly of focal adhesions, how they are modulated in response to mechanical challenges and which mechanisms are used for their disassembly.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2012.06.010", + "pmid": "22819514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Assembly and disassembly of cell matrix adhesions." + } + }, + { + "pmid": "22797926", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": "From the extracellular matrix to the cytoskeleton, a network of molecular links connects cells to their environment. Molecules in this network transmit and detect mechanical forces, which subsequently determine cell behavior and fate. Here, we reconstruct the mechanical pathway followed by these forces. From matrix proteins to actin through integrins and adaptor proteins, we review how forces affect the lifetime of bonds and stretch or alter the conformation of proteins, and how these mechanical changes are converted into biochemical signals in mechanotransduction events. We evaluate which of the proteins in the network can participate in mechanotransduction and which are simply responsible for transmitting forces in a dynamic network. Besides their individual properties, we also analyze how the mechanical responses of a protein are determined by their serial connections from the matrix to actin, their parallel connections in integrin clusters and by the rate at which force is applied to them. All these define mechanical molecular pathways in cells, which are emerging as key regulators of cell function alongside better studied biochemical pathways.", + "authors": { + "abbreviation": "Pere Roca-Cusachs, Thomas Iskratsch, Michael P Sheetz", + "authorList": [ + { + "ForeName": "Pere", + "LastName": "Roca-Cusachs", + "abbrevName": "Roca-Cusachs P", + "email": "rocacusachs@ub.edu", + "isCollectiveName": false, + "name": "Pere Roca-Cusachs" + }, + { + "ForeName": "Thomas", + "LastName": "Iskratsch", + "abbrevName": "Iskratsch T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Iskratsch" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + } + ], + "contacts": [ + { + "ForeName": "Pere", + "LastName": "Roca-Cusachs", + "email": [ + "rocacusachs@ub.edu" + ], + "name": "Pere Roca-Cusachs" + } + ] + }, + "doi": "10.1242/jcs.095794", + "pmid": "22797926", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 125 2012", + "title": "Finding the weakest link: exploring integrin-mediated mechanical molecular pathways." + } + }, + { + "pmid": "22270917", + "pubmed": { + "ISODate": "2012-01-23T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that involves the continuous formation, maturation, and turnover of matrix-cell adhesion sites. New (nascent) adhesions form at the protruding cell edge in a tension-independent manner and are comprised of integrin receptors, signaling, and cytoskeletal-associated proteins. Integrins recruit focal adhesion kinase (FAK) and the cytoskeletal protein talin to nascent adhesions. Canonical models support a role for talin in mediating FAK localization and activation at adhesions. Here, alternatively, we show that FAK promotes talin recruitment to nascent adhesions occurring independently of talin binding to β1 integrins. The direct binding site for talin on FAK was identified, and a point mutation in FAK (E1015A) prevented talin association and talin localization to nascent adhesions but did not alter integrin-mediated FAK recruitment and activation at adhesions. Moreover, FAK E1015A inhibited cell motility and proteolytic talin cleavage needed for efficient adhesion dynamics. These results support an alternative linkage for FAK-talin interactions within nascent adhesions essential for the control of cell migration.", + "authors": { + "abbreviation": "Christine Lawson, Ssang-Taek Lim, Sean Uryu, ..., David D Schlaepfer", + "authorList": [ + { + "ForeName": "Christine", + "LastName": "Lawson", + "abbrevName": "Lawson C", + "email": null, + "isCollectiveName": false, + "name": "Christine Lawson" + }, + { + "ForeName": "Ssang-Taek", + "LastName": "Lim", + "abbrevName": "Lim ST", + "email": null, + "isCollectiveName": false, + "name": "Ssang-Taek Lim" + }, + { + "ForeName": "Sean", + "LastName": "Uryu", + "abbrevName": "Uryu S", + "email": null, + "isCollectiveName": false, + "name": "Sean Uryu" + }, + { + "ForeName": "Xiao", + "LastName": "Chen", + "abbrevName": "Chen XL", + "email": null, + "isCollectiveName": false, + "name": "Xiao Lei Chen" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "David", + "LastName": "Schlaepfer", + "abbrevName": "Schlaepfer DD", + "email": null, + "isCollectiveName": false, + "name": "David D Schlaepfer" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201108078", + "pmid": "22270917", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 196 2012", + "title": "FAK promotes recruitment of talin to nascent adhesions to control cell motility." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "21749900", + "pubmed": { + "ISODate": "2011-01-01T00:00:00.000Z", + "abstract": "Upon detachment from the extracellular matrix, tumor epithelial cells and tumor-associated endothelial cells are capable of overcoming anoikis, gain survival benefits, and hence contribute to the process of metastasis. The focal-adhesion complex formation recruits the association of key adaptor proteins such as FAK (focal-adhesion kinase). Vimentin, paxillin, and talin are responsible for mediating the interaction between the actin cytoskeleton and integrins. Talin is an early-recruited focal-adhesion player that is of structural and functional significance in mediating interactions with integrin cytoplasmic tails leading to destabilization of the transmembrane complex and resulting in rearrangements in the extracellular integrin compartments that mediate integrin activation. Talin-mediated integrin activation plays a definitive role in integrin-mediated signaling and induction of downstream survival pathways leading to protection from anoikis and consequently resulting in cancer progression to metastasis. We recently reported that talin expression is significantly increased in prostate cancer compared with benign and normal prostate tissue and that this overexpression correlates with progression to metastatic disease implicating a prognostic value for talin during tumor progression. At the molecular level, talin is functionally associated with enhanced survival and proliferation pathways and confers anoikis resistance and metastatic spread of primary tumor cells via activation of the Akt survival pathway. In this review, we discuss the growing evidence surrounding the value of talin as a prognostic marker of cancer progression to metastasis and as therapeutic target in advanced prostate cancer, as well as the current understanding of mechanisms regulating its signaling activity in cancer.", + "authors": { + "abbreviation": "Andreas Desiniotis, Natasha Kyprianou", + "authorList": [ + { + "ForeName": "Andreas", + "LastName": "Desiniotis", + "abbrevName": "Desiniotis A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Desiniotis" + }, + { + "ForeName": "Natasha", + "LastName": "Kyprianou", + "abbrevName": "Kyprianou N", + "email": null, + "isCollectiveName": false, + "name": "Natasha Kyprianou" + } + ], + "contacts": [] + }, + "doi": "10.1016/B978-0-12-386039-2.00004-3", + "pmid": "21749900", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int Rev Cell Mol Biol 289 2011", + "title": "Significance of talin in cancer progression and metastasis." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "19732724", + "pubmed": { + "ISODate": "2009-09-08T00:00:00.000Z", + "abstract": "In cell lines from advanced lung cancer, breast cancer, and melanoma, endogenous tensin-3 contributes to cell migration, anchorage-independent growth, and tumorigenesis. Although SH2 domains have not been reported previously to be phosphorylated, the tensin-3 SH2 domain is a physiologic substrate for Src. Tyrosines in the SH2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. In a mouse breast cancer model, tensin-3 tyrosines are phosphorylated in a Src-associated manner in primary tumors, and experimental metastases induced by tumor-derived cell lines depend on endogenous tensin-3. Thus, tensin-3 is implicated as an oncoprotein regulated by Src and possessing an SH2 domain with a previously undescribed mechanism for the regulation of ligand binding.", + "authors": { + "abbreviation": "Xiaolan Qian, Guorong Li, William C Vass, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge A", + "email": null, + "isCollectiveName": false, + "name": "Alex Papageorge" + }, + { + "ForeName": "Renard", + "LastName": "Walker", + "abbrevName": "Walker RC", + "email": null, + "isCollectiveName": false, + "name": "Renard C Walker" + }, + { + "ForeName": "Laura", + "LastName": "Asnaghi", + "abbrevName": "Asnaghi L", + "email": null, + "isCollectiveName": false, + "name": "Laura Asnaghi" + }, + { + "ForeName": "Peter", + "LastName": "Steinbach", + "abbrevName": "Steinbach PJ", + "email": null, + "isCollectiveName": false, + "name": "Peter J Steinbach" + }, + { + "ForeName": "Giovanna", + "LastName": "Tosato", + "abbrevName": "Tosato G", + "email": null, + "isCollectiveName": false, + "name": "Giovanna Tosato" + }, + { + "ForeName": "Kent", + "LastName": "Hunter", + "abbrevName": "Hunter K", + "email": null, + "isCollectiveName": false, + "name": "Kent Hunter" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ccr.2009.07.031", + "pmid": "19732724", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Cell 16 2009", + "title": "The Tensin-3 protein, including its SH2 domain, is phosphorylated by Src and contributes to tumorigenesis and metastasis." + } + }, + { + "pmid": "19575647", + "pubmed": { + "ISODate": "2010-01-01T00:00:00.000Z", + "abstract": "Directed cell migration is a physical process that requires dramatic changes in cell shape and adhesion to the extracellular matrix. For efficient movement, these processes must be spatiotemporally coordinated. To a large degree, the morphological changes and physical forces that occur during migration are generated by a dynamic filamentous actin (F-actin) cytoskeleton. Adhesion is regulated by dynamic assemblies of structural and signaling proteins that couple the F-actin cytoskeleton to the extracellular matrix. Here, we review current knowledge of the dynamic organization of the F-actin cytoskeleton in cell migration and the regulation of focal adhesion assembly and disassembly with an emphasis on how mechanical and biochemical signaling between these two systems regulate the coordination of physical processes in cell migration.", + "authors": { + "abbreviation": "Margaret L Gardel, Ian C Schneider, Yvonne Aratyn-Schaus, Clare M Waterman", + "authorList": [ + { + "ForeName": "Margaret", + "LastName": "Gardel", + "abbrevName": "Gardel ML", + "email": null, + "isCollectiveName": false, + "name": "Margaret L Gardel" + }, + { + "ForeName": "Ian", + "LastName": "Schneider", + "abbrevName": "Schneider IC", + "email": null, + "isCollectiveName": false, + "name": "Ian C Schneider" + }, + { + "ForeName": "Yvonne", + "LastName": "Aratyn-Schaus", + "abbrevName": "Aratyn-Schaus Y", + "email": null, + "isCollectiveName": false, + "name": "Yvonne Aratyn-Schaus" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + } + ], + "contacts": [] + }, + "doi": "10.1146/annurev.cellbio.011209.122036", + "pmid": "19575647", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Annu Rev Cell Dev Biol 26 2010", + "title": "Mechanical integration of actin and adhesion dynamics in cell migration." + } + }, + { + "pmid": "19179532", + "pubmed": { + "ISODate": "2009-01-30T00:00:00.000Z", + "abstract": "The molecular mechanism by which a mechanical stimulus is translated into a chemical response in biological systems is still unclear. We show that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules. We used magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy to investigate the effect of force on the interaction between talin, a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system. Such protein stretching may be a more general mechanism for force transduction.", + "authors": { + "abbreviation": "Armando del Rio, Raul Perez-Jimenez, Ruchuan Liu, ..., Michael P Sheetz", + "authorList": [ + { + "ForeName": "Armando", + "LastName": "del Rio", + "abbrevName": "del Rio A", + "email": null, + "isCollectiveName": false, + "name": "Armando del Rio" + }, + { + "ForeName": "Raul", + "LastName": "Perez-Jimenez", + "abbrevName": "Perez-Jimenez R", + "email": null, + "isCollectiveName": false, + "name": "Raul Perez-Jimenez" + }, + { + "ForeName": "Ruchuan", + "LastName": "Liu", + "abbrevName": "Liu R", + "email": null, + "isCollectiveName": false, + "name": "Ruchuan Liu" + }, + { + "ForeName": "Pere", + "LastName": "Roca-Cusachs", + "abbrevName": "Roca-Cusachs P", + "email": null, + "isCollectiveName": false, + "name": "Pere Roca-Cusachs" + }, + { + "ForeName": "Julio", + "LastName": "Fernandez", + "abbrevName": "Fernandez JM", + "email": null, + "isCollectiveName": false, + "name": "Julio M Fernandez" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1162912", + "pmid": "19179532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 323 2009", + "title": "Stretching single talin rod molecules activates vinculin binding." + } + }, + { + "pmid": "19160486", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Cell spreading, adhesion and remodelling of the extracellular matrix (ECM) involve bi-directional signalling and physical linkages between the ECM, integrins and the cell cytoskeleton. The actin-binding proteins talin1 and 2 link ligand-bound integrins to the actin cytoskeleton and increase the affinity of integrin for the ECM. Here we report that depletion of talin2 in talin1-null (talin1(-/-)) cells did not affect the initiation of matrix-activated spreading or Src family kinase (SFK) activation, but abolished the ECM-integrin-cytoskeleton linkage and sustained cell spreading and adhesion. Specifically, focal adhesion assembly, focal adhesion kinase (FAK) signalling and traction force generation on substrates were severely affected. The talin1 head domain restored beta1 integrin activation but only full-length talin1 restored the ECM-cytoskeleton linkage and normal cytoskeleton organization. Our results demonstrate three biochemically distinct steps in fibronectin-activated cell spreading and adhesion: (1) fibronectin-integrin binding and initiation of spreading, (2) fast cell spreading and (3) focal adhesion formation and substrate traction. We suggest that talin is not required for initial cell spreading. However, talin provides the important mechanical linkage between ligand-bound integrins and the actin cytoskeleton required to catalyse focal adhesion-dependent pathways.", + "authors": { + "abbreviation": "Xian Zhang, Guoying Jiang, Yunfei Cai, ..., Michael P Sheetz", + "authorList": [ + { + "ForeName": "Xian", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xian Zhang" + }, + { + "ForeName": "Guoying", + "LastName": "Jiang", + "abbrevName": "Jiang G", + "email": null, + "isCollectiveName": false, + "name": "Guoying Jiang" + }, + { + "ForeName": "Yunfei", + "LastName": "Cai", + "abbrevName": "Cai Y", + "email": null, + "isCollectiveName": false, + "name": "Yunfei Cai" + }, + { + "ForeName": "Susan", + "LastName": "Monkley", + "abbrevName": "Monkley SJ", + "email": null, + "isCollectiveName": false, + "name": "Susan J Monkley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1765", + "pmid": "19160486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 10 2008", + "title": "Talin depletion reveals independence of initial cell spreading from integrin activation and traction." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "19059267", + "pubmed": { + "ISODate": "2009-01-23T00:00:00.000Z", + "abstract": "Coiled coils are protein structure domains with two or more alpha-helices packed together via interlacing of side chains known as knob-into-hole packing. We analysed and classified a large set of coiled-coil structures using a combination of automated and manual methods. This led to a systematic classification that we termed a \"periodic table of coiled coils,\" which we have made available at http://coiledcoils.chm.bris.ac.uk/ccplus/search/periodic_table. In this table, coiled-coil assemblies are arranged in columns with increasing numbers of alpha-helices and in rows of increased complexity. The table provides a framework for understanding possibilities in and limits on coiled-coil structures and a basis for future prediction, engineering and design studies.", + "authors": { + "abbreviation": "Efrosini Moutevelis, Derek N Woolfson", + "authorList": [ + { + "ForeName": "Efrosini", + "LastName": "Moutevelis", + "abbrevName": "Moutevelis E", + "email": null, + "isCollectiveName": false, + "name": "Efrosini Moutevelis" + }, + { + "ForeName": "Derek", + "LastName": "Woolfson", + "abbrevName": "Woolfson DN", + "email": null, + "isCollectiveName": false, + "name": "Derek N Woolfson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2008.11.028", + "pmid": "19059267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 385 2009", + "title": "A periodic table of coiled-coil protein structures." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "16460027", + "pubmed": { + "ISODate": "2006-02-14T00:00:00.000Z", + "abstract": "Talin is a key protein involved in linking integrins to the actin cytoskeleton. The long flexible talin rod domain contains a number of binding sites for vinculin, a cytoskeletal protein important in stabilizing integrin-mediated cell-matrix junctions. Here we report the solution structure of a talin rod polypeptide (residues 1843-1973) which contains a single vinculin binding site (VBS; residues 1944-1969). Like other talin rod polypeptides, it consists of a helical bundle, in this case a four-helix bundle with a right-handed topology. The residues in the VBS important for vinculin binding were identified by studying the binding of a series of VBS-related peptides to the vinculin Vd1 domain. The key binding determinants are buried in the interior of the helical bundle, suggesting that a substantial structural change in the talin polypeptide is required for vinculin binding. Direct evidence for this was obtained by NMR and EPR spectroscopy. [1H,15N]-HSQC spectra of the talin fragment indicate that vinculin binding caused approximately two-thirds of the protein to adopt a flexible random coil. For EPR spectroscopy, nitroxide spin labels were attached to the talin polypeptide via appropriately located cysteine residues. Measurements of inter-nitroxide distances in doubly spin-labeled protein showed clearly that the helical bundle is disrupted and the mobility of the helices, except for the VBS helix, is markedly increased. Binding of vinculin to talin is thus a clear example of the unusual phenomenon of protein unfolding being required for protein/protein interaction.", + "authors": { + "abbreviation": "Alexandre R Gingras, Klaus-Peter Vogel, Heinz-Jürgen Steinhoff, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Klaus-Peter", + "LastName": "Vogel", + "abbrevName": "Vogel KP", + "email": null, + "isCollectiveName": false, + "name": "Klaus-Peter Vogel" + }, + { + "ForeName": "Heinz-Jürgen", + "LastName": "Steinhoff", + "abbrevName": "Steinhoff HJ", + "email": null, + "isCollectiveName": false, + "name": "Heinz-Jürgen Steinhoff" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi052136l", + "pmid": "16460027", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 45 2006", + "title": "Structural and dynamic characterization of a vinculin binding site in the talin rod." + } + }, + { + "pmid": "15837513", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "alpha-Helical coiled coils are versatile protein domains, supporting a wide range of biological functions. Their fold is probably better understood than that of any other protein; indeed, uniquely among folds, their structure can be computed from a set of parametric equations. Here, we review the principles of coiled-coil structure, the determinants of their folding and stability, and the diversity of structural forms they assume.", + "authors": { + "abbreviation": "Andrei N Lupas, Markus Gruber", + "authorList": [ + { + "ForeName": "Andrei", + "LastName": "Lupas", + "abbrevName": "Lupas AN", + "email": null, + "isCollectiveName": false, + "name": "Andrei N Lupas" + }, + { + "ForeName": "Markus", + "LastName": "Gruber", + "abbrevName": "Gruber M", + "email": null, + "isCollectiveName": false, + "name": "Markus Gruber" + } + ], + "contacts": [] + }, + "doi": "10.1016/S0065-3233(05)70003-6", + "pmid": "15837513", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Adv Protein Chem 70 2005", + "title": "The structure of alpha-helical coiled coils." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "14527389", + "pubmed": { + "ISODate": "2003-10-01T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are large submembrane signaling complexes formed at sites of cellular attachment to the extracellular matrix. The interaction of LD motifs with their targets plays an important role in the assembly of FAs. We have determined the molecular basis for the recognition of two paxillin LD motifs by the FA targeting (FAT) domain of FA kinase using a combination of X-ray crystallography, solution NMR, and homology modeling. The four-helix FAT domain displays two LD binding sites on opposite sites of the molecule that bind LD peptides in a helical conformation. Threading studies suggest that the LD-interacting domain of p95PKL shares a common four-helical core with the FAT domain and the tail of vinculin, defining a structural family of LD motif binding modules.", + "authors": { + "abbreviation": "Maria K Hoellerer, Martin E M Noble, Gilles Labesse, ..., Stefan T Arold", + "authorList": [ + { + "ForeName": "Maria", + "LastName": "Hoellerer", + "abbrevName": "Hoellerer MK", + "email": null, + "isCollectiveName": false, + "name": "Maria K Hoellerer" + }, + { + "ForeName": "Martin", + "LastName": "Noble", + "abbrevName": "Noble ME", + "email": null, + "isCollectiveName": false, + "name": "Martin E M Noble" + }, + { + "ForeName": "Gilles", + "LastName": "Labesse", + "abbrevName": "Labesse G", + "email": null, + "isCollectiveName": false, + "name": "Gilles Labesse" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "Jörn", + "LastName": "Werner", + "abbrevName": "Werner JM", + "email": null, + "isCollectiveName": false, + "name": "Jörn M Werner" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2003.08.010", + "pmid": "14527389", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 11 2003", + "title": "Molecular recognition of paxillin LD motifs by the focal adhesion targeting domain." + } + }, + { + "pmid": "11799401", + "pubmed": { + "ISODate": "2002-02-01T00:00:00.000Z", + "abstract": "Focal adhesion kinase (FAK) is a tyrosine kinase found in focal adhesions, intracellular signaling complexes that are formed following engagement of the extracellular matrix by integrins. The C-terminal 'focal adhesion targeting' (FAT) region is necessary and sufficient for localizing FAK to focal adhesions. We have determined the crystal structure of FAT and show that it forms a four-helix bundle that resembles those found in two other proteins involved in cell adhesion, alpha-catenin and vinculin. The binding of FAT to the focal adhesion protein, paxillin, requires the integrity of the helical bundle, whereas binding to another focal adhesion protein, talin, does not. We show by mutagenesis that paxillin binding involves two hydrophobic patches on opposite faces of the bundle and propose a model in which two LD motifs of paxillin adopt amphipathic helices that augment the hydrophobic core of FAT, creating a six-helix bundle.", + "authors": { + "abbreviation": "Ikuko Hayashi, Kristiina Vuori, Robert C Liddington", + "authorList": [ + { + "ForeName": "Ikuko", + "LastName": "Hayashi", + "abbrevName": "Hayashi I", + "email": null, + "isCollectiveName": false, + "name": "Ikuko Hayashi" + }, + { + "ForeName": "Kristiina", + "LastName": "Vuori", + "abbrevName": "Vuori K", + "email": null, + "isCollectiveName": false, + "name": "Kristiina Vuori" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + } + ], + "contacts": [] + }, + "doi": "10.1038/nsb755", + "pmid": "11799401", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nat Struct Biol 9 2002", + "title": "The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin." + } + } + ], + "relatedPapers": [ + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "25452387", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. ", + "authors": { + "abbreviation": "Brajendra K Tripathi, Xiaolan Qian, Philipp Mertins, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201405105", + "pmid": "25452387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 207 2014", + "title": "CDK5 is a major regulator of the tumor suppressor DLC1." + } + }, + { + "pmid": "22645138", + "pubmed": { + "ISODate": "2012-07-27T00:00:00.000Z", + "abstract": "The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.", + "authors": { + "abbreviation": "Lihong Chen, Changdong Liu, Frankie Chi Fat Ko, ..., Guang Zhu", + "authorList": [ + { + "ForeName": "Lihong", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Lihong Chen" + }, + { + "ForeName": "Changdong", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Changdong Liu" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Naining", + "LastName": "Xu", + "abbrevName": "Xu N", + "email": null, + "isCollectiveName": false, + "name": "Naining Xu" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Guang", + "LastName": "Zhu", + "abbrevName": "Zhu G", + "email": null, + "isCollectiveName": false, + "name": "Guang Zhu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.360206", + "pmid": "22645138", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode." + } + }, + { + "pmid": "27150043", + "pubmed": { + "ISODate": "2016-05-03T00:00:00.000Z", + "abstract": "Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.", + "authors": { + "abbreviation": "Hao Zhang, Yu-Chung Chang, Qingqiu Huang, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Qingqiu", + "LastName": "Huang", + "abbrevName": "Huang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqiu Huang" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2016.02.020", + "pmid": "27150043", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 24 2016", + "title": "Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration." + } + }, + { + "pmid": "31806702", + "pubmed": { + "ISODate": "2020-01-10T00:00:00.000Z", + "abstract": "Deleted-in-liver cancer 1 (DLC1) exerts its tumor suppressive function mainly through the Rho-GTPase-activating protein (RhoGAP) domain. When activated, the domain promotes the hydrolysis of RhoA-GTP, leading to reduced cell migration. DLC1 is kept in an inactive state by an intramolecular interaction between its RhoGAP domain and the DLC1 sterile α motif (SAM) domain. We have shown previously that this autoinhibited state of DLC1 may be alleviated by tensin-3 (TNS3) or PTEN. We show here that the TNS3/PTEN-DLC1 interactions are mediated by the C2 domains of the former and the SAM domain of the latter. Intriguingly, the DLC1 SAM domain was capable of binding to specific peptide motifs within the C2 domains. Indeed, peptides containing the binding motifs were highly effective in blocking the C2-SAM domain-domain interaction. Importantly, when fused to the tat protein-transduction sequence and subsequently introduced into cells, the C2 peptides potently promoted the RhoGAP function in DLC1, leading to decreased RhoA activation and reduced tumor cell growth in soft agar and migration in response to growth factor stimulation. To facilitate the development of the C2 peptides as potential therapeutic agents, we created a cyclic version of the TNS3 C2 domain-derived peptide and showed that this peptide readily entered the MDA-MB-231 breast cancer cells and effectively inhibited their migration. Our work shows, for the first time, that the SAM domain is a peptide-binding module and establishes the framework on which to explore DLC1 SAM domain-binding peptides as potential therapeutic agents for cancer treatment.", + "authors": { + "abbreviation": "Rakesh Joshi, Lyugao Qin, Xuan Cao, ..., Shawn S C Li", + "authorList": [ + { + "ForeName": "Rakesh", + "LastName": "Joshi", + "abbrevName": "Joshi R", + "email": null, + "isCollectiveName": false, + "name": "Rakesh Joshi" + }, + { + "ForeName": "Lyugao", + "LastName": "Qin", + "abbrevName": "Qin L", + "email": null, + "isCollectiveName": false, + "name": "Lyugao Qin" + }, + { + "ForeName": "Xuan", + "LastName": "Cao", + "abbrevName": "Cao X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Cao" + }, + { + "ForeName": "Shanshan", + "LastName": "Zhong", + "abbrevName": "Zhong S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Zhong" + }, + { + "ForeName": "Courtney", + "LastName": "Voss", + "abbrevName": "Voss C", + "email": null, + "isCollectiveName": false, + "name": "Courtney Voss" + }, + { + "ForeName": "Weiping", + "LastName": "Min", + "abbrevName": "Min W", + "email": "weiping.min@uwo.ca", + "isCollectiveName": false, + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "abbrevName": "Li SSC", + "email": "sli@uwo.ca", + "isCollectiveName": false, + "name": "Shawn S C Li" + } + ], + "contacts": [ + { + "ForeName": "Weiping", + "LastName": "Min", + "email": [ + "weiping.min@uwo.ca" + ], + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "email": [ + "sli@uwo.ca" + ], + "name": "Shawn S C Li" + } + ] + }, + "doi": "10.1074/jbc.RA119.011929", + "pmid": "31806702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 295 2020", + "title": "DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA." + } + }, + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "21087603", + "pubmed": { + "ISODate": "2011-02-15T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Johan O R Gustafsson, Peter Hoffmann, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Johan", + "LastName": "Gustafsson", + "abbrevName": "Gustafsson JO", + "email": null, + "isCollectiveName": false, + "name": "Johan O R Gustafsson" + }, + { + "ForeName": "Peter", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann P", + "email": null, + "isCollectiveName": false, + "name": "Peter Hoffmann" + }, + { + "ForeName": "Mamta", + "LastName": "Jaiswal", + "abbrevName": "Jaiswal M", + "email": null, + "isCollectiveName": false, + "name": "Mamta Jaiswal" + }, + { + "ForeName": "Mohammed", + "LastName": "Ahmadian", + "abbrevName": "Ahmadian MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Reza Ahmadian" + }, + { + "ForeName": "Stephan", + "LastName": "Eisler", + "abbrevName": "Eisler SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Eisler" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2010.11.003", + "pmid": "21087603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 317 2011", + "title": "The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation." + } + }, + { + "pmid": "25448629", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.", + "authors": { + "abbreviation": "Shelly Kaushik, Archna Ravi, Feroz M Hameed, Boon Chuan Low", + "authorList": [ + { + "ForeName": "Shelly", + "LastName": "Kaushik", + "abbrevName": "Kaushik S", + "email": null, + "isCollectiveName": false, + "name": "Shelly Kaushik" + }, + { + "ForeName": "Archna", + "LastName": "Ravi", + "abbrevName": "Ravi A", + "email": null, + "isCollectiveName": false, + "name": "Archna Ravi" + }, + { + "ForeName": "Feroz", + "LastName": "Hameed", + "abbrevName": "Hameed FM", + "email": null, + "isCollectiveName": false, + "name": "Feroz M Hameed" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21201", + "pmid": "25448629", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cytoskeleton (Hoboken) 71 2014", + "title": "Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "21372205", + "pubmed": { + "ISODate": "2011-04-15T00:00:00.000Z", + "abstract": "The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.", + "authors": { + "abbreviation": "Xuyu Yang, Nicholas C Popescu, Drazen B Zimonjic", + "authorList": [ + { + "ForeName": "Xuyu", + "LastName": "Yang", + "abbrevName": "Yang X", + "email": null, + "isCollectiveName": false, + "name": "Xuyu Yang" + }, + { + "ForeName": "Nicholas", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "Nicholas C Popescu" + }, + { + "ForeName": "Drazen", + "LastName": "Zimonjic", + "abbrevName": "Zimonjic DB", + "email": null, + "isCollectiveName": false, + "name": "Drazen B Zimonjic" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-10-2158", + "pmid": "21372205", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 71 2011", + "title": "DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism." + } + }, + { + "pmid": "29153504", + "pubmed": { + "ISODate": "2017-12-05T00:00:00.000Z", + "abstract": "Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch.", + "authors": { + "abbreviation": "Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson", + "authorList": [ + { + "ForeName": "Nicola", + "LastName": "Baxter", + "abbrevName": "Baxter NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicola J Baxter" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Mike", + "LastName": "Williamson", + "abbrevName": "Williamson MP", + "email": "m.williamson@sheffield.ac.uk", + "isCollectiveName": false, + "name": "Mike P Williamson" + } + ], + "contacts": [ + { + "ForeName": "Mike", + "LastName": "Williamson", + "email": [ + "m.williamson@sheffield.ac.uk" + ], + "name": "Mike P Williamson" + } + ] + }, + "doi": "10.1016/j.str.2017.10.008", + "pmid": "29153504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 25 2017", + "title": "Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM." + } + }, + { + "pmid": "16951145", + "pubmed": { + "ISODate": "2006-09-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell lines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immunoprecipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.", + "authors": { + "abbreviation": "Judy Wai Ping Yam, Frankie Chi Fat Ko, Chung-Yiu Chan, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Chung-Yiu", + "LastName": "Chan", + "abbrevName": "Chan CY", + "email": null, + "isCollectiveName": false, + "name": "Chung-Yiu Chan" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-2850", + "pmid": "16951145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 66 2006", + "title": "Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression." + } + }, + { + "pmid": "19066281", + "pubmed": { + "ISODate": "2009-01-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Jennifer Regner, Anke Theil, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Jennifer", + "LastName": "Regner", + "abbrevName": "Regner J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Regner" + }, + { + "ForeName": "Anke", + "LastName": "Theil", + "abbrevName": "Theil A", + "email": null, + "isCollectiveName": false, + "name": "Anke Theil" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Gerlinde", + "LastName": "Holeiter", + "abbrevName": "Holeiter G", + "email": null, + "isCollectiveName": false, + "name": "Gerlinde Holeiter" + }, + { + "ForeName": "Ruth", + "LastName": "Jähne", + "abbrevName": "Jähne R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Jähne" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.036251", + "pmid": "19066281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "19158340", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.", + "authors": { + "abbreviation": "Dandan Zhong, Jingfeng Zhang, Shuai Yang, ..., Boon Chuan Low", + "authorList": [ + { + "ForeName": "Dandan", + "LastName": "Zhong", + "abbrevName": "Zhong D", + "email": null, + "isCollectiveName": false, + "name": "Dandan Zhong" + }, + { + "ForeName": "Jingfeng", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Zhang" + }, + { + "ForeName": "Shuai", + "LastName": "Yang", + "abbrevName": "Yang S", + "email": null, + "isCollectiveName": false, + "name": "Shuai Yang" + }, + { + "ForeName": "Unice", + "LastName": "Soh", + "abbrevName": "Soh UJ", + "email": null, + "isCollectiveName": false, + "name": "Unice J K Soh" + }, + { + "ForeName": "Jan", + "LastName": "Buschdorf", + "abbrevName": "Buschdorf JP", + "email": null, + "isCollectiveName": false, + "name": "Jan Paul Buschdorf" + }, + { + "ForeName": "Yi", + "LastName": "Zhou", + "abbrevName": "Zhou YT", + "email": null, + "isCollectiveName": false, + "name": "Yi Ting Zhou" + }, + { + "ForeName": "Daiwen", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Daiwen Yang" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.027482", + "pmid": "19158340", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration." + } + }, + { + "pmid": "31308216", + "pubmed": { + "ISODate": "2019-09-02T00:00:00.000Z", + "abstract": "SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1's tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors.", + "authors": { + "abbreviation": "Brajendra K Tripathi, Meghan F Anderman, Xiaolan Qian, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "tripathib@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Meghan", + "LastName": "Anderman", + "abbrevName": "Anderman MF", + "email": null, + "isCollectiveName": false, + "name": "Meghan F Anderman" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Ming", + "LastName": "Zhou", + "abbrevName": "Zhou M", + "email": null, + "isCollectiveName": false, + "name": "Ming Zhou" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201810098", + "pmid": "31308216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 218 2019", + "title": "SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions." + } + }, + { + "pmid": "24446374", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several β integrin cytoplasmic tails (βCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with β3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with β3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbβ3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the β3 subunit. The study presented, defines a novel direct interaction of VD1 with β3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.", + "authors": { + "abbreviation": "Suman Yadav Nanda, Thuy Hoang, Priya Patel, Hao Zhang", + "authorList": [ + { + "ForeName": "Suman", + "LastName": "Nanda", + "abbrevName": "Nanda SY", + "email": null, + "isCollectiveName": false, + "name": "Suman Yadav Nanda" + }, + { + "ForeName": "Thuy", + "LastName": "Hoang", + "abbrevName": "Hoang T", + "email": null, + "isCollectiveName": false, + "name": "Thuy Hoang" + }, + { + "ForeName": "Priya", + "LastName": "Patel", + "abbrevName": "Patel P", + "email": null, + "isCollectiveName": false, + "name": "Priya Patel" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24772", + "pmid": "24446374", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biochem 115 2014", + "title": "Vinculin regulates assembly of talin: β3 integrin complexes." + } + }, + { + "pmid": "26427649", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. ", + "authors": { + "abbreviation": "Yi-Ping Shih, Peng Sun, Aifeng Wang, Su Hao Lo", + "authorList": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "abbrevName": "Shih YP", + "email": "ypshih@ucdavis.edu", + "isCollectiveName": false, + "name": "Yi-Ping Shih" + }, + { + "ForeName": "Peng", + "LastName": "Sun", + "abbrevName": "Sun P", + "email": null, + "isCollectiveName": false, + "name": "Peng Sun" + }, + { + "ForeName": "Aifeng", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aifeng Wang" + }, + { + "ForeName": "Su", + "LastName": "Lo", + "abbrevName": "Lo SH", + "email": null, + "isCollectiveName": false, + "name": "Su Hao Lo" + } + ], + "contacts": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "email": [ + "ypshih@ucdavis.edu" + ], + "name": "Yi-Ping Shih" + } + ] + }, + "doi": "10.1016/j.bbamcr.2015.09.028", + "pmid": "26427649", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochim Biophys Acta 1853 2015", + "title": "Tensin1 positively regulates RhoA activity through its interaction with DLC1." + } + }, + { + "pmid": "19151751", + "pubmed": { + "ISODate": "2009-03-19T00:00:00.000Z", + "abstract": "DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610", + "authors": { + "abbreviation": "X-Y Yang, M Guan, D Vigil, ..., N C Popescu", + "authorList": [ + { + "ForeName": "X-Y", + "LastName": "Yang", + "abbrevName": "Yang XY", + "email": null, + "isCollectiveName": false, + "name": "X-Y Yang" + }, + { + "ForeName": "M", + "LastName": "Guan", + "abbrevName": "Guan M", + "email": null, + "isCollectiveName": false, + "name": "M Guan" + }, + { + "ForeName": "D", + "LastName": "Vigil", + "abbrevName": "Vigil D", + "email": null, + "isCollectiveName": false, + "name": "D Vigil" + }, + { + "ForeName": "C", + "LastName": "Der", + "abbrevName": "Der CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Der" + }, + { + "ForeName": "D", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "D R Lowy" + }, + { + "ForeName": "N", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "N C Popescu" + } + ], + "contacts": [] + }, + "doi": "10.1038/onc.2008.498", + "pmid": "19151751", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncogene 28 2009", + "title": "p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "16204057", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.", + "authors": { + "abbreviation": "Chun-Ming Wong, Judy Wai-Ping Yam, Yick-Pang Ching, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Chun-Ming", + "LastName": "Wong", + "abbrevName": "Wong CM", + "email": null, + "isCollectiveName": false, + "name": "Chun-Ming Wong" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai-Ping Yam" + }, + { + "ForeName": "Yick-Pang", + "LastName": "Ching", + "abbrevName": "Ching YP", + "email": null, + "isCollectiveName": false, + "name": "Yick-Pang Ching" + }, + { + "ForeName": "Tai-On", + "LastName": "Yau", + "abbrevName": "Yau TO", + "email": null, + "isCollectiveName": false, + "name": "Tai-On Yau" + }, + { + "ForeName": "Thomas", + "LastName": "Leung", + "abbrevName": "Leung TH", + "email": null, + "isCollectiveName": false, + "name": "Thomas Ho-Yin Leung" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-1318", + "pmid": "16204057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 65 2005", + "title": "Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "32606003", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.", + "authors": { + "abbreviation": "Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Beatriz", + "LastName": "Sanchez-Solana", + "abbrevName": "Sanchez-Solana B", + "email": null, + "isCollectiveName": false, + "name": "Beatriz Sanchez-Solana" + }, + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": null, + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Marian", + "LastName": "Durkin", + "abbrevName": "Durkin ME", + "email": null, + "isCollectiveName": false, + "name": "Marian E Durkin" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-19-3984", + "pmid": "32606003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 80 2020", + "title": "Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function." + } + }, + { + "pmid": "28155884", + "pubmed": { + "ISODate": "2017-02-03T00:00:00.000Z", + "abstract": "Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.", + "authors": { + "abbreviation": "Yaxia Yuan, Liqing Li, Yanyan Zhu, ..., Cai Huang", + "authorList": [ + { + "ForeName": "Yaxia", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yaxia Yuan" + }, + { + "ForeName": "Liqing", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Liqing Li" + }, + { + "ForeName": "Yanyan", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhu" + }, + { + "ForeName": "Lei", + "LastName": "Qi", + "abbrevName": "Qi L", + "email": null, + "isCollectiveName": false, + "name": "Lei Qi" + }, + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Chang-Guo", + "LastName": "Zhan", + "abbrevName": "Zhan CG", + "email": null, + "isCollectiveName": false, + "name": "Chang-Guo Zhan" + }, + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep41989", + "pmid": "28155884", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "The molecular basis of talin2's high affinity toward β1-integrin." + } + }, + { + "pmid": "21130076", + "pubmed": { + "ISODate": "2011-01-07T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1), a tumor suppressor gene identified in a primary human hepatocellular carcinoma, encodes a Rho GTPase-activating protein (RhoGAP). Although DLC1 expression has been studied at the transcriptional level, little is known about its regulation at the protein level. Here we show that DLC1 is an unstable protein that is degraded by the 26S proteasome in human hepatocellular carcinoma Hep3B cells. In addition, five putative PEST motifs were identified in the N-terminus of DLC1. Unexpectedly, the N-terminus of DLC1 appeared to be stable. Furthermore, deletion of any one of the five PEST motifs except PEST2 decreased the stability of the N-terminus of DLC1, which suggests that the PEST motifs may play an unrevealed role in maintaining the stability of DLC1. These data indicated that the intracellular stability of DLC1 is regulated by the 26S proteasome via its PEST motifs.", + "authors": { + "abbreviation": "Hong-wei Luo, Qiu-ping Luo, Ying Yuan, ..., Wen-li Feng", + "authorList": [ + { + "ForeName": "Hong-wei", + "LastName": "Luo", + "abbrevName": "Luo HW", + "email": null, + "isCollectiveName": false, + "name": "Hong-wei Luo" + }, + { + "ForeName": "Qiu-ping", + "LastName": "Luo", + "abbrevName": "Luo QP", + "email": null, + "isCollectiveName": false, + "name": "Qiu-ping Luo" + }, + { + "ForeName": "Ying", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Yuan" + }, + { + "ForeName": "Xiao-ying", + "LastName": "Zhu", + "abbrevName": "Zhu XY", + "email": null, + "isCollectiveName": false, + "name": "Xiao-ying Zhu" + }, + { + "ForeName": "Shi-feng", + "LastName": "Huang", + "abbrevName": "Huang SF", + "email": null, + "isCollectiveName": false, + "name": "Shi-feng Huang" + }, + { + "ForeName": "Zhi", + "LastName": "Peng", + "abbrevName": "Peng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Peng" + }, + { + "ForeName": "Chun-li", + "LastName": "Li", + "abbrevName": "Li CL", + "email": null, + "isCollectiveName": false, + "name": "Chun-li Li" + }, + { + "ForeName": "Zong-gan", + "LastName": "Huang", + "abbrevName": "Huang ZG", + "email": null, + "isCollectiveName": false, + "name": "Zong-gan Huang" + }, + { + "ForeName": "Wen-li", + "LastName": "Feng", + "abbrevName": "Feng WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-li Feng" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2010.11.107", + "pmid": "21130076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 404 2011", + "title": "The intracellular stability of DLC1 is regulated by the 26S proteasome in human hepatocellular carcinoma cell line Hep3B." + } + }, + { + "pmid": "25277990", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links β3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the β-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the β-integrin still remains bound to talin. The epithelial integrin β6 reportedly activates latent TGFβ1, and we propose that its function may involve direct interaction with talin. ", + "authors": { + "abbreviation": "Sampo Kukkurainen, Juha A Määttä, John Saeger, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "abbrevName": "Kukkurainen S", + "email": "vesa.hytonen@uta.fi", + "isCollectiveName": false, + "name": "Sampo Kukkurainen" + }, + { + "ForeName": "Juha", + "LastName": "Määttä", + "abbrevName": "Määttä JA", + "email": null, + "isCollectiveName": false, + "name": "Juha A Määttä" + }, + { + "ForeName": "John", + "LastName": "Saeger", + "abbrevName": "Saeger J", + "email": null, + "isCollectiveName": false, + "name": "John Saeger" + }, + { + "ForeName": "Jarkko", + "LastName": "Valjakka", + "abbrevName": "Valjakka J", + "email": null, + "isCollectiveName": false, + "name": "Jarkko Valjakka" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "email": [ + "vesa.hytonen@uta.fi" + ], + "name": "Sampo Kukkurainen" + } + ] + }, + "doi": "10.1039/c4mb00341a", + "pmid": "25277990", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biosyst 10 2014", + "title": "The talin-integrin interface under mechanical stress." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "24114040", + "pubmed": { + "ISODate": "2014-07-15T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1. ", + "authors": { + "abbreviation": "Frankie Chi Fat Ko, Judy Wai Ping Yam", + "authorList": [ + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Judy", + "LastName": "Ping Yam", + "abbrevName": "Ping Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28505", + "pmid": "24114040", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Cancer 135 2014", + "title": "Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation." + } + } + ], + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2022-02-02T21:50:21.182Z", + "_newestOpId": "178890b6-54ca-45d0-87c5-ece81c2f0352", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "186745" + }, + { + "db": "HGNC", + "id": "HGNC:11845" + }, + { + "db": "Ensembl", + "id": "ENSG00000137076" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.344946, + "formulae": null, + "id": "7094", + "inchi": null, + "inchiKey": null, + "mass": null, + "monoisotopicMass": null, + "name": "TLN1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "ILWEQ", + "TLN", + "talin-1", + "talin 1" + ], + "summary": null, + "synonyms": [ + "ILWEQ", + "TLN", + "talin-1", + "talin 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "63eb9fac-573b-4bb2-8ac9-22b7da2ac361", + "liveId": "32ac59d3-7f1c-42d4-9bfe-3d39b021d4f3", + "lock": null, + "locked": false, + "name": "Tln1", + "position": { + "x": 200, + "y": 111.39240506329114 + }, + "relatedPapers": [ + { + "pmid": "16951145", + "pubmed": { + "ISODate": "2006-09-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell lines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immunoprecipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.", + "authors": { + "abbreviation": "Judy Wai Ping Yam, Frankie Chi Fat Ko, Chung-Yiu Chan, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Chung-Yiu", + "LastName": "Chan", + "abbrevName": "Chan CY", + "email": null, + "isCollectiveName": false, + "name": "Chung-Yiu Chan" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-2850", + "pmid": "16951145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 66 2006", + "title": "Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "22645138", + "pubmed": { + "ISODate": "2012-07-27T00:00:00.000Z", + "abstract": "The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.", + "authors": { + "abbreviation": "Lihong Chen, Changdong Liu, Frankie Chi Fat Ko, ..., Guang Zhu", + "authorList": [ + { + "ForeName": "Lihong", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Lihong Chen" + }, + { + "ForeName": "Changdong", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Changdong Liu" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Naining", + "LastName": "Xu", + "abbrevName": "Xu N", + "email": null, + "isCollectiveName": false, + "name": "Naining Xu" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Guang", + "LastName": "Zhu", + "abbrevName": "Zhu G", + "email": null, + "isCollectiveName": false, + "name": "Guang Zhu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.360206", + "pmid": "22645138", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode." + } + }, + { + "pmid": "31806702", + "pubmed": { + "ISODate": "2020-01-10T00:00:00.000Z", + "abstract": "Deleted-in-liver cancer 1 (DLC1) exerts its tumor suppressive function mainly through the Rho-GTPase-activating protein (RhoGAP) domain. When activated, the domain promotes the hydrolysis of RhoA-GTP, leading to reduced cell migration. DLC1 is kept in an inactive state by an intramolecular interaction between its RhoGAP domain and the DLC1 sterile α motif (SAM) domain. We have shown previously that this autoinhibited state of DLC1 may be alleviated by tensin-3 (TNS3) or PTEN. We show here that the TNS3/PTEN-DLC1 interactions are mediated by the C2 domains of the former and the SAM domain of the latter. Intriguingly, the DLC1 SAM domain was capable of binding to specific peptide motifs within the C2 domains. Indeed, peptides containing the binding motifs were highly effective in blocking the C2-SAM domain-domain interaction. Importantly, when fused to the tat protein-transduction sequence and subsequently introduced into cells, the C2 peptides potently promoted the RhoGAP function in DLC1, leading to decreased RhoA activation and reduced tumor cell growth in soft agar and migration in response to growth factor stimulation. To facilitate the development of the C2 peptides as potential therapeutic agents, we created a cyclic version of the TNS3 C2 domain-derived peptide and showed that this peptide readily entered the MDA-MB-231 breast cancer cells and effectively inhibited their migration. Our work shows, for the first time, that the SAM domain is a peptide-binding module and establishes the framework on which to explore DLC1 SAM domain-binding peptides as potential therapeutic agents for cancer treatment.", + "authors": { + "abbreviation": "Rakesh Joshi, Lyugao Qin, Xuan Cao, ..., Shawn S C Li", + "authorList": [ + { + "ForeName": "Rakesh", + "LastName": "Joshi", + "abbrevName": "Joshi R", + "email": null, + "isCollectiveName": false, + "name": "Rakesh Joshi" + }, + { + "ForeName": "Lyugao", + "LastName": "Qin", + "abbrevName": "Qin L", + "email": null, + "isCollectiveName": false, + "name": "Lyugao Qin" + }, + { + "ForeName": "Xuan", + "LastName": "Cao", + "abbrevName": "Cao X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Cao" + }, + { + "ForeName": "Shanshan", + "LastName": "Zhong", + "abbrevName": "Zhong S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Zhong" + }, + { + "ForeName": "Courtney", + "LastName": "Voss", + "abbrevName": "Voss C", + "email": null, + "isCollectiveName": false, + "name": "Courtney Voss" + }, + { + "ForeName": "Weiping", + "LastName": "Min", + "abbrevName": "Min W", + "email": "weiping.min@uwo.ca", + "isCollectiveName": false, + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "abbrevName": "Li SSC", + "email": "sli@uwo.ca", + "isCollectiveName": false, + "name": "Shawn S C Li" + } + ], + "contacts": [ + { + "ForeName": "Weiping", + "LastName": "Min", + "email": [ + "weiping.min@uwo.ca" + ], + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "email": [ + "sli@uwo.ca" + ], + "name": "Shawn S C Li" + } + ] + }, + "doi": "10.1074/jbc.RA119.011929", + "pmid": "31806702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 295 2020", + "title": "DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "24446374", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several β integrin cytoplasmic tails (βCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with β3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with β3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbβ3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the β3 subunit. The study presented, defines a novel direct interaction of VD1 with β3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.", + "authors": { + "abbreviation": "Suman Yadav Nanda, Thuy Hoang, Priya Patel, Hao Zhang", + "authorList": [ + { + "ForeName": "Suman", + "LastName": "Nanda", + "abbrevName": "Nanda SY", + "email": null, + "isCollectiveName": false, + "name": "Suman Yadav Nanda" + }, + { + "ForeName": "Thuy", + "LastName": "Hoang", + "abbrevName": "Hoang T", + "email": null, + "isCollectiveName": false, + "name": "Thuy Hoang" + }, + { + "ForeName": "Priya", + "LastName": "Patel", + "abbrevName": "Patel P", + "email": null, + "isCollectiveName": false, + "name": "Priya Patel" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24772", + "pmid": "24446374", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biochem 115 2014", + "title": "Vinculin regulates assembly of talin: β3 integrin complexes." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "21372205", + "pubmed": { + "ISODate": "2011-04-15T00:00:00.000Z", + "abstract": "The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.", + "authors": { + "abbreviation": "Xuyu Yang, Nicholas C Popescu, Drazen B Zimonjic", + "authorList": [ + { + "ForeName": "Xuyu", + "LastName": "Yang", + "abbrevName": "Yang X", + "email": null, + "isCollectiveName": false, + "name": "Xuyu Yang" + }, + { + "ForeName": "Nicholas", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "Nicholas C Popescu" + }, + { + "ForeName": "Drazen", + "LastName": "Zimonjic", + "abbrevName": "Zimonjic DB", + "email": null, + "isCollectiveName": false, + "name": "Drazen B Zimonjic" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-10-2158", + "pmid": "21372205", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 71 2011", + "title": "DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism." + } + }, + { + "pmid": "24114040", + "pubmed": { + "ISODate": "2014-07-15T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1. ", + "authors": { + "abbreviation": "Frankie Chi Fat Ko, Judy Wai Ping Yam", + "authorList": [ + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Judy", + "LastName": "Ping Yam", + "abbrevName": "Ping Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28505", + "pmid": "24114040", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Cancer 135 2014", + "title": "Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation." + } + }, + { + "pmid": "16204057", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.", + "authors": { + "abbreviation": "Chun-Ming Wong, Judy Wai-Ping Yam, Yick-Pang Ching, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Chun-Ming", + "LastName": "Wong", + "abbrevName": "Wong CM", + "email": null, + "isCollectiveName": false, + "name": "Chun-Ming Wong" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai-Ping Yam" + }, + { + "ForeName": "Yick-Pang", + "LastName": "Ching", + "abbrevName": "Ching YP", + "email": null, + "isCollectiveName": false, + "name": "Yick-Pang Ching" + }, + { + "ForeName": "Tai-On", + "LastName": "Yau", + "abbrevName": "Yau TO", + "email": null, + "isCollectiveName": false, + "name": "Tai-On Yau" + }, + { + "ForeName": "Thomas", + "LastName": "Leung", + "abbrevName": "Leung TH", + "email": null, + "isCollectiveName": false, + "name": "Thomas Ho-Yin Leung" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-1318", + "pmid": "16204057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 65 2005", + "title": "Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma." + } + }, + { + "pmid": "25452387", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. ", + "authors": { + "abbreviation": "Brajendra K Tripathi, Xiaolan Qian, Philipp Mertins, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201405105", + "pmid": "25452387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 207 2014", + "title": "CDK5 is a major regulator of the tumor suppressor DLC1." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "21130076", + "pubmed": { + "ISODate": "2011-01-07T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1), a tumor suppressor gene identified in a primary human hepatocellular carcinoma, encodes a Rho GTPase-activating protein (RhoGAP). Although DLC1 expression has been studied at the transcriptional level, little is known about its regulation at the protein level. Here we show that DLC1 is an unstable protein that is degraded by the 26S proteasome in human hepatocellular carcinoma Hep3B cells. In addition, five putative PEST motifs were identified in the N-terminus of DLC1. Unexpectedly, the N-terminus of DLC1 appeared to be stable. Furthermore, deletion of any one of the five PEST motifs except PEST2 decreased the stability of the N-terminus of DLC1, which suggests that the PEST motifs may play an unrevealed role in maintaining the stability of DLC1. These data indicated that the intracellular stability of DLC1 is regulated by the 26S proteasome via its PEST motifs.", + "authors": { + "abbreviation": "Hong-wei Luo, Qiu-ping Luo, Ying Yuan, ..., Wen-li Feng", + "authorList": [ + { + "ForeName": "Hong-wei", + "LastName": "Luo", + "abbrevName": "Luo HW", + "email": null, + "isCollectiveName": false, + "name": "Hong-wei Luo" + }, + { + "ForeName": "Qiu-ping", + "LastName": "Luo", + "abbrevName": "Luo QP", + "email": null, + "isCollectiveName": false, + "name": "Qiu-ping Luo" + }, + { + "ForeName": "Ying", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Yuan" + }, + { + "ForeName": "Xiao-ying", + "LastName": "Zhu", + "abbrevName": "Zhu XY", + "email": null, + "isCollectiveName": false, + "name": "Xiao-ying Zhu" + }, + { + "ForeName": "Shi-feng", + "LastName": "Huang", + "abbrevName": "Huang SF", + "email": null, + "isCollectiveName": false, + "name": "Shi-feng Huang" + }, + { + "ForeName": "Zhi", + "LastName": "Peng", + "abbrevName": "Peng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Peng" + }, + { + "ForeName": "Chun-li", + "LastName": "Li", + "abbrevName": "Li CL", + "email": null, + "isCollectiveName": false, + "name": "Chun-li Li" + }, + { + "ForeName": "Zong-gan", + "LastName": "Huang", + "abbrevName": "Huang ZG", + "email": null, + "isCollectiveName": false, + "name": "Zong-gan Huang" + }, + { + "ForeName": "Wen-li", + "LastName": "Feng", + "abbrevName": "Feng WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-li Feng" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2010.11.107", + "pmid": "21130076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 404 2011", + "title": "The intracellular stability of DLC1 is regulated by the 26S proteasome in human hepatocellular carcinoma cell line Hep3B." + } + }, + { + "pmid": "25277990", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links β3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the β-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the β-integrin still remains bound to talin. The epithelial integrin β6 reportedly activates latent TGFβ1, and we propose that its function may involve direct interaction with talin. ", + "authors": { + "abbreviation": "Sampo Kukkurainen, Juha A Määttä, John Saeger, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "abbrevName": "Kukkurainen S", + "email": "vesa.hytonen@uta.fi", + "isCollectiveName": false, + "name": "Sampo Kukkurainen" + }, + { + "ForeName": "Juha", + "LastName": "Määttä", + "abbrevName": "Määttä JA", + "email": null, + "isCollectiveName": false, + "name": "Juha A Määttä" + }, + { + "ForeName": "John", + "LastName": "Saeger", + "abbrevName": "Saeger J", + "email": null, + "isCollectiveName": false, + "name": "John Saeger" + }, + { + "ForeName": "Jarkko", + "LastName": "Valjakka", + "abbrevName": "Valjakka J", + "email": null, + "isCollectiveName": false, + "name": "Jarkko Valjakka" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "email": [ + "vesa.hytonen@uta.fi" + ], + "name": "Sampo Kukkurainen" + } + ] + }, + "doi": "10.1039/c4mb00341a", + "pmid": "25277990", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biosyst 10 2014", + "title": "The talin-integrin interface under mechanical stress." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "19158340", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.", + "authors": { + "abbreviation": "Dandan Zhong, Jingfeng Zhang, Shuai Yang, ..., Boon Chuan Low", + "authorList": [ + { + "ForeName": "Dandan", + "LastName": "Zhong", + "abbrevName": "Zhong D", + "email": null, + "isCollectiveName": false, + "name": "Dandan Zhong" + }, + { + "ForeName": "Jingfeng", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Zhang" + }, + { + "ForeName": "Shuai", + "LastName": "Yang", + "abbrevName": "Yang S", + "email": null, + "isCollectiveName": false, + "name": "Shuai Yang" + }, + { + "ForeName": "Unice", + "LastName": "Soh", + "abbrevName": "Soh UJ", + "email": null, + "isCollectiveName": false, + "name": "Unice J K Soh" + }, + { + "ForeName": "Jan", + "LastName": "Buschdorf", + "abbrevName": "Buschdorf JP", + "email": null, + "isCollectiveName": false, + "name": "Jan Paul Buschdorf" + }, + { + "ForeName": "Yi", + "LastName": "Zhou", + "abbrevName": "Zhou YT", + "email": null, + "isCollectiveName": false, + "name": "Yi Ting Zhou" + }, + { + "ForeName": "Daiwen", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Daiwen Yang" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.027482", + "pmid": "19158340", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration." + } + }, + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "27150043", + "pubmed": { + "ISODate": "2016-05-03T00:00:00.000Z", + "abstract": "Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.", + "authors": { + "abbreviation": "Hao Zhang, Yu-Chung Chang, Qingqiu Huang, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Qingqiu", + "LastName": "Huang", + "abbrevName": "Huang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqiu Huang" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2016.02.020", + "pmid": "27150043", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 24 2016", + "title": "Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration." + } + }, + { + "pmid": "31308216", + "pubmed": { + "ISODate": "2019-09-02T00:00:00.000Z", + "abstract": "SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1's tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors.", + "authors": { + "abbreviation": "Brajendra K Tripathi, Meghan F Anderman, Xiaolan Qian, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "tripathib@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Meghan", + "LastName": "Anderman", + "abbrevName": "Anderman MF", + "email": null, + "isCollectiveName": false, + "name": "Meghan F Anderman" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Ming", + "LastName": "Zhou", + "abbrevName": "Zhou M", + "email": null, + "isCollectiveName": false, + "name": "Ming Zhou" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201810098", + "pmid": "31308216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 218 2019", + "title": "SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "29153504", + "pubmed": { + "ISODate": "2017-12-05T00:00:00.000Z", + "abstract": "Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch.", + "authors": { + "abbreviation": "Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson", + "authorList": [ + { + "ForeName": "Nicola", + "LastName": "Baxter", + "abbrevName": "Baxter NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicola J Baxter" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Mike", + "LastName": "Williamson", + "abbrevName": "Williamson MP", + "email": "m.williamson@sheffield.ac.uk", + "isCollectiveName": false, + "name": "Mike P Williamson" + } + ], + "contacts": [ + { + "ForeName": "Mike", + "LastName": "Williamson", + "email": [ + "m.williamson@sheffield.ac.uk" + ], + "name": "Mike P Williamson" + } + ] + }, + "doi": "10.1016/j.str.2017.10.008", + "pmid": "29153504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 25 2017", + "title": "Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM." + } + }, + { + "pmid": "19151751", + "pubmed": { + "ISODate": "2009-03-19T00:00:00.000Z", + "abstract": "DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610", + "authors": { + "abbreviation": "X-Y Yang, M Guan, D Vigil, ..., N C Popescu", + "authorList": [ + { + "ForeName": "X-Y", + "LastName": "Yang", + "abbrevName": "Yang XY", + "email": null, + "isCollectiveName": false, + "name": "X-Y Yang" + }, + { + "ForeName": "M", + "LastName": "Guan", + "abbrevName": "Guan M", + "email": null, + "isCollectiveName": false, + "name": "M Guan" + }, + { + "ForeName": "D", + "LastName": "Vigil", + "abbrevName": "Vigil D", + "email": null, + "isCollectiveName": false, + "name": "D Vigil" + }, + { + "ForeName": "C", + "LastName": "Der", + "abbrevName": "Der CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Der" + }, + { + "ForeName": "D", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "D R Lowy" + }, + { + "ForeName": "N", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "N C Popescu" + } + ], + "contacts": [] + }, + "doi": "10.1038/onc.2008.498", + "pmid": "19151751", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncogene 28 2009", + "title": "p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities." + } + }, + { + "pmid": "26427649", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. ", + "authors": { + "abbreviation": "Yi-Ping Shih, Peng Sun, Aifeng Wang, Su Hao Lo", + "authorList": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "abbrevName": "Shih YP", + "email": "ypshih@ucdavis.edu", + "isCollectiveName": false, + "name": "Yi-Ping Shih" + }, + { + "ForeName": "Peng", + "LastName": "Sun", + "abbrevName": "Sun P", + "email": null, + "isCollectiveName": false, + "name": "Peng Sun" + }, + { + "ForeName": "Aifeng", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aifeng Wang" + }, + { + "ForeName": "Su", + "LastName": "Lo", + "abbrevName": "Lo SH", + "email": null, + "isCollectiveName": false, + "name": "Su Hao Lo" + } + ], + "contacts": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "email": [ + "ypshih@ucdavis.edu" + ], + "name": "Yi-Ping Shih" + } + ] + }, + "doi": "10.1016/j.bbamcr.2015.09.028", + "pmid": "26427649", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochim Biophys Acta 1853 2015", + "title": "Tensin1 positively regulates RhoA activity through its interaction with DLC1." + } + }, + { + "pmid": "32606003", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.", + "authors": { + "abbreviation": "Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Beatriz", + "LastName": "Sanchez-Solana", + "abbrevName": "Sanchez-Solana B", + "email": null, + "isCollectiveName": false, + "name": "Beatriz Sanchez-Solana" + }, + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": null, + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Marian", + "LastName": "Durkin", + "abbrevName": "Durkin ME", + "email": null, + "isCollectiveName": false, + "name": "Marian E Durkin" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-19-3984", + "pmid": "32606003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 80 2020", + "title": "Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function." + } + }, + { + "pmid": "28155884", + "pubmed": { + "ISODate": "2017-02-03T00:00:00.000Z", + "abstract": "Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.", + "authors": { + "abbreviation": "Yaxia Yuan, Liqing Li, Yanyan Zhu, ..., Cai Huang", + "authorList": [ + { + "ForeName": "Yaxia", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yaxia Yuan" + }, + { + "ForeName": "Liqing", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Liqing Li" + }, + { + "ForeName": "Yanyan", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhu" + }, + { + "ForeName": "Lei", + "LastName": "Qi", + "abbrevName": "Qi L", + "email": null, + "isCollectiveName": false, + "name": "Lei Qi" + }, + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Chang-Guo", + "LastName": "Zhan", + "abbrevName": "Zhan CG", + "email": null, + "isCollectiveName": false, + "name": "Chang-Guo Zhan" + }, + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep41989", + "pmid": "28155884", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "The molecular basis of talin2's high affinity toward β1-integrin." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "21087603", + "pubmed": { + "ISODate": "2011-02-15T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Johan O R Gustafsson, Peter Hoffmann, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Johan", + "LastName": "Gustafsson", + "abbrevName": "Gustafsson JO", + "email": null, + "isCollectiveName": false, + "name": "Johan O R Gustafsson" + }, + { + "ForeName": "Peter", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann P", + "email": null, + "isCollectiveName": false, + "name": "Peter Hoffmann" + }, + { + "ForeName": "Mamta", + "LastName": "Jaiswal", + "abbrevName": "Jaiswal M", + "email": null, + "isCollectiveName": false, + "name": "Mamta Jaiswal" + }, + { + "ForeName": "Mohammed", + "LastName": "Ahmadian", + "abbrevName": "Ahmadian MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Reza Ahmadian" + }, + { + "ForeName": "Stephan", + "LastName": "Eisler", + "abbrevName": "Eisler SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Eisler" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2010.11.003", + "pmid": "21087603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 317 2011", + "title": "The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation." + } + }, + { + "pmid": "25448629", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.", + "authors": { + "abbreviation": "Shelly Kaushik, Archna Ravi, Feroz M Hameed, Boon Chuan Low", + "authorList": [ + { + "ForeName": "Shelly", + "LastName": "Kaushik", + "abbrevName": "Kaushik S", + "email": null, + "isCollectiveName": false, + "name": "Shelly Kaushik" + }, + { + "ForeName": "Archna", + "LastName": "Ravi", + "abbrevName": "Ravi A", + "email": null, + "isCollectiveName": false, + "name": "Archna Ravi" + }, + { + "ForeName": "Feroz", + "LastName": "Hameed", + "abbrevName": "Hameed FM", + "email": null, + "isCollectiveName": false, + "name": "Feroz M Hameed" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21201", + "pmid": "25448629", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cytoskeleton (Hoboken) 71 2014", + "title": "Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading." + } + }, + { + "pmid": "19066281", + "pubmed": { + "ISODate": "2009-01-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Jennifer Regner, Anke Theil, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Jennifer", + "LastName": "Regner", + "abbrevName": "Regner J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Regner" + }, + { + "ForeName": "Anke", + "LastName": "Theil", + "abbrevName": "Theil A", + "email": null, + "isCollectiveName": false, + "name": "Anke Theil" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Gerlinde", + "LastName": "Holeiter", + "abbrevName": "Holeiter G", + "email": null, + "isCollectiveName": false, + "name": "Gerlinde Holeiter" + }, + { + "ForeName": "Ruth", + "LastName": "Jähne", + "abbrevName": "Jähne R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Jähne" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.036251", + "pmid": "19066281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T21:51:14.991Z", + "_newestOpId": "30aba62d-2504-4d89-ae01-e7063ff89b41", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "602505" + }, + { + "db": "HGNC", + "id": "HGNC:9718" + }, + { + "db": "Ensembl", + "id": "ENSG00000089159" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.754366, + "id": "5829", + "name": "PXN", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100, + "shortSynonyms": [ + "PXN", + "paxillin", + "testicular tissue protein Li 134" + ], + "synonyms": [ + "paxillin", + "testicular tissue protein Li 134" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "7df04752-5ce5-4d50-9acb-5ea0f54e11e9", + "liveId": "44b29fa7-fb6c-4527-a622-d3a2794fd5d0", + "lock": null, + "locked": false, + "name": "Paxillin", + "position": { + "x": 204.05063291139243, + "y": 195.4430379746835 + }, + "relatedPapers": [ + { + "pmid": "21130076", + "pubmed": { + "ISODate": "2011-01-07T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1), a tumor suppressor gene identified in a primary human hepatocellular carcinoma, encodes a Rho GTPase-activating protein (RhoGAP). Although DLC1 expression has been studied at the transcriptional level, little is known about its regulation at the protein level. Here we show that DLC1 is an unstable protein that is degraded by the 26S proteasome in human hepatocellular carcinoma Hep3B cells. In addition, five putative PEST motifs were identified in the N-terminus of DLC1. Unexpectedly, the N-terminus of DLC1 appeared to be stable. Furthermore, deletion of any one of the five PEST motifs except PEST2 decreased the stability of the N-terminus of DLC1, which suggests that the PEST motifs may play an unrevealed role in maintaining the stability of DLC1. These data indicated that the intracellular stability of DLC1 is regulated by the 26S proteasome via its PEST motifs.", + "authors": { + "abbreviation": "Hong-wei Luo, Qiu-ping Luo, Ying Yuan, ..., Wen-li Feng", + "authorList": [ + { + "ForeName": "Hong-wei", + "LastName": "Luo", + "abbrevName": "Luo HW", + "email": null, + "isCollectiveName": false, + "name": "Hong-wei Luo" + }, + { + "ForeName": "Qiu-ping", + "LastName": "Luo", + "abbrevName": "Luo QP", + "email": null, + "isCollectiveName": false, + "name": "Qiu-ping Luo" + }, + { + "ForeName": "Ying", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Yuan" + }, + { + "ForeName": "Xiao-ying", + "LastName": "Zhu", + "abbrevName": "Zhu XY", + "email": null, + "isCollectiveName": false, + "name": "Xiao-ying Zhu" + }, + { + "ForeName": "Shi-feng", + "LastName": "Huang", + "abbrevName": "Huang SF", + "email": null, + "isCollectiveName": false, + "name": "Shi-feng Huang" + }, + { + "ForeName": "Zhi", + "LastName": "Peng", + "abbrevName": "Peng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Peng" + }, + { + "ForeName": "Chun-li", + "LastName": "Li", + "abbrevName": "Li CL", + "email": null, + "isCollectiveName": false, + "name": "Chun-li Li" + }, + { + "ForeName": "Zong-gan", + "LastName": "Huang", + "abbrevName": "Huang ZG", + "email": null, + "isCollectiveName": false, + "name": "Zong-gan Huang" + }, + { + "ForeName": "Wen-li", + "LastName": "Feng", + "abbrevName": "Feng WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-li Feng" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2010.11.107", + "pmid": "21130076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 404 2011", + "title": "The intracellular stability of DLC1 is regulated by the 26S proteasome in human hepatocellular carcinoma cell line Hep3B." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "25277990", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links β3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the β-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the β-integrin still remains bound to talin. The epithelial integrin β6 reportedly activates latent TGFβ1, and we propose that its function may involve direct interaction with talin. ", + "authors": { + "abbreviation": "Sampo Kukkurainen, Juha A Määttä, John Saeger, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "abbrevName": "Kukkurainen S", + "email": "vesa.hytonen@uta.fi", + "isCollectiveName": false, + "name": "Sampo Kukkurainen" + }, + { + "ForeName": "Juha", + "LastName": "Määttä", + "abbrevName": "Määttä JA", + "email": null, + "isCollectiveName": false, + "name": "Juha A Määttä" + }, + { + "ForeName": "John", + "LastName": "Saeger", + "abbrevName": "Saeger J", + "email": null, + "isCollectiveName": false, + "name": "John Saeger" + }, + { + "ForeName": "Jarkko", + "LastName": "Valjakka", + "abbrevName": "Valjakka J", + "email": null, + "isCollectiveName": false, + "name": "Jarkko Valjakka" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "email": [ + "vesa.hytonen@uta.fi" + ], + "name": "Sampo Kukkurainen" + } + ] + }, + "doi": "10.1039/c4mb00341a", + "pmid": "25277990", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biosyst 10 2014", + "title": "The talin-integrin interface under mechanical stress." + } + }, + { + "pmid": "32606003", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.", + "authors": { + "abbreviation": "Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Beatriz", + "LastName": "Sanchez-Solana", + "abbrevName": "Sanchez-Solana B", + "email": null, + "isCollectiveName": false, + "name": "Beatriz Sanchez-Solana" + }, + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": null, + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Marian", + "LastName": "Durkin", + "abbrevName": "Durkin ME", + "email": null, + "isCollectiveName": false, + "name": "Marian E Durkin" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-19-3984", + "pmid": "32606003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 80 2020", + "title": "Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function." + } + }, + { + "pmid": "26427649", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. ", + "authors": { + "abbreviation": "Yi-Ping Shih, Peng Sun, Aifeng Wang, Su Hao Lo", + "authorList": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "abbrevName": "Shih YP", + "email": "ypshih@ucdavis.edu", + "isCollectiveName": false, + "name": "Yi-Ping Shih" + }, + { + "ForeName": "Peng", + "LastName": "Sun", + "abbrevName": "Sun P", + "email": null, + "isCollectiveName": false, + "name": "Peng Sun" + }, + { + "ForeName": "Aifeng", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aifeng Wang" + }, + { + "ForeName": "Su", + "LastName": "Lo", + "abbrevName": "Lo SH", + "email": null, + "isCollectiveName": false, + "name": "Su Hao Lo" + } + ], + "contacts": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "email": [ + "ypshih@ucdavis.edu" + ], + "name": "Yi-Ping Shih" + } + ] + }, + "doi": "10.1016/j.bbamcr.2015.09.028", + "pmid": "26427649", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochim Biophys Acta 1853 2015", + "title": "Tensin1 positively regulates RhoA activity through its interaction with DLC1." + } + }, + { + "pmid": "21087603", + "pubmed": { + "ISODate": "2011-02-15T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Johan O R Gustafsson, Peter Hoffmann, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Johan", + "LastName": "Gustafsson", + "abbrevName": "Gustafsson JO", + "email": null, + "isCollectiveName": false, + "name": "Johan O R Gustafsson" + }, + { + "ForeName": "Peter", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann P", + "email": null, + "isCollectiveName": false, + "name": "Peter Hoffmann" + }, + { + "ForeName": "Mamta", + "LastName": "Jaiswal", + "abbrevName": "Jaiswal M", + "email": null, + "isCollectiveName": false, + "name": "Mamta Jaiswal" + }, + { + "ForeName": "Mohammed", + "LastName": "Ahmadian", + "abbrevName": "Ahmadian MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Reza Ahmadian" + }, + { + "ForeName": "Stephan", + "LastName": "Eisler", + "abbrevName": "Eisler SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Eisler" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2010.11.003", + "pmid": "21087603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 317 2011", + "title": "The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "24446374", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several β integrin cytoplasmic tails (βCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with β3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with β3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbβ3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the β3 subunit. The study presented, defines a novel direct interaction of VD1 with β3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.", + "authors": { + "abbreviation": "Suman Yadav Nanda, Thuy Hoang, Priya Patel, Hao Zhang", + "authorList": [ + { + "ForeName": "Suman", + "LastName": "Nanda", + "abbrevName": "Nanda SY", + "email": null, + "isCollectiveName": false, + "name": "Suman Yadav Nanda" + }, + { + "ForeName": "Thuy", + "LastName": "Hoang", + "abbrevName": "Hoang T", + "email": null, + "isCollectiveName": false, + "name": "Thuy Hoang" + }, + { + "ForeName": "Priya", + "LastName": "Patel", + "abbrevName": "Patel P", + "email": null, + "isCollectiveName": false, + "name": "Priya Patel" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24772", + "pmid": "24446374", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biochem 115 2014", + "title": "Vinculin regulates assembly of talin: β3 integrin complexes." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "22645138", + "pubmed": { + "ISODate": "2012-07-27T00:00:00.000Z", + "abstract": "The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.", + "authors": { + "abbreviation": "Lihong Chen, Changdong Liu, Frankie Chi Fat Ko, ..., Guang Zhu", + "authorList": [ + { + "ForeName": "Lihong", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Lihong Chen" + }, + { + "ForeName": "Changdong", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Changdong Liu" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Naining", + "LastName": "Xu", + "abbrevName": "Xu N", + "email": null, + "isCollectiveName": false, + "name": "Naining Xu" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Guang", + "LastName": "Zhu", + "abbrevName": "Zhu G", + "email": null, + "isCollectiveName": false, + "name": "Guang Zhu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.360206", + "pmid": "22645138", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "31308216", + "pubmed": { + "ISODate": "2019-09-02T00:00:00.000Z", + "abstract": "SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1's tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors.", + "authors": { + "abbreviation": "Brajendra K Tripathi, Meghan F Anderman, Xiaolan Qian, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "tripathib@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Meghan", + "LastName": "Anderman", + "abbrevName": "Anderman MF", + "email": null, + "isCollectiveName": false, + "name": "Meghan F Anderman" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Ming", + "LastName": "Zhou", + "abbrevName": "Zhou M", + "email": null, + "isCollectiveName": false, + "name": "Ming Zhou" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201810098", + "pmid": "31308216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 218 2019", + "title": "SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions." + } + }, + { + "pmid": "25452387", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. ", + "authors": { + "abbreviation": "Brajendra K Tripathi, Xiaolan Qian, Philipp Mertins, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201405105", + "pmid": "25452387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 207 2014", + "title": "CDK5 is a major regulator of the tumor suppressor DLC1." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "21372205", + "pubmed": { + "ISODate": "2011-04-15T00:00:00.000Z", + "abstract": "The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.", + "authors": { + "abbreviation": "Xuyu Yang, Nicholas C Popescu, Drazen B Zimonjic", + "authorList": [ + { + "ForeName": "Xuyu", + "LastName": "Yang", + "abbrevName": "Yang X", + "email": null, + "isCollectiveName": false, + "name": "Xuyu Yang" + }, + { + "ForeName": "Nicholas", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "Nicholas C Popescu" + }, + { + "ForeName": "Drazen", + "LastName": "Zimonjic", + "abbrevName": "Zimonjic DB", + "email": null, + "isCollectiveName": false, + "name": "Drazen B Zimonjic" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-10-2158", + "pmid": "21372205", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 71 2011", + "title": "DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism." + } + }, + { + "pmid": "27150043", + "pubmed": { + "ISODate": "2016-05-03T00:00:00.000Z", + "abstract": "Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.", + "authors": { + "abbreviation": "Hao Zhang, Yu-Chung Chang, Qingqiu Huang, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Qingqiu", + "LastName": "Huang", + "abbrevName": "Huang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqiu Huang" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2016.02.020", + "pmid": "27150043", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 24 2016", + "title": "Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "25448629", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.", + "authors": { + "abbreviation": "Shelly Kaushik, Archna Ravi, Feroz M Hameed, Boon Chuan Low", + "authorList": [ + { + "ForeName": "Shelly", + "LastName": "Kaushik", + "abbrevName": "Kaushik S", + "email": null, + "isCollectiveName": false, + "name": "Shelly Kaushik" + }, + { + "ForeName": "Archna", + "LastName": "Ravi", + "abbrevName": "Ravi A", + "email": null, + "isCollectiveName": false, + "name": "Archna Ravi" + }, + { + "ForeName": "Feroz", + "LastName": "Hameed", + "abbrevName": "Hameed FM", + "email": null, + "isCollectiveName": false, + "name": "Feroz M Hameed" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21201", + "pmid": "25448629", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cytoskeleton (Hoboken) 71 2014", + "title": "Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "16951145", + "pubmed": { + "ISODate": "2006-09-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell lines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immunoprecipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.", + "authors": { + "abbreviation": "Judy Wai Ping Yam, Frankie Chi Fat Ko, Chung-Yiu Chan, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Chung-Yiu", + "LastName": "Chan", + "abbrevName": "Chan CY", + "email": null, + "isCollectiveName": false, + "name": "Chung-Yiu Chan" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-2850", + "pmid": "16951145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 66 2006", + "title": "Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression." + } + }, + { + "pmid": "24114040", + "pubmed": { + "ISODate": "2014-07-15T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1. ", + "authors": { + "abbreviation": "Frankie Chi Fat Ko, Judy Wai Ping Yam", + "authorList": [ + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Judy", + "LastName": "Ping Yam", + "abbrevName": "Ping Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28505", + "pmid": "24114040", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Cancer 135 2014", + "title": "Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation." + } + }, + { + "pmid": "19066281", + "pubmed": { + "ISODate": "2009-01-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Jennifer Regner, Anke Theil, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Jennifer", + "LastName": "Regner", + "abbrevName": "Regner J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Regner" + }, + { + "ForeName": "Anke", + "LastName": "Theil", + "abbrevName": "Theil A", + "email": null, + "isCollectiveName": false, + "name": "Anke Theil" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Gerlinde", + "LastName": "Holeiter", + "abbrevName": "Holeiter G", + "email": null, + "isCollectiveName": false, + "name": "Gerlinde Holeiter" + }, + { + "ForeName": "Ruth", + "LastName": "Jähne", + "abbrevName": "Jähne R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Jähne" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.036251", + "pmid": "19066281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling." + } + }, + { + "pmid": "16204057", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.", + "authors": { + "abbreviation": "Chun-Ming Wong, Judy Wai-Ping Yam, Yick-Pang Ching, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Chun-Ming", + "LastName": "Wong", + "abbrevName": "Wong CM", + "email": null, + "isCollectiveName": false, + "name": "Chun-Ming Wong" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai-Ping Yam" + }, + { + "ForeName": "Yick-Pang", + "LastName": "Ching", + "abbrevName": "Ching YP", + "email": null, + "isCollectiveName": false, + "name": "Yick-Pang Ching" + }, + { + "ForeName": "Tai-On", + "LastName": "Yau", + "abbrevName": "Yau TO", + "email": null, + "isCollectiveName": false, + "name": "Tai-On Yau" + }, + { + "ForeName": "Thomas", + "LastName": "Leung", + "abbrevName": "Leung TH", + "email": null, + "isCollectiveName": false, + "name": "Thomas Ho-Yin Leung" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-1318", + "pmid": "16204057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 65 2005", + "title": "Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma." + } + }, + { + "pmid": "28155884", + "pubmed": { + "ISODate": "2017-02-03T00:00:00.000Z", + "abstract": "Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.", + "authors": { + "abbreviation": "Yaxia Yuan, Liqing Li, Yanyan Zhu, ..., Cai Huang", + "authorList": [ + { + "ForeName": "Yaxia", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yaxia Yuan" + }, + { + "ForeName": "Liqing", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Liqing Li" + }, + { + "ForeName": "Yanyan", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhu" + }, + { + "ForeName": "Lei", + "LastName": "Qi", + "abbrevName": "Qi L", + "email": null, + "isCollectiveName": false, + "name": "Lei Qi" + }, + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Chang-Guo", + "LastName": "Zhan", + "abbrevName": "Zhan CG", + "email": null, + "isCollectiveName": false, + "name": "Chang-Guo Zhan" + }, + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep41989", + "pmid": "28155884", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "The molecular basis of talin2's high affinity toward β1-integrin." + } + }, + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "29153504", + "pubmed": { + "ISODate": "2017-12-05T00:00:00.000Z", + "abstract": "Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch.", + "authors": { + "abbreviation": "Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson", + "authorList": [ + { + "ForeName": "Nicola", + "LastName": "Baxter", + "abbrevName": "Baxter NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicola J Baxter" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Mike", + "LastName": "Williamson", + "abbrevName": "Williamson MP", + "email": "m.williamson@sheffield.ac.uk", + "isCollectiveName": false, + "name": "Mike P Williamson" + } + ], + "contacts": [ + { + "ForeName": "Mike", + "LastName": "Williamson", + "email": [ + "m.williamson@sheffield.ac.uk" + ], + "name": "Mike P Williamson" + } + ] + }, + "doi": "10.1016/j.str.2017.10.008", + "pmid": "29153504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 25 2017", + "title": "Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM." + } + }, + { + "pmid": "19151751", + "pubmed": { + "ISODate": "2009-03-19T00:00:00.000Z", + "abstract": "DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610", + "authors": { + "abbreviation": "X-Y Yang, M Guan, D Vigil, ..., N C Popescu", + "authorList": [ + { + "ForeName": "X-Y", + "LastName": "Yang", + "abbrevName": "Yang XY", + "email": null, + "isCollectiveName": false, + "name": "X-Y Yang" + }, + { + "ForeName": "M", + "LastName": "Guan", + "abbrevName": "Guan M", + "email": null, + "isCollectiveName": false, + "name": "M Guan" + }, + { + "ForeName": "D", + "LastName": "Vigil", + "abbrevName": "Vigil D", + "email": null, + "isCollectiveName": false, + "name": "D Vigil" + }, + { + "ForeName": "C", + "LastName": "Der", + "abbrevName": "Der CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Der" + }, + { + "ForeName": "D", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "D R Lowy" + }, + { + "ForeName": "N", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "N C Popescu" + } + ], + "contacts": [] + }, + "doi": "10.1038/onc.2008.498", + "pmid": "19151751", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncogene 28 2009", + "title": "p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "31806702", + "pubmed": { + "ISODate": "2020-01-10T00:00:00.000Z", + "abstract": "Deleted-in-liver cancer 1 (DLC1) exerts its tumor suppressive function mainly through the Rho-GTPase-activating protein (RhoGAP) domain. When activated, the domain promotes the hydrolysis of RhoA-GTP, leading to reduced cell migration. DLC1 is kept in an inactive state by an intramolecular interaction between its RhoGAP domain and the DLC1 sterile α motif (SAM) domain. We have shown previously that this autoinhibited state of DLC1 may be alleviated by tensin-3 (TNS3) or PTEN. We show here that the TNS3/PTEN-DLC1 interactions are mediated by the C2 domains of the former and the SAM domain of the latter. Intriguingly, the DLC1 SAM domain was capable of binding to specific peptide motifs within the C2 domains. Indeed, peptides containing the binding motifs were highly effective in blocking the C2-SAM domain-domain interaction. Importantly, when fused to the tat protein-transduction sequence and subsequently introduced into cells, the C2 peptides potently promoted the RhoGAP function in DLC1, leading to decreased RhoA activation and reduced tumor cell growth in soft agar and migration in response to growth factor stimulation. To facilitate the development of the C2 peptides as potential therapeutic agents, we created a cyclic version of the TNS3 C2 domain-derived peptide and showed that this peptide readily entered the MDA-MB-231 breast cancer cells and effectively inhibited their migration. Our work shows, for the first time, that the SAM domain is a peptide-binding module and establishes the framework on which to explore DLC1 SAM domain-binding peptides as potential therapeutic agents for cancer treatment.", + "authors": { + "abbreviation": "Rakesh Joshi, Lyugao Qin, Xuan Cao, ..., Shawn S C Li", + "authorList": [ + { + "ForeName": "Rakesh", + "LastName": "Joshi", + "abbrevName": "Joshi R", + "email": null, + "isCollectiveName": false, + "name": "Rakesh Joshi" + }, + { + "ForeName": "Lyugao", + "LastName": "Qin", + "abbrevName": "Qin L", + "email": null, + "isCollectiveName": false, + "name": "Lyugao Qin" + }, + { + "ForeName": "Xuan", + "LastName": "Cao", + "abbrevName": "Cao X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Cao" + }, + { + "ForeName": "Shanshan", + "LastName": "Zhong", + "abbrevName": "Zhong S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Zhong" + }, + { + "ForeName": "Courtney", + "LastName": "Voss", + "abbrevName": "Voss C", + "email": null, + "isCollectiveName": false, + "name": "Courtney Voss" + }, + { + "ForeName": "Weiping", + "LastName": "Min", + "abbrevName": "Min W", + "email": "weiping.min@uwo.ca", + "isCollectiveName": false, + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "abbrevName": "Li SSC", + "email": "sli@uwo.ca", + "isCollectiveName": false, + "name": "Shawn S C Li" + } + ], + "contacts": [ + { + "ForeName": "Weiping", + "LastName": "Min", + "email": [ + "weiping.min@uwo.ca" + ], + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "email": [ + "sli@uwo.ca" + ], + "name": "Shawn S C Li" + } + ] + }, + "doi": "10.1074/jbc.RA119.011929", + "pmid": "31806702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 295 2020", + "title": "DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA." + } + }, + { + "pmid": "19158340", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.", + "authors": { + "abbreviation": "Dandan Zhong, Jingfeng Zhang, Shuai Yang, ..., Boon Chuan Low", + "authorList": [ + { + "ForeName": "Dandan", + "LastName": "Zhong", + "abbrevName": "Zhong D", + "email": null, + "isCollectiveName": false, + "name": "Dandan Zhong" + }, + { + "ForeName": "Jingfeng", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Zhang" + }, + { + "ForeName": "Shuai", + "LastName": "Yang", + "abbrevName": "Yang S", + "email": null, + "isCollectiveName": false, + "name": "Shuai Yang" + }, + { + "ForeName": "Unice", + "LastName": "Soh", + "abbrevName": "Soh UJ", + "email": null, + "isCollectiveName": false, + "name": "Unice J K Soh" + }, + { + "ForeName": "Jan", + "LastName": "Buschdorf", + "abbrevName": "Buschdorf JP", + "email": null, + "isCollectiveName": false, + "name": "Jan Paul Buschdorf" + }, + { + "ForeName": "Yi", + "LastName": "Zhou", + "abbrevName": "Zhou YT", + "email": null, + "isCollectiveName": false, + "name": "Yi Ting Zhou" + }, + { + "ForeName": "Daiwen", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Daiwen Yang" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.027482", + "pmid": "19158340", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T21:51:27.490Z", + "_newestOpId": "8dde310b-d871-4a7d-957d-6a8922469087", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "63eb9fac-573b-4bb2-8ac9-22b7da2ac361" + }, + { + "group": "unsigned", + "id": "7df04752-5ce5-4d50-9acb-5ea0f54e11e9" + } + ], + "id": "80a4d403-8bc1-4ddb-a4f9-5227e87ef6fa", + "liveId": "b000498c-fe95-4c44-9e8d-5251cef8f64e", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "26427649", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. ", + "authors": { + "abbreviation": "Yi-Ping Shih, Peng Sun, Aifeng Wang, Su Hao Lo", + "authorList": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "abbrevName": "Shih YP", + "email": "ypshih@ucdavis.edu", + "isCollectiveName": false, + "name": "Yi-Ping Shih" + }, + { + "ForeName": "Peng", + "LastName": "Sun", + "abbrevName": "Sun P", + "email": null, + "isCollectiveName": false, + "name": "Peng Sun" + }, + { + "ForeName": "Aifeng", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aifeng Wang" + }, + { + "ForeName": "Su", + "LastName": "Lo", + "abbrevName": "Lo SH", + "email": null, + "isCollectiveName": false, + "name": "Su Hao Lo" + } + ], + "contacts": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "email": [ + "ypshih@ucdavis.edu" + ], + "name": "Yi-Ping Shih" + } + ] + }, + "doi": "10.1016/j.bbamcr.2015.09.028", + "pmid": "26427649", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochim Biophys Acta 1853 2015", + "title": "Tensin1 positively regulates RhoA activity through its interaction with DLC1." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "24446374", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several β integrin cytoplasmic tails (βCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with β3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with β3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbβ3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the β3 subunit. The study presented, defines a novel direct interaction of VD1 with β3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.", + "authors": { + "abbreviation": "Suman Yadav Nanda, Thuy Hoang, Priya Patel, Hao Zhang", + "authorList": [ + { + "ForeName": "Suman", + "LastName": "Nanda", + "abbrevName": "Nanda SY", + "email": null, + "isCollectiveName": false, + "name": "Suman Yadav Nanda" + }, + { + "ForeName": "Thuy", + "LastName": "Hoang", + "abbrevName": "Hoang T", + "email": null, + "isCollectiveName": false, + "name": "Thuy Hoang" + }, + { + "ForeName": "Priya", + "LastName": "Patel", + "abbrevName": "Patel P", + "email": null, + "isCollectiveName": false, + "name": "Priya Patel" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24772", + "pmid": "24446374", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biochem 115 2014", + "title": "Vinculin regulates assembly of talin: β3 integrin complexes." + } + }, + { + "pmid": "19158340", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.", + "authors": { + "abbreviation": "Dandan Zhong, Jingfeng Zhang, Shuai Yang, ..., Boon Chuan Low", + "authorList": [ + { + "ForeName": "Dandan", + "LastName": "Zhong", + "abbrevName": "Zhong D", + "email": null, + "isCollectiveName": false, + "name": "Dandan Zhong" + }, + { + "ForeName": "Jingfeng", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Zhang" + }, + { + "ForeName": "Shuai", + "LastName": "Yang", + "abbrevName": "Yang S", + "email": null, + "isCollectiveName": false, + "name": "Shuai Yang" + }, + { + "ForeName": "Unice", + "LastName": "Soh", + "abbrevName": "Soh UJ", + "email": null, + "isCollectiveName": false, + "name": "Unice J K Soh" + }, + { + "ForeName": "Jan", + "LastName": "Buschdorf", + "abbrevName": "Buschdorf JP", + "email": null, + "isCollectiveName": false, + "name": "Jan Paul Buschdorf" + }, + { + "ForeName": "Yi", + "LastName": "Zhou", + "abbrevName": "Zhou YT", + "email": null, + "isCollectiveName": false, + "name": "Yi Ting Zhou" + }, + { + "ForeName": "Daiwen", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Daiwen Yang" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.027482", + "pmid": "19158340", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "21372205", + "pubmed": { + "ISODate": "2011-04-15T00:00:00.000Z", + "abstract": "The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.", + "authors": { + "abbreviation": "Xuyu Yang, Nicholas C Popescu, Drazen B Zimonjic", + "authorList": [ + { + "ForeName": "Xuyu", + "LastName": "Yang", + "abbrevName": "Yang X", + "email": null, + "isCollectiveName": false, + "name": "Xuyu Yang" + }, + { + "ForeName": "Nicholas", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "Nicholas C Popescu" + }, + { + "ForeName": "Drazen", + "LastName": "Zimonjic", + "abbrevName": "Zimonjic DB", + "email": null, + "isCollectiveName": false, + "name": "Drazen B Zimonjic" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-10-2158", + "pmid": "21372205", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 71 2011", + "title": "DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism." + } + }, + { + "pmid": "27150043", + "pubmed": { + "ISODate": "2016-05-03T00:00:00.000Z", + "abstract": "Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.", + "authors": { + "abbreviation": "Hao Zhang, Yu-Chung Chang, Qingqiu Huang, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Qingqiu", + "LastName": "Huang", + "abbrevName": "Huang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqiu Huang" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2016.02.020", + "pmid": "27150043", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 24 2016", + "title": "Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration." + } + }, + { + "pmid": "16204057", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.", + "authors": { + "abbreviation": "Chun-Ming Wong, Judy Wai-Ping Yam, Yick-Pang Ching, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Chun-Ming", + "LastName": "Wong", + "abbrevName": "Wong CM", + "email": null, + "isCollectiveName": false, + "name": "Chun-Ming Wong" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai-Ping Yam" + }, + { + "ForeName": "Yick-Pang", + "LastName": "Ching", + "abbrevName": "Ching YP", + "email": null, + "isCollectiveName": false, + "name": "Yick-Pang Ching" + }, + { + "ForeName": "Tai-On", + "LastName": "Yau", + "abbrevName": "Yau TO", + "email": null, + "isCollectiveName": false, + "name": "Tai-On Yau" + }, + { + "ForeName": "Thomas", + "LastName": "Leung", + "abbrevName": "Leung TH", + "email": null, + "isCollectiveName": false, + "name": "Thomas Ho-Yin Leung" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-1318", + "pmid": "16204057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 65 2005", + "title": "Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma." + } + }, + { + "pmid": "22645138", + "pubmed": { + "ISODate": "2012-07-27T00:00:00.000Z", + "abstract": "The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.", + "authors": { + "abbreviation": "Lihong Chen, Changdong Liu, Frankie Chi Fat Ko, ..., Guang Zhu", + "authorList": [ + { + "ForeName": "Lihong", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Lihong Chen" + }, + { + "ForeName": "Changdong", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Changdong Liu" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Naining", + "LastName": "Xu", + "abbrevName": "Xu N", + "email": null, + "isCollectiveName": false, + "name": "Naining Xu" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Guang", + "LastName": "Zhu", + "abbrevName": "Zhu G", + "email": null, + "isCollectiveName": false, + "name": "Guang Zhu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.360206", + "pmid": "22645138", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode." + } + }, + { + "pmid": "28155884", + "pubmed": { + "ISODate": "2017-02-03T00:00:00.000Z", + "abstract": "Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.", + "authors": { + "abbreviation": "Yaxia Yuan, Liqing Li, Yanyan Zhu, ..., Cai Huang", + "authorList": [ + { + "ForeName": "Yaxia", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yaxia Yuan" + }, + { + "ForeName": "Liqing", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Liqing Li" + }, + { + "ForeName": "Yanyan", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhu" + }, + { + "ForeName": "Lei", + "LastName": "Qi", + "abbrevName": "Qi L", + "email": null, + "isCollectiveName": false, + "name": "Lei Qi" + }, + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Chang-Guo", + "LastName": "Zhan", + "abbrevName": "Zhan CG", + "email": null, + "isCollectiveName": false, + "name": "Chang-Guo Zhan" + }, + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep41989", + "pmid": "28155884", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "The molecular basis of talin2's high affinity toward β1-integrin." + } + }, + { + "pmid": "25452387", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. ", + "authors": { + "abbreviation": "Brajendra K Tripathi, Xiaolan Qian, Philipp Mertins, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201405105", + "pmid": "25452387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 207 2014", + "title": "CDK5 is a major regulator of the tumor suppressor DLC1." + } + }, + { + "pmid": "25448629", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.", + "authors": { + "abbreviation": "Shelly Kaushik, Archna Ravi, Feroz M Hameed, Boon Chuan Low", + "authorList": [ + { + "ForeName": "Shelly", + "LastName": "Kaushik", + "abbrevName": "Kaushik S", + "email": null, + "isCollectiveName": false, + "name": "Shelly Kaushik" + }, + { + "ForeName": "Archna", + "LastName": "Ravi", + "abbrevName": "Ravi A", + "email": null, + "isCollectiveName": false, + "name": "Archna Ravi" + }, + { + "ForeName": "Feroz", + "LastName": "Hameed", + "abbrevName": "Hameed FM", + "email": null, + "isCollectiveName": false, + "name": "Feroz M Hameed" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21201", + "pmid": "25448629", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cytoskeleton (Hoboken) 71 2014", + "title": "Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading." + } + }, + { + "pmid": "21087603", + "pubmed": { + "ISODate": "2011-02-15T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Johan O R Gustafsson, Peter Hoffmann, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Johan", + "LastName": "Gustafsson", + "abbrevName": "Gustafsson JO", + "email": null, + "isCollectiveName": false, + "name": "Johan O R Gustafsson" + }, + { + "ForeName": "Peter", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann P", + "email": null, + "isCollectiveName": false, + "name": "Peter Hoffmann" + }, + { + "ForeName": "Mamta", + "LastName": "Jaiswal", + "abbrevName": "Jaiswal M", + "email": null, + "isCollectiveName": false, + "name": "Mamta Jaiswal" + }, + { + "ForeName": "Mohammed", + "LastName": "Ahmadian", + "abbrevName": "Ahmadian MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Reza Ahmadian" + }, + { + "ForeName": "Stephan", + "LastName": "Eisler", + "abbrevName": "Eisler SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Eisler" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2010.11.003", + "pmid": "21087603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 317 2011", + "title": "The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "31308216", + "pubmed": { + "ISODate": "2019-09-02T00:00:00.000Z", + "abstract": "SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1's tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors.", + "authors": { + "abbreviation": "Brajendra K Tripathi, Meghan F Anderman, Xiaolan Qian, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "tripathib@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Meghan", + "LastName": "Anderman", + "abbrevName": "Anderman MF", + "email": null, + "isCollectiveName": false, + "name": "Meghan F Anderman" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Ming", + "LastName": "Zhou", + "abbrevName": "Zhou M", + "email": null, + "isCollectiveName": false, + "name": "Ming Zhou" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201810098", + "pmid": "31308216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 218 2019", + "title": "SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "29153504", + "pubmed": { + "ISODate": "2017-12-05T00:00:00.000Z", + "abstract": "Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch.", + "authors": { + "abbreviation": "Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson", + "authorList": [ + { + "ForeName": "Nicola", + "LastName": "Baxter", + "abbrevName": "Baxter NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicola J Baxter" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Mike", + "LastName": "Williamson", + "abbrevName": "Williamson MP", + "email": "m.williamson@sheffield.ac.uk", + "isCollectiveName": false, + "name": "Mike P Williamson" + } + ], + "contacts": [ + { + "ForeName": "Mike", + "LastName": "Williamson", + "email": [ + "m.williamson@sheffield.ac.uk" + ], + "name": "Mike P Williamson" + } + ] + }, + "doi": "10.1016/j.str.2017.10.008", + "pmid": "29153504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 25 2017", + "title": "Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM." + } + }, + { + "pmid": "24114040", + "pubmed": { + "ISODate": "2014-07-15T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1. ", + "authors": { + "abbreviation": "Frankie Chi Fat Ko, Judy Wai Ping Yam", + "authorList": [ + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Judy", + "LastName": "Ping Yam", + "abbrevName": "Ping Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28505", + "pmid": "24114040", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Cancer 135 2014", + "title": "Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation." + } + }, + { + "pmid": "31806702", + "pubmed": { + "ISODate": "2020-01-10T00:00:00.000Z", + "abstract": "Deleted-in-liver cancer 1 (DLC1) exerts its tumor suppressive function mainly through the Rho-GTPase-activating protein (RhoGAP) domain. When activated, the domain promotes the hydrolysis of RhoA-GTP, leading to reduced cell migration. DLC1 is kept in an inactive state by an intramolecular interaction between its RhoGAP domain and the DLC1 sterile α motif (SAM) domain. We have shown previously that this autoinhibited state of DLC1 may be alleviated by tensin-3 (TNS3) or PTEN. We show here that the TNS3/PTEN-DLC1 interactions are mediated by the C2 domains of the former and the SAM domain of the latter. Intriguingly, the DLC1 SAM domain was capable of binding to specific peptide motifs within the C2 domains. Indeed, peptides containing the binding motifs were highly effective in blocking the C2-SAM domain-domain interaction. Importantly, when fused to the tat protein-transduction sequence and subsequently introduced into cells, the C2 peptides potently promoted the RhoGAP function in DLC1, leading to decreased RhoA activation and reduced tumor cell growth in soft agar and migration in response to growth factor stimulation. To facilitate the development of the C2 peptides as potential therapeutic agents, we created a cyclic version of the TNS3 C2 domain-derived peptide and showed that this peptide readily entered the MDA-MB-231 breast cancer cells and effectively inhibited their migration. Our work shows, for the first time, that the SAM domain is a peptide-binding module and establishes the framework on which to explore DLC1 SAM domain-binding peptides as potential therapeutic agents for cancer treatment.", + "authors": { + "abbreviation": "Rakesh Joshi, Lyugao Qin, Xuan Cao, ..., Shawn S C Li", + "authorList": [ + { + "ForeName": "Rakesh", + "LastName": "Joshi", + "abbrevName": "Joshi R", + "email": null, + "isCollectiveName": false, + "name": "Rakesh Joshi" + }, + { + "ForeName": "Lyugao", + "LastName": "Qin", + "abbrevName": "Qin L", + "email": null, + "isCollectiveName": false, + "name": "Lyugao Qin" + }, + { + "ForeName": "Xuan", + "LastName": "Cao", + "abbrevName": "Cao X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Cao" + }, + { + "ForeName": "Shanshan", + "LastName": "Zhong", + "abbrevName": "Zhong S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Zhong" + }, + { + "ForeName": "Courtney", + "LastName": "Voss", + "abbrevName": "Voss C", + "email": null, + "isCollectiveName": false, + "name": "Courtney Voss" + }, + { + "ForeName": "Weiping", + "LastName": "Min", + "abbrevName": "Min W", + "email": "weiping.min@uwo.ca", + "isCollectiveName": false, + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "abbrevName": "Li SSC", + "email": "sli@uwo.ca", + "isCollectiveName": false, + "name": "Shawn S C Li" + } + ], + "contacts": [ + { + "ForeName": "Weiping", + "LastName": "Min", + "email": [ + "weiping.min@uwo.ca" + ], + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "email": [ + "sli@uwo.ca" + ], + "name": "Shawn S C Li" + } + ] + }, + "doi": "10.1074/jbc.RA119.011929", + "pmid": "31806702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 295 2020", + "title": "DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "25277990", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links β3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the β-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the β-integrin still remains bound to talin. The epithelial integrin β6 reportedly activates latent TGFβ1, and we propose that its function may involve direct interaction with talin. ", + "authors": { + "abbreviation": "Sampo Kukkurainen, Juha A Määttä, John Saeger, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "abbrevName": "Kukkurainen S", + "email": "vesa.hytonen@uta.fi", + "isCollectiveName": false, + "name": "Sampo Kukkurainen" + }, + { + "ForeName": "Juha", + "LastName": "Määttä", + "abbrevName": "Määttä JA", + "email": null, + "isCollectiveName": false, + "name": "Juha A Määttä" + }, + { + "ForeName": "John", + "LastName": "Saeger", + "abbrevName": "Saeger J", + "email": null, + "isCollectiveName": false, + "name": "John Saeger" + }, + { + "ForeName": "Jarkko", + "LastName": "Valjakka", + "abbrevName": "Valjakka J", + "email": null, + "isCollectiveName": false, + "name": "Jarkko Valjakka" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "email": [ + "vesa.hytonen@uta.fi" + ], + "name": "Sampo Kukkurainen" + } + ] + }, + "doi": "10.1039/c4mb00341a", + "pmid": "25277990", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biosyst 10 2014", + "title": "The talin-integrin interface under mechanical stress." + } + }, + { + "pmid": "21130076", + "pubmed": { + "ISODate": "2011-01-07T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1), a tumor suppressor gene identified in a primary human hepatocellular carcinoma, encodes a Rho GTPase-activating protein (RhoGAP). Although DLC1 expression has been studied at the transcriptional level, little is known about its regulation at the protein level. Here we show that DLC1 is an unstable protein that is degraded by the 26S proteasome in human hepatocellular carcinoma Hep3B cells. In addition, five putative PEST motifs were identified in the N-terminus of DLC1. Unexpectedly, the N-terminus of DLC1 appeared to be stable. Furthermore, deletion of any one of the five PEST motifs except PEST2 decreased the stability of the N-terminus of DLC1, which suggests that the PEST motifs may play an unrevealed role in maintaining the stability of DLC1. These data indicated that the intracellular stability of DLC1 is regulated by the 26S proteasome via its PEST motifs.", + "authors": { + "abbreviation": "Hong-wei Luo, Qiu-ping Luo, Ying Yuan, ..., Wen-li Feng", + "authorList": [ + { + "ForeName": "Hong-wei", + "LastName": "Luo", + "abbrevName": "Luo HW", + "email": null, + "isCollectiveName": false, + "name": "Hong-wei Luo" + }, + { + "ForeName": "Qiu-ping", + "LastName": "Luo", + "abbrevName": "Luo QP", + "email": null, + "isCollectiveName": false, + "name": "Qiu-ping Luo" + }, + { + "ForeName": "Ying", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Yuan" + }, + { + "ForeName": "Xiao-ying", + "LastName": "Zhu", + "abbrevName": "Zhu XY", + "email": null, + "isCollectiveName": false, + "name": "Xiao-ying Zhu" + }, + { + "ForeName": "Shi-feng", + "LastName": "Huang", + "abbrevName": "Huang SF", + "email": null, + "isCollectiveName": false, + "name": "Shi-feng Huang" + }, + { + "ForeName": "Zhi", + "LastName": "Peng", + "abbrevName": "Peng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Peng" + }, + { + "ForeName": "Chun-li", + "LastName": "Li", + "abbrevName": "Li CL", + "email": null, + "isCollectiveName": false, + "name": "Chun-li Li" + }, + { + "ForeName": "Zong-gan", + "LastName": "Huang", + "abbrevName": "Huang ZG", + "email": null, + "isCollectiveName": false, + "name": "Zong-gan Huang" + }, + { + "ForeName": "Wen-li", + "LastName": "Feng", + "abbrevName": "Feng WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-li Feng" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2010.11.107", + "pmid": "21130076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 404 2011", + "title": "The intracellular stability of DLC1 is regulated by the 26S proteasome in human hepatocellular carcinoma cell line Hep3B." + } + }, + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "19151751", + "pubmed": { + "ISODate": "2009-03-19T00:00:00.000Z", + "abstract": "DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610", + "authors": { + "abbreviation": "X-Y Yang, M Guan, D Vigil, ..., N C Popescu", + "authorList": [ + { + "ForeName": "X-Y", + "LastName": "Yang", + "abbrevName": "Yang XY", + "email": null, + "isCollectiveName": false, + "name": "X-Y Yang" + }, + { + "ForeName": "M", + "LastName": "Guan", + "abbrevName": "Guan M", + "email": null, + "isCollectiveName": false, + "name": "M Guan" + }, + { + "ForeName": "D", + "LastName": "Vigil", + "abbrevName": "Vigil D", + "email": null, + "isCollectiveName": false, + "name": "D Vigil" + }, + { + "ForeName": "C", + "LastName": "Der", + "abbrevName": "Der CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Der" + }, + { + "ForeName": "D", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "D R Lowy" + }, + { + "ForeName": "N", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "N C Popescu" + } + ], + "contacts": [] + }, + "doi": "10.1038/onc.2008.498", + "pmid": "19151751", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncogene 28 2009", + "title": "p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "16951145", + "pubmed": { + "ISODate": "2006-09-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell lines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immunoprecipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.", + "authors": { + "abbreviation": "Judy Wai Ping Yam, Frankie Chi Fat Ko, Chung-Yiu Chan, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Chung-Yiu", + "LastName": "Chan", + "abbrevName": "Chan CY", + "email": null, + "isCollectiveName": false, + "name": "Chung-Yiu Chan" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-2850", + "pmid": "16951145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 66 2006", + "title": "Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression." + } + }, + { + "pmid": "32606003", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.", + "authors": { + "abbreviation": "Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Beatriz", + "LastName": "Sanchez-Solana", + "abbrevName": "Sanchez-Solana B", + "email": null, + "isCollectiveName": false, + "name": "Beatriz Sanchez-Solana" + }, + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": null, + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Marian", + "LastName": "Durkin", + "abbrevName": "Durkin ME", + "email": null, + "isCollectiveName": false, + "name": "Marian E Durkin" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-19-3984", + "pmid": "32606003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 80 2020", + "title": "Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "19066281", + "pubmed": { + "ISODate": "2009-01-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Jennifer Regner, Anke Theil, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Jennifer", + "LastName": "Regner", + "abbrevName": "Regner J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Regner" + }, + { + "ForeName": "Anke", + "LastName": "Theil", + "abbrevName": "Theil A", + "email": null, + "isCollectiveName": false, + "name": "Anke Theil" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Gerlinde", + "LastName": "Holeiter", + "abbrevName": "Holeiter G", + "email": null, + "isCollectiveName": false, + "name": "Gerlinde Holeiter" + }, + { + "ForeName": "Ruth", + "LastName": "Jähne", + "abbrevName": "Jähne R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Jähne" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.036251", + "pmid": "19066281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T21:50:40.232Z", + "_newestOpId": "243d780c-9504-46f7-b017-f34eb3cf5ec7", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "604258" + }, + { + "db": "HGNC", + "id": "HGNC:2897" + }, + { + "db": "Ensembl", + "id": "ENSG00000164741" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.352453, + "id": "10395", + "name": "DLC1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "ARHGAP7", + "HP", + "STARD12", + "p122-RhoGAP", + "rho GTPase-activating protein 7", + "DLC1 Rho GTPase activating protein", + "epididymis secretory sperm binding protein", + "StAR-related lipid transfer (START) domain containing 12", + "START domain-containing protein 12", + "deleted in liver cancer variant 4" + ], + "synonyms": [ + "ARHGAP7", + "HP", + "STARD12", + "p122-RhoGAP", + "rho GTPase-activating protein 7", + "Rho-GTPase-activating protein 7", + "START domain-containing protein 12", + "StAR-related lipid transfer (START) domain containing 12", + "deleted in liver cancer 1 protein", + "deleted in liver cancer 1 variant 2", + "deleted in liver cancer variant 4", + "epididymis secretory sperm binding protein", + "rho-type GTPase-activating protein 7", + "DLC1 Rho GTPase activating protein" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "5c0d65ae-a038-436c-99e5-78a6e58a773d", + "liveId": "cfbbb5e2-573d-4890-80c8-2a733d70ac66", + "lock": null, + "locked": false, + "name": "DLC1", + "position": { + "x": 123.54430379746836, + "y": 110.37974683544303 + }, + "relatedPapers": [ + { + "pmid": "21372205", + "pubmed": { + "ISODate": "2011-04-15T00:00:00.000Z", + "abstract": "The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.", + "authors": { + "abbreviation": "Xuyu Yang, Nicholas C Popescu, Drazen B Zimonjic", + "authorList": [ + { + "ForeName": "Xuyu", + "LastName": "Yang", + "abbrevName": "Yang X", + "email": null, + "isCollectiveName": false, + "name": "Xuyu Yang" + }, + { + "ForeName": "Nicholas", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "Nicholas C Popescu" + }, + { + "ForeName": "Drazen", + "LastName": "Zimonjic", + "abbrevName": "Zimonjic DB", + "email": null, + "isCollectiveName": false, + "name": "Drazen B Zimonjic" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-10-2158", + "pmid": "21372205", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 71 2011", + "title": "DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism." + } + }, + { + "pmid": "16951145", + "pubmed": { + "ISODate": "2006-09-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell lines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immunoprecipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.", + "authors": { + "abbreviation": "Judy Wai Ping Yam, Frankie Chi Fat Ko, Chung-Yiu Chan, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Chung-Yiu", + "LastName": "Chan", + "abbrevName": "Chan CY", + "email": null, + "isCollectiveName": false, + "name": "Chung-Yiu Chan" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-2850", + "pmid": "16951145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 66 2006", + "title": "Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression." + } + }, + { + "pmid": "24446374", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several β integrin cytoplasmic tails (βCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with β3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with β3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbβ3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the β3 subunit. The study presented, defines a novel direct interaction of VD1 with β3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.", + "authors": { + "abbreviation": "Suman Yadav Nanda, Thuy Hoang, Priya Patel, Hao Zhang", + "authorList": [ + { + "ForeName": "Suman", + "LastName": "Nanda", + "abbrevName": "Nanda SY", + "email": null, + "isCollectiveName": false, + "name": "Suman Yadav Nanda" + }, + { + "ForeName": "Thuy", + "LastName": "Hoang", + "abbrevName": "Hoang T", + "email": null, + "isCollectiveName": false, + "name": "Thuy Hoang" + }, + { + "ForeName": "Priya", + "LastName": "Patel", + "abbrevName": "Patel P", + "email": null, + "isCollectiveName": false, + "name": "Priya Patel" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24772", + "pmid": "24446374", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biochem 115 2014", + "title": "Vinculin regulates assembly of talin: β3 integrin complexes." + } + }, + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "22645138", + "pubmed": { + "ISODate": "2012-07-27T00:00:00.000Z", + "abstract": "The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.", + "authors": { + "abbreviation": "Lihong Chen, Changdong Liu, Frankie Chi Fat Ko, ..., Guang Zhu", + "authorList": [ + { + "ForeName": "Lihong", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Lihong Chen" + }, + { + "ForeName": "Changdong", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Changdong Liu" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Naining", + "LastName": "Xu", + "abbrevName": "Xu N", + "email": null, + "isCollectiveName": false, + "name": "Naining Xu" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Guang", + "LastName": "Zhu", + "abbrevName": "Zhu G", + "email": null, + "isCollectiveName": false, + "name": "Guang Zhu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.360206", + "pmid": "22645138", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode." + } + }, + { + "pmid": "21130076", + "pubmed": { + "ISODate": "2011-01-07T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1), a tumor suppressor gene identified in a primary human hepatocellular carcinoma, encodes a Rho GTPase-activating protein (RhoGAP). Although DLC1 expression has been studied at the transcriptional level, little is known about its regulation at the protein level. Here we show that DLC1 is an unstable protein that is degraded by the 26S proteasome in human hepatocellular carcinoma Hep3B cells. In addition, five putative PEST motifs were identified in the N-terminus of DLC1. Unexpectedly, the N-terminus of DLC1 appeared to be stable. Furthermore, deletion of any one of the five PEST motifs except PEST2 decreased the stability of the N-terminus of DLC1, which suggests that the PEST motifs may play an unrevealed role in maintaining the stability of DLC1. These data indicated that the intracellular stability of DLC1 is regulated by the 26S proteasome via its PEST motifs.", + "authors": { + "abbreviation": "Hong-wei Luo, Qiu-ping Luo, Ying Yuan, ..., Wen-li Feng", + "authorList": [ + { + "ForeName": "Hong-wei", + "LastName": "Luo", + "abbrevName": "Luo HW", + "email": null, + "isCollectiveName": false, + "name": "Hong-wei Luo" + }, + { + "ForeName": "Qiu-ping", + "LastName": "Luo", + "abbrevName": "Luo QP", + "email": null, + "isCollectiveName": false, + "name": "Qiu-ping Luo" + }, + { + "ForeName": "Ying", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Yuan" + }, + { + "ForeName": "Xiao-ying", + "LastName": "Zhu", + "abbrevName": "Zhu XY", + "email": null, + "isCollectiveName": false, + "name": "Xiao-ying Zhu" + }, + { + "ForeName": "Shi-feng", + "LastName": "Huang", + "abbrevName": "Huang SF", + "email": null, + "isCollectiveName": false, + "name": "Shi-feng Huang" + }, + { + "ForeName": "Zhi", + "LastName": "Peng", + "abbrevName": "Peng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Peng" + }, + { + "ForeName": "Chun-li", + "LastName": "Li", + "abbrevName": "Li CL", + "email": null, + "isCollectiveName": false, + "name": "Chun-li Li" + }, + { + "ForeName": "Zong-gan", + "LastName": "Huang", + "abbrevName": "Huang ZG", + "email": null, + "isCollectiveName": false, + "name": "Zong-gan Huang" + }, + { + "ForeName": "Wen-li", + "LastName": "Feng", + "abbrevName": "Feng WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-li Feng" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2010.11.107", + "pmid": "21130076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 404 2011", + "title": "The intracellular stability of DLC1 is regulated by the 26S proteasome in human hepatocellular carcinoma cell line Hep3B." + } + }, + { + "pmid": "25452387", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. ", + "authors": { + "abbreviation": "Brajendra K Tripathi, Xiaolan Qian, Philipp Mertins, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201405105", + "pmid": "25452387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 207 2014", + "title": "CDK5 is a major regulator of the tumor suppressor DLC1." + } + }, + { + "pmid": "31308216", + "pubmed": { + "ISODate": "2019-09-02T00:00:00.000Z", + "abstract": "SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1's tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors.", + "authors": { + "abbreviation": "Brajendra K Tripathi, Meghan F Anderman, Xiaolan Qian, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "tripathib@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Meghan", + "LastName": "Anderman", + "abbrevName": "Anderman MF", + "email": null, + "isCollectiveName": false, + "name": "Meghan F Anderman" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Ming", + "LastName": "Zhou", + "abbrevName": "Zhou M", + "email": null, + "isCollectiveName": false, + "name": "Ming Zhou" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201810098", + "pmid": "31308216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 218 2019", + "title": "SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions." + } + }, + { + "pmid": "25277990", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links β3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the β-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the β-integrin still remains bound to talin. The epithelial integrin β6 reportedly activates latent TGFβ1, and we propose that its function may involve direct interaction with talin. ", + "authors": { + "abbreviation": "Sampo Kukkurainen, Juha A Määttä, John Saeger, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "abbrevName": "Kukkurainen S", + "email": "vesa.hytonen@uta.fi", + "isCollectiveName": false, + "name": "Sampo Kukkurainen" + }, + { + "ForeName": "Juha", + "LastName": "Määttä", + "abbrevName": "Määttä JA", + "email": null, + "isCollectiveName": false, + "name": "Juha A Määttä" + }, + { + "ForeName": "John", + "LastName": "Saeger", + "abbrevName": "Saeger J", + "email": null, + "isCollectiveName": false, + "name": "John Saeger" + }, + { + "ForeName": "Jarkko", + "LastName": "Valjakka", + "abbrevName": "Valjakka J", + "email": null, + "isCollectiveName": false, + "name": "Jarkko Valjakka" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "email": [ + "vesa.hytonen@uta.fi" + ], + "name": "Sampo Kukkurainen" + } + ] + }, + "doi": "10.1039/c4mb00341a", + "pmid": "25277990", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biosyst 10 2014", + "title": "The talin-integrin interface under mechanical stress." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "16204057", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.", + "authors": { + "abbreviation": "Chun-Ming Wong, Judy Wai-Ping Yam, Yick-Pang Ching, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Chun-Ming", + "LastName": "Wong", + "abbrevName": "Wong CM", + "email": null, + "isCollectiveName": false, + "name": "Chun-Ming Wong" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai-Ping Yam" + }, + { + "ForeName": "Yick-Pang", + "LastName": "Ching", + "abbrevName": "Ching YP", + "email": null, + "isCollectiveName": false, + "name": "Yick-Pang Ching" + }, + { + "ForeName": "Tai-On", + "LastName": "Yau", + "abbrevName": "Yau TO", + "email": null, + "isCollectiveName": false, + "name": "Tai-On Yau" + }, + { + "ForeName": "Thomas", + "LastName": "Leung", + "abbrevName": "Leung TH", + "email": null, + "isCollectiveName": false, + "name": "Thomas Ho-Yin Leung" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-1318", + "pmid": "16204057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 65 2005", + "title": "Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma." + } + }, + { + "pmid": "29153504", + "pubmed": { + "ISODate": "2017-12-05T00:00:00.000Z", + "abstract": "Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch.", + "authors": { + "abbreviation": "Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson", + "authorList": [ + { + "ForeName": "Nicola", + "LastName": "Baxter", + "abbrevName": "Baxter NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicola J Baxter" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Mike", + "LastName": "Williamson", + "abbrevName": "Williamson MP", + "email": "m.williamson@sheffield.ac.uk", + "isCollectiveName": false, + "name": "Mike P Williamson" + } + ], + "contacts": [ + { + "ForeName": "Mike", + "LastName": "Williamson", + "email": [ + "m.williamson@sheffield.ac.uk" + ], + "name": "Mike P Williamson" + } + ] + }, + "doi": "10.1016/j.str.2017.10.008", + "pmid": "29153504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 25 2017", + "title": "Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM." + } + }, + { + "pmid": "19158340", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.", + "authors": { + "abbreviation": "Dandan Zhong, Jingfeng Zhang, Shuai Yang, ..., Boon Chuan Low", + "authorList": [ + { + "ForeName": "Dandan", + "LastName": "Zhong", + "abbrevName": "Zhong D", + "email": null, + "isCollectiveName": false, + "name": "Dandan Zhong" + }, + { + "ForeName": "Jingfeng", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Zhang" + }, + { + "ForeName": "Shuai", + "LastName": "Yang", + "abbrevName": "Yang S", + "email": null, + "isCollectiveName": false, + "name": "Shuai Yang" + }, + { + "ForeName": "Unice", + "LastName": "Soh", + "abbrevName": "Soh UJ", + "email": null, + "isCollectiveName": false, + "name": "Unice J K Soh" + }, + { + "ForeName": "Jan", + "LastName": "Buschdorf", + "abbrevName": "Buschdorf JP", + "email": null, + "isCollectiveName": false, + "name": "Jan Paul Buschdorf" + }, + { + "ForeName": "Yi", + "LastName": "Zhou", + "abbrevName": "Zhou YT", + "email": null, + "isCollectiveName": false, + "name": "Yi Ting Zhou" + }, + { + "ForeName": "Daiwen", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Daiwen Yang" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.027482", + "pmid": "19158340", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration." + } + }, + { + "pmid": "19151751", + "pubmed": { + "ISODate": "2009-03-19T00:00:00.000Z", + "abstract": "DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610", + "authors": { + "abbreviation": "X-Y Yang, M Guan, D Vigil, ..., N C Popescu", + "authorList": [ + { + "ForeName": "X-Y", + "LastName": "Yang", + "abbrevName": "Yang XY", + "email": null, + "isCollectiveName": false, + "name": "X-Y Yang" + }, + { + "ForeName": "M", + "LastName": "Guan", + "abbrevName": "Guan M", + "email": null, + "isCollectiveName": false, + "name": "M Guan" + }, + { + "ForeName": "D", + "LastName": "Vigil", + "abbrevName": "Vigil D", + "email": null, + "isCollectiveName": false, + "name": "D Vigil" + }, + { + "ForeName": "C", + "LastName": "Der", + "abbrevName": "Der CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Der" + }, + { + "ForeName": "D", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "D R Lowy" + }, + { + "ForeName": "N", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "N C Popescu" + } + ], + "contacts": [] + }, + "doi": "10.1038/onc.2008.498", + "pmid": "19151751", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncogene 28 2009", + "title": "p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities." + } + }, + { + "pmid": "24114040", + "pubmed": { + "ISODate": "2014-07-15T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1. ", + "authors": { + "abbreviation": "Frankie Chi Fat Ko, Judy Wai Ping Yam", + "authorList": [ + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Judy", + "LastName": "Ping Yam", + "abbrevName": "Ping Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28505", + "pmid": "24114040", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Cancer 135 2014", + "title": "Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation." + } + }, + { + "pmid": "27150043", + "pubmed": { + "ISODate": "2016-05-03T00:00:00.000Z", + "abstract": "Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.", + "authors": { + "abbreviation": "Hao Zhang, Yu-Chung Chang, Qingqiu Huang, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Qingqiu", + "LastName": "Huang", + "abbrevName": "Huang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqiu Huang" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2016.02.020", + "pmid": "27150043", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 24 2016", + "title": "Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration." + } + }, + { + "pmid": "21087603", + "pubmed": { + "ISODate": "2011-02-15T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Johan O R Gustafsson, Peter Hoffmann, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Johan", + "LastName": "Gustafsson", + "abbrevName": "Gustafsson JO", + "email": null, + "isCollectiveName": false, + "name": "Johan O R Gustafsson" + }, + { + "ForeName": "Peter", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann P", + "email": null, + "isCollectiveName": false, + "name": "Peter Hoffmann" + }, + { + "ForeName": "Mamta", + "LastName": "Jaiswal", + "abbrevName": "Jaiswal M", + "email": null, + "isCollectiveName": false, + "name": "Mamta Jaiswal" + }, + { + "ForeName": "Mohammed", + "LastName": "Ahmadian", + "abbrevName": "Ahmadian MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Reza Ahmadian" + }, + { + "ForeName": "Stephan", + "LastName": "Eisler", + "abbrevName": "Eisler SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Eisler" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2010.11.003", + "pmid": "21087603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 317 2011", + "title": "The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation." + } + }, + { + "pmid": "32606003", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.", + "authors": { + "abbreviation": "Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Beatriz", + "LastName": "Sanchez-Solana", + "abbrevName": "Sanchez-Solana B", + "email": null, + "isCollectiveName": false, + "name": "Beatriz Sanchez-Solana" + }, + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": null, + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Marian", + "LastName": "Durkin", + "abbrevName": "Durkin ME", + "email": null, + "isCollectiveName": false, + "name": "Marian E Durkin" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-19-3984", + "pmid": "32606003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 80 2020", + "title": "Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "26427649", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. ", + "authors": { + "abbreviation": "Yi-Ping Shih, Peng Sun, Aifeng Wang, Su Hao Lo", + "authorList": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "abbrevName": "Shih YP", + "email": "ypshih@ucdavis.edu", + "isCollectiveName": false, + "name": "Yi-Ping Shih" + }, + { + "ForeName": "Peng", + "LastName": "Sun", + "abbrevName": "Sun P", + "email": null, + "isCollectiveName": false, + "name": "Peng Sun" + }, + { + "ForeName": "Aifeng", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aifeng Wang" + }, + { + "ForeName": "Su", + "LastName": "Lo", + "abbrevName": "Lo SH", + "email": null, + "isCollectiveName": false, + "name": "Su Hao Lo" + } + ], + "contacts": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "email": [ + "ypshih@ucdavis.edu" + ], + "name": "Yi-Ping Shih" + } + ] + }, + "doi": "10.1016/j.bbamcr.2015.09.028", + "pmid": "26427649", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochim Biophys Acta 1853 2015", + "title": "Tensin1 positively regulates RhoA activity through its interaction with DLC1." + } + }, + { + "pmid": "19066281", + "pubmed": { + "ISODate": "2009-01-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Jennifer Regner, Anke Theil, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Jennifer", + "LastName": "Regner", + "abbrevName": "Regner J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Regner" + }, + { + "ForeName": "Anke", + "LastName": "Theil", + "abbrevName": "Theil A", + "email": null, + "isCollectiveName": false, + "name": "Anke Theil" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Gerlinde", + "LastName": "Holeiter", + "abbrevName": "Holeiter G", + "email": null, + "isCollectiveName": false, + "name": "Gerlinde Holeiter" + }, + { + "ForeName": "Ruth", + "LastName": "Jähne", + "abbrevName": "Jähne R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Jähne" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.036251", + "pmid": "19066281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling." + } + }, + { + "pmid": "28155884", + "pubmed": { + "ISODate": "2017-02-03T00:00:00.000Z", + "abstract": "Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.", + "authors": { + "abbreviation": "Yaxia Yuan, Liqing Li, Yanyan Zhu, ..., Cai Huang", + "authorList": [ + { + "ForeName": "Yaxia", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yaxia Yuan" + }, + { + "ForeName": "Liqing", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Liqing Li" + }, + { + "ForeName": "Yanyan", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhu" + }, + { + "ForeName": "Lei", + "LastName": "Qi", + "abbrevName": "Qi L", + "email": null, + "isCollectiveName": false, + "name": "Lei Qi" + }, + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Chang-Guo", + "LastName": "Zhan", + "abbrevName": "Zhan CG", + "email": null, + "isCollectiveName": false, + "name": "Chang-Guo Zhan" + }, + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep41989", + "pmid": "28155884", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "The molecular basis of talin2's high affinity toward β1-integrin." + } + }, + { + "pmid": "25448629", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.", + "authors": { + "abbreviation": "Shelly Kaushik, Archna Ravi, Feroz M Hameed, Boon Chuan Low", + "authorList": [ + { + "ForeName": "Shelly", + "LastName": "Kaushik", + "abbrevName": "Kaushik S", + "email": null, + "isCollectiveName": false, + "name": "Shelly Kaushik" + }, + { + "ForeName": "Archna", + "LastName": "Ravi", + "abbrevName": "Ravi A", + "email": null, + "isCollectiveName": false, + "name": "Archna Ravi" + }, + { + "ForeName": "Feroz", + "LastName": "Hameed", + "abbrevName": "Hameed FM", + "email": null, + "isCollectiveName": false, + "name": "Feroz M Hameed" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21201", + "pmid": "25448629", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cytoskeleton (Hoboken) 71 2014", + "title": "Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "31806702", + "pubmed": { + "ISODate": "2020-01-10T00:00:00.000Z", + "abstract": "Deleted-in-liver cancer 1 (DLC1) exerts its tumor suppressive function mainly through the Rho-GTPase-activating protein (RhoGAP) domain. When activated, the domain promotes the hydrolysis of RhoA-GTP, leading to reduced cell migration. DLC1 is kept in an inactive state by an intramolecular interaction between its RhoGAP domain and the DLC1 sterile α motif (SAM) domain. We have shown previously that this autoinhibited state of DLC1 may be alleviated by tensin-3 (TNS3) or PTEN. We show here that the TNS3/PTEN-DLC1 interactions are mediated by the C2 domains of the former and the SAM domain of the latter. Intriguingly, the DLC1 SAM domain was capable of binding to specific peptide motifs within the C2 domains. Indeed, peptides containing the binding motifs were highly effective in blocking the C2-SAM domain-domain interaction. Importantly, when fused to the tat protein-transduction sequence and subsequently introduced into cells, the C2 peptides potently promoted the RhoGAP function in DLC1, leading to decreased RhoA activation and reduced tumor cell growth in soft agar and migration in response to growth factor stimulation. To facilitate the development of the C2 peptides as potential therapeutic agents, we created a cyclic version of the TNS3 C2 domain-derived peptide and showed that this peptide readily entered the MDA-MB-231 breast cancer cells and effectively inhibited their migration. Our work shows, for the first time, that the SAM domain is a peptide-binding module and establishes the framework on which to explore DLC1 SAM domain-binding peptides as potential therapeutic agents for cancer treatment.", + "authors": { + "abbreviation": "Rakesh Joshi, Lyugao Qin, Xuan Cao, ..., Shawn S C Li", + "authorList": [ + { + "ForeName": "Rakesh", + "LastName": "Joshi", + "abbrevName": "Joshi R", + "email": null, + "isCollectiveName": false, + "name": "Rakesh Joshi" + }, + { + "ForeName": "Lyugao", + "LastName": "Qin", + "abbrevName": "Qin L", + "email": null, + "isCollectiveName": false, + "name": "Lyugao Qin" + }, + { + "ForeName": "Xuan", + "LastName": "Cao", + "abbrevName": "Cao X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Cao" + }, + { + "ForeName": "Shanshan", + "LastName": "Zhong", + "abbrevName": "Zhong S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Zhong" + }, + { + "ForeName": "Courtney", + "LastName": "Voss", + "abbrevName": "Voss C", + "email": null, + "isCollectiveName": false, + "name": "Courtney Voss" + }, + { + "ForeName": "Weiping", + "LastName": "Min", + "abbrevName": "Min W", + "email": "weiping.min@uwo.ca", + "isCollectiveName": false, + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "abbrevName": "Li SSC", + "email": "sli@uwo.ca", + "isCollectiveName": false, + "name": "Shawn S C Li" + } + ], + "contacts": [ + { + "ForeName": "Weiping", + "LastName": "Min", + "email": [ + "weiping.min@uwo.ca" + ], + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "email": [ + "sli@uwo.ca" + ], + "name": "Shawn S C Li" + } + ] + }, + "doi": "10.1074/jbc.RA119.011929", + "pmid": "31806702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 295 2020", + "title": "DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T21:50:51.236Z", + "_newestOpId": "efb75d2b-70f0-464d-b12d-6a0a0110281b", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "5c0d65ae-a038-436c-99e5-78a6e58a773d" + }, + { + "group": "unsigned", + "id": "63eb9fac-573b-4bb2-8ac9-22b7da2ac361" + } + ], + "id": "028e7366-9779-4466-96ea-18a45bfe3f38", + "liveId": "68ea8ee1-3065-4b11-bb5e-0356cf5367b0", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "31806702", + "pubmed": { + "ISODate": "2020-01-10T00:00:00.000Z", + "abstract": "Deleted-in-liver cancer 1 (DLC1) exerts its tumor suppressive function mainly through the Rho-GTPase-activating protein (RhoGAP) domain. When activated, the domain promotes the hydrolysis of RhoA-GTP, leading to reduced cell migration. DLC1 is kept in an inactive state by an intramolecular interaction between its RhoGAP domain and the DLC1 sterile α motif (SAM) domain. We have shown previously that this autoinhibited state of DLC1 may be alleviated by tensin-3 (TNS3) or PTEN. We show here that the TNS3/PTEN-DLC1 interactions are mediated by the C2 domains of the former and the SAM domain of the latter. Intriguingly, the DLC1 SAM domain was capable of binding to specific peptide motifs within the C2 domains. Indeed, peptides containing the binding motifs were highly effective in blocking the C2-SAM domain-domain interaction. Importantly, when fused to the tat protein-transduction sequence and subsequently introduced into cells, the C2 peptides potently promoted the RhoGAP function in DLC1, leading to decreased RhoA activation and reduced tumor cell growth in soft agar and migration in response to growth factor stimulation. To facilitate the development of the C2 peptides as potential therapeutic agents, we created a cyclic version of the TNS3 C2 domain-derived peptide and showed that this peptide readily entered the MDA-MB-231 breast cancer cells and effectively inhibited their migration. Our work shows, for the first time, that the SAM domain is a peptide-binding module and establishes the framework on which to explore DLC1 SAM domain-binding peptides as potential therapeutic agents for cancer treatment.", + "authors": { + "abbreviation": "Rakesh Joshi, Lyugao Qin, Xuan Cao, ..., Shawn S C Li", + "authorList": [ + { + "ForeName": "Rakesh", + "LastName": "Joshi", + "abbrevName": "Joshi R", + "email": null, + "isCollectiveName": false, + "name": "Rakesh Joshi" + }, + { + "ForeName": "Lyugao", + "LastName": "Qin", + "abbrevName": "Qin L", + "email": null, + "isCollectiveName": false, + "name": "Lyugao Qin" + }, + { + "ForeName": "Xuan", + "LastName": "Cao", + "abbrevName": "Cao X", + "email": null, + "isCollectiveName": false, + "name": "Xuan Cao" + }, + { + "ForeName": "Shanshan", + "LastName": "Zhong", + "abbrevName": "Zhong S", + "email": null, + "isCollectiveName": false, + "name": "Shanshan Zhong" + }, + { + "ForeName": "Courtney", + "LastName": "Voss", + "abbrevName": "Voss C", + "email": null, + "isCollectiveName": false, + "name": "Courtney Voss" + }, + { + "ForeName": "Weiping", + "LastName": "Min", + "abbrevName": "Min W", + "email": "weiping.min@uwo.ca", + "isCollectiveName": false, + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "abbrevName": "Li SSC", + "email": "sli@uwo.ca", + "isCollectiveName": false, + "name": "Shawn S C Li" + } + ], + "contacts": [ + { + "ForeName": "Weiping", + "LastName": "Min", + "email": [ + "weiping.min@uwo.ca" + ], + "name": "Weiping Min" + }, + { + "ForeName": "Shawn", + "LastName": "Li", + "email": [ + "sli@uwo.ca" + ], + "name": "Shawn S C Li" + } + ] + }, + "doi": "10.1074/jbc.RA119.011929", + "pmid": "31806702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 295 2020", + "title": "DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "19151751", + "pubmed": { + "ISODate": "2009-03-19T00:00:00.000Z", + "abstract": "DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610", + "authors": { + "abbreviation": "X-Y Yang, M Guan, D Vigil, ..., N C Popescu", + "authorList": [ + { + "ForeName": "X-Y", + "LastName": "Yang", + "abbrevName": "Yang XY", + "email": null, + "isCollectiveName": false, + "name": "X-Y Yang" + }, + { + "ForeName": "M", + "LastName": "Guan", + "abbrevName": "Guan M", + "email": null, + "isCollectiveName": false, + "name": "M Guan" + }, + { + "ForeName": "D", + "LastName": "Vigil", + "abbrevName": "Vigil D", + "email": null, + "isCollectiveName": false, + "name": "D Vigil" + }, + { + "ForeName": "C", + "LastName": "Der", + "abbrevName": "Der CJ", + "email": null, + "isCollectiveName": false, + "name": "C J Der" + }, + { + "ForeName": "D", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "D R Lowy" + }, + { + "ForeName": "N", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "N C Popescu" + } + ], + "contacts": [] + }, + "doi": "10.1038/onc.2008.498", + "pmid": "19151751", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncogene 28 2009", + "title": "p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "25448629", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.", + "authors": { + "abbreviation": "Shelly Kaushik, Archna Ravi, Feroz M Hameed, Boon Chuan Low", + "authorList": [ + { + "ForeName": "Shelly", + "LastName": "Kaushik", + "abbrevName": "Kaushik S", + "email": null, + "isCollectiveName": false, + "name": "Shelly Kaushik" + }, + { + "ForeName": "Archna", + "LastName": "Ravi", + "abbrevName": "Ravi A", + "email": null, + "isCollectiveName": false, + "name": "Archna Ravi" + }, + { + "ForeName": "Feroz", + "LastName": "Hameed", + "abbrevName": "Hameed FM", + "email": null, + "isCollectiveName": false, + "name": "Feroz M Hameed" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21201", + "pmid": "25448629", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cytoskeleton (Hoboken) 71 2014", + "title": "Concerted modulation of paxillin dynamics at focal adhesions by Deleted in Liver Cancer-1 and focal adhesion kinase during early cell spreading." + } + }, + { + "pmid": "29153504", + "pubmed": { + "ISODate": "2017-12-05T00:00:00.000Z", + "abstract": "Talin mediates attachment of the cell to the extracellular matrix. It is targeted by the Rap1 effector RIAM to focal adhesion sites and subsequently undergoes force-induced conformational opening to recruit the actin-interacting protein vinculin. The conformational switch involves the talin R3 domain, which binds RIAM when closed and vinculin when open. Here, we apply pressure to R3 and measure 1H, 15N, and 13C chemical shift changes, which are fitted using a simple model, and indicate that R3 is only 50% closed: the closed form is a four-helix bundle, while in the open state helix 1 is twisted out. Strikingly, a mutant of R3 that binds RIAM with an affinity similar to wild-type but more weakly to vinculin is shown to be 0.84 kJ mol-1 more stable when closed. These results demonstrate that R3 is thermodynamically poised to bind either RIAM or vinculin, and thus constitutes a good mechanosensitive switch.", + "authors": { + "abbreviation": "Nicola J Baxter, Thomas Zacharchenko, Igor L Barsukov, Mike P Williamson", + "authorList": [ + { + "ForeName": "Nicola", + "LastName": "Baxter", + "abbrevName": "Baxter NJ", + "email": null, + "isCollectiveName": false, + "name": "Nicola J Baxter" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Mike", + "LastName": "Williamson", + "abbrevName": "Williamson MP", + "email": "m.williamson@sheffield.ac.uk", + "isCollectiveName": false, + "name": "Mike P Williamson" + } + ], + "contacts": [ + { + "ForeName": "Mike", + "LastName": "Williamson", + "email": [ + "m.williamson@sheffield.ac.uk" + ], + "name": "Mike P Williamson" + } + ] + }, + "doi": "10.1016/j.str.2017.10.008", + "pmid": "29153504", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 25 2017", + "title": "Pressure-Dependent Chemical Shifts in the R3 Domain of Talin Show that It Is Thermodynamically Poised for Binding to Either Vinculin or RIAM." + } + }, + { + "pmid": "16204057", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292- to 648-amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.", + "authors": { + "abbreviation": "Chun-Ming Wong, Judy Wai-Ping Yam, Yick-Pang Ching, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Chun-Ming", + "LastName": "Wong", + "abbrevName": "Wong CM", + "email": null, + "isCollectiveName": false, + "name": "Chun-Ming Wong" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai-Ping Yam" + }, + { + "ForeName": "Yick-Pang", + "LastName": "Ching", + "abbrevName": "Ching YP", + "email": null, + "isCollectiveName": false, + "name": "Yick-Pang Ching" + }, + { + "ForeName": "Tai-On", + "LastName": "Yau", + "abbrevName": "Yau TO", + "email": null, + "isCollectiveName": false, + "name": "Tai-On Yau" + }, + { + "ForeName": "Thomas", + "LastName": "Leung", + "abbrevName": "Leung TH", + "email": null, + "isCollectiveName": false, + "name": "Thomas Ho-Yin Leung" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-1318", + "pmid": "16204057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 65 2005", + "title": "Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma." + } + }, + { + "pmid": "25452387", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho-GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. ", + "authors": { + "abbreviation": "Brajendra K Tripathi, Xiaolan Qian, Philipp Mertins, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov", + "tripathib@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201405105", + "pmid": "25452387", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 207 2014", + "title": "CDK5 is a major regulator of the tumor suppressor DLC1." + } + }, + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "21372205", + "pubmed": { + "ISODate": "2011-04-15T00:00:00.000Z", + "abstract": "The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.", + "authors": { + "abbreviation": "Xuyu Yang, Nicholas C Popescu, Drazen B Zimonjic", + "authorList": [ + { + "ForeName": "Xuyu", + "LastName": "Yang", + "abbrevName": "Yang X", + "email": null, + "isCollectiveName": false, + "name": "Xuyu Yang" + }, + { + "ForeName": "Nicholas", + "LastName": "Popescu", + "abbrevName": "Popescu NC", + "email": null, + "isCollectiveName": false, + "name": "Nicholas C Popescu" + }, + { + "ForeName": "Drazen", + "LastName": "Zimonjic", + "abbrevName": "Zimonjic DB", + "email": null, + "isCollectiveName": false, + "name": "Drazen B Zimonjic" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-10-2158", + "pmid": "21372205", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 71 2011", + "title": "DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism." + } + }, + { + "pmid": "31308216", + "pubmed": { + "ISODate": "2019-09-02T00:00:00.000Z", + "abstract": "SRC and ERK kinases control many cell biological processes that promote tumorigenesis by altering the activity of oncogenic and tumor suppressor proteins. We identify here a physiological interaction between DLC1, a focal adhesion protein and tumor suppressor, with SRC and ERK. The tumor suppressor function of DLC1 is attenuated by phosphorylation of tyrosines Y451 and Y701 by SRC, which down-regulates DLC1's tensin-binding and Rho-GAP activities. ERK1/2 phosphorylate DLC1 on serine S129, which increases both the binding of SRC to DLC1 and SRC-dependent phosphorylation of DLC1. SRC inhibitors exhibit potent antitumor activity in a DLC1-positive transgenic cancer model and a DLC1-positive tumor xenograft model, due to reactivation of the tumor suppressor activities of DLC1. Combined treatment of DLC1-positive tumors with SRC plus AKT inhibitors has even greater antitumor activity. Together, these findings indicate cooperation between the SRC, ERK1/2, and AKT kinases to reduce DLC1 Rho-GAP and tumor suppressor activities in cancer cells, which can be reactivated by the kinase inhibitors.", + "authors": { + "abbreviation": "Brajendra K Tripathi, Meghan F Anderman, Xiaolan Qian, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": "tripathib@mail.nih.gov", + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Meghan", + "LastName": "Anderman", + "abbrevName": "Anderman MF", + "email": null, + "isCollectiveName": false, + "name": "Meghan F Anderman" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Ming", + "LastName": "Zhou", + "abbrevName": "Zhou M", + "email": null, + "isCollectiveName": false, + "name": "Ming Zhou" + }, + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "email": [ + "tripathib@mail.nih.gov" + ], + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1083/jcb.201810098", + "pmid": "31308216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "J Cell Biol 218 2019", + "title": "SRC and ERK cooperatively phosphorylate DLC1 and attenuate its Rho-GAP and tumor suppressor functions." + } + }, + { + "pmid": "27150043", + "pubmed": { + "ISODate": "2016-05-03T00:00:00.000Z", + "abstract": "Talin plays an important role in regulating integrin-mediated signaling. Talin function is autoinhibited by intramolecular interactions between the integrin-binding F3 domain and the autoinhibitory domain (R9). We determined the crystal structure of a triple-domain fragment, R7R8R9, which contains R9 and the RIAM (Rap1-interacting adaptor molecule) binding domain (R8). The structure reveals a crystallographic contact between R9 and a symmetrically related R8 domain, representing a homodimeric interaction in talin. Strikingly, we demonstrated that the α5 helix of R9 also interacts with the F3 domain, despite no interdomain contact involving the α5 helix in the crystal structure of an F2F3:R9 autoinhibitory complex reported previously. Mutations on the α5 helix significantly diminish the F3:R9 association and lead to elevated talin activity. Our results offer biochemical and functional evidence of the existence of a new talin autoinhibitory configuration, thus providing a more comprehensive understanding of talin autoinhibition, regulation, and quaternary structure assembly.", + "authors": { + "abbreviation": "Hao Zhang, Yu-Chung Chang, Qingqiu Huang, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Qingqiu", + "LastName": "Huang", + "abbrevName": "Huang Q", + "email": null, + "isCollectiveName": false, + "name": "Qingqiu Huang" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2016.02.020", + "pmid": "27150043", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 24 2016", + "title": "Structural and Functional Analysis of a Talin Triple-Domain Module Suggests an Alternative Talin Autoinhibitory Configuration." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "21087603", + "pubmed": { + "ISODate": "2011-02-15T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Johan O R Gustafsson, Peter Hoffmann, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Johan", + "LastName": "Gustafsson", + "abbrevName": "Gustafsson JO", + "email": null, + "isCollectiveName": false, + "name": "Johan O R Gustafsson" + }, + { + "ForeName": "Peter", + "LastName": "Hoffmann", + "abbrevName": "Hoffmann P", + "email": null, + "isCollectiveName": false, + "name": "Peter Hoffmann" + }, + { + "ForeName": "Mamta", + "LastName": "Jaiswal", + "abbrevName": "Jaiswal M", + "email": null, + "isCollectiveName": false, + "name": "Mamta Jaiswal" + }, + { + "ForeName": "Mohammed", + "LastName": "Ahmadian", + "abbrevName": "Ahmadian MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Reza Ahmadian" + }, + { + "ForeName": "Stephan", + "LastName": "Eisler", + "abbrevName": "Eisler SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Eisler" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2010.11.003", + "pmid": "21087603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 317 2011", + "title": "The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation." + } + }, + { + "pmid": "19158340", + "pubmed": { + "ISODate": "2009-02-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel partner for the sterile alpha motif (SAM) domain of DLC1 but not the SAM domain of DLC2. The solution structure of DLC1 SAM revealed a new monomeric fold with four parallel helices, similar to that of DLC2 SAM but distinct from other SAM domains. Mutating F38, L39 and F40 within a hydrophobic patch retained its overall structure but abolished its interaction with EF1A1 with F38 and L39 forming an indispensable interacting motif. DLC1 SAM did not localize to and was not required for DLC1 to suppress the turnover of focal adhesions. Instead, DLC1 SAM facilitated EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation. Compared with wild-type DLC1, the non-interactive DLC1 mutant is less potent in suppressing cell migration, whereas overexpression of the DLC1 SAM domain alone, but not the non-interactive mutant SAM or DLC2 SAM, greatly enhanced cell migration. This finding reveals a novel contribution of the SAM-EF1A1 interaction as a potentially important GAP-independent modulation of cell migration by DLC1.", + "authors": { + "abbreviation": "Dandan Zhong, Jingfeng Zhang, Shuai Yang, ..., Boon Chuan Low", + "authorList": [ + { + "ForeName": "Dandan", + "LastName": "Zhong", + "abbrevName": "Zhong D", + "email": null, + "isCollectiveName": false, + "name": "Dandan Zhong" + }, + { + "ForeName": "Jingfeng", + "LastName": "Zhang", + "abbrevName": "Zhang J", + "email": null, + "isCollectiveName": false, + "name": "Jingfeng Zhang" + }, + { + "ForeName": "Shuai", + "LastName": "Yang", + "abbrevName": "Yang S", + "email": null, + "isCollectiveName": false, + "name": "Shuai Yang" + }, + { + "ForeName": "Unice", + "LastName": "Soh", + "abbrevName": "Soh UJ", + "email": null, + "isCollectiveName": false, + "name": "Unice J K Soh" + }, + { + "ForeName": "Jan", + "LastName": "Buschdorf", + "abbrevName": "Buschdorf JP", + "email": null, + "isCollectiveName": false, + "name": "Jan Paul Buschdorf" + }, + { + "ForeName": "Yi", + "LastName": "Zhou", + "abbrevName": "Zhou YT", + "email": null, + "isCollectiveName": false, + "name": "Yi Ting Zhou" + }, + { + "ForeName": "Daiwen", + "LastName": "Yang", + "abbrevName": "Yang D", + "email": null, + "isCollectiveName": false, + "name": "Daiwen Yang" + }, + { + "ForeName": "Boon", + "LastName": "Low", + "abbrevName": "Low BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Chuan Low" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.027482", + "pmid": "19158340", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "The SAM domain of the RhoGAP DLC1 binds EF1A1 to regulate cell migration." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "26427649", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "DLC1 is a RhoGAP-containing tumor suppressor and many of DLC1's functions are absolutely dependent on its RhoGAP activity. Through its RhoGAP domain, DLC1 inhibits the activity of RhoA GTPase, which regulates actin cytoskeleton networks and dis/assembly of focal adhesions. Tensin1 (TNS1) is a focal adhesion molecule that links the actin cytoskeleton to integrins and forms signaling complexes through its multiple binding domains. Here, we report that TNS1 enhances RhoA activity in a DLC1-dependent manner. This is accomplished by binding to DLC1 through TNS1's C2, SH2, and PTB domains. Point mutations at these three sites disrupt TNS1's interaction with DLC1 as well as its effect on RhoA activity. The biological relevance of this TNS1-DLC1-RhoA signaling axis is investigated in TNS1 knockout (KO) cells and mice. Endothelial cells isolated from TNS1 KO mice or those silenced with TNS1 siRNA show significant reduction in proliferation, migration, and tube formation activities. Concomitantly, the RhoA activity is down-regulated in TNS1 KO cells and this reduction is restored by further silencing of DLC1. Furthermore, the angiogenic process is compromised in TNS1 KO mice. These studies demonstrate that TNS1 binds to DLC1 and fine-tunes its RhoGAP activity toward RhoA and that the TNS1-DLC1-RhoA signaling axis is critical in regulating cellular functions that lead to angiogenesis. ", + "authors": { + "abbreviation": "Yi-Ping Shih, Peng Sun, Aifeng Wang, Su Hao Lo", + "authorList": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "abbrevName": "Shih YP", + "email": "ypshih@ucdavis.edu", + "isCollectiveName": false, + "name": "Yi-Ping Shih" + }, + { + "ForeName": "Peng", + "LastName": "Sun", + "abbrevName": "Sun P", + "email": null, + "isCollectiveName": false, + "name": "Peng Sun" + }, + { + "ForeName": "Aifeng", + "LastName": "Wang", + "abbrevName": "Wang A", + "email": null, + "isCollectiveName": false, + "name": "Aifeng Wang" + }, + { + "ForeName": "Su", + "LastName": "Lo", + "abbrevName": "Lo SH", + "email": null, + "isCollectiveName": false, + "name": "Su Hao Lo" + } + ], + "contacts": [ + { + "ForeName": "Yi-Ping", + "LastName": "Shih", + "email": [ + "ypshih@ucdavis.edu" + ], + "name": "Yi-Ping Shih" + } + ] + }, + "doi": "10.1016/j.bbamcr.2015.09.028", + "pmid": "26427649", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Biochim Biophys Acta 1853 2015", + "title": "Tensin1 positively regulates RhoA activity through its interaction with DLC1." + } + }, + { + "pmid": "24446374", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several β integrin cytoplasmic tails (βCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with β3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with β3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbβ3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the β3 subunit. The study presented, defines a novel direct interaction of VD1 with β3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.", + "authors": { + "abbreviation": "Suman Yadav Nanda, Thuy Hoang, Priya Patel, Hao Zhang", + "authorList": [ + { + "ForeName": "Suman", + "LastName": "Nanda", + "abbrevName": "Nanda SY", + "email": null, + "isCollectiveName": false, + "name": "Suman Yadav Nanda" + }, + { + "ForeName": "Thuy", + "LastName": "Hoang", + "abbrevName": "Hoang T", + "email": null, + "isCollectiveName": false, + "name": "Thuy Hoang" + }, + { + "ForeName": "Priya", + "LastName": "Patel", + "abbrevName": "Patel P", + "email": null, + "isCollectiveName": false, + "name": "Priya Patel" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24772", + "pmid": "24446374", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biochem 115 2014", + "title": "Vinculin regulates assembly of talin: β3 integrin complexes." + } + }, + { + "pmid": "32606003", + "pubmed": { + "ISODate": "2020-09-01T00:00:00.000Z", + "abstract": "In advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity. SIGNIFICANCE: These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.", + "authors": { + "abbreviation": "Dunrui Wang, Xiaolan Qian, Beatriz Sanchez-Solana, ..., Douglas R Lowy", + "authorList": [ + { + "ForeName": "Dunrui", + "LastName": "Wang", + "abbrevName": "Wang D", + "email": null, + "isCollectiveName": false, + "name": "Dunrui Wang" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Beatriz", + "LastName": "Sanchez-Solana", + "abbrevName": "Sanchez-Solana B", + "email": null, + "isCollectiveName": false, + "name": "Beatriz Sanchez-Solana" + }, + { + "ForeName": "Brajendra", + "LastName": "Tripathi", + "abbrevName": "Tripathi BK", + "email": null, + "isCollectiveName": false, + "name": "Brajendra K Tripathi" + }, + { + "ForeName": "Marian", + "LastName": "Durkin", + "abbrevName": "Durkin ME", + "email": null, + "isCollectiveName": false, + "name": "Marian E Durkin" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": "lowyd@mail.nih.gov", + "isCollectiveName": false, + "name": "Douglas R Lowy" + } + ], + "contacts": [ + { + "ForeName": "Douglas", + "LastName": "Lowy", + "email": [ + "lowyd@mail.nih.gov" + ], + "name": "Douglas R Lowy" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-19-3984", + "pmid": "32606003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Cancer Res 80 2020", + "title": "Cancer-Associated Point Mutations in the DLC1 Tumor Suppressor and Other Rho-GAPs Occur Frequently and Are Associated with Decreased Function." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "21130076", + "pubmed": { + "ISODate": "2011-01-07T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1), a tumor suppressor gene identified in a primary human hepatocellular carcinoma, encodes a Rho GTPase-activating protein (RhoGAP). Although DLC1 expression has been studied at the transcriptional level, little is known about its regulation at the protein level. Here we show that DLC1 is an unstable protein that is degraded by the 26S proteasome in human hepatocellular carcinoma Hep3B cells. In addition, five putative PEST motifs were identified in the N-terminus of DLC1. Unexpectedly, the N-terminus of DLC1 appeared to be stable. Furthermore, deletion of any one of the five PEST motifs except PEST2 decreased the stability of the N-terminus of DLC1, which suggests that the PEST motifs may play an unrevealed role in maintaining the stability of DLC1. These data indicated that the intracellular stability of DLC1 is regulated by the 26S proteasome via its PEST motifs.", + "authors": { + "abbreviation": "Hong-wei Luo, Qiu-ping Luo, Ying Yuan, ..., Wen-li Feng", + "authorList": [ + { + "ForeName": "Hong-wei", + "LastName": "Luo", + "abbrevName": "Luo HW", + "email": null, + "isCollectiveName": false, + "name": "Hong-wei Luo" + }, + { + "ForeName": "Qiu-ping", + "LastName": "Luo", + "abbrevName": "Luo QP", + "email": null, + "isCollectiveName": false, + "name": "Qiu-ping Luo" + }, + { + "ForeName": "Ying", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Yuan" + }, + { + "ForeName": "Xiao-ying", + "LastName": "Zhu", + "abbrevName": "Zhu XY", + "email": null, + "isCollectiveName": false, + "name": "Xiao-ying Zhu" + }, + { + "ForeName": "Shi-feng", + "LastName": "Huang", + "abbrevName": "Huang SF", + "email": null, + "isCollectiveName": false, + "name": "Shi-feng Huang" + }, + { + "ForeName": "Zhi", + "LastName": "Peng", + "abbrevName": "Peng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Peng" + }, + { + "ForeName": "Chun-li", + "LastName": "Li", + "abbrevName": "Li CL", + "email": null, + "isCollectiveName": false, + "name": "Chun-li Li" + }, + { + "ForeName": "Zong-gan", + "LastName": "Huang", + "abbrevName": "Huang ZG", + "email": null, + "isCollectiveName": false, + "name": "Zong-gan Huang" + }, + { + "ForeName": "Wen-li", + "LastName": "Feng", + "abbrevName": "Feng WL", + "email": null, + "isCollectiveName": false, + "name": "Wen-li Feng" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2010.11.107", + "pmid": "21130076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 404 2011", + "title": "The intracellular stability of DLC1 is regulated by the 26S proteasome in human hepatocellular carcinoma cell line Hep3B." + } + }, + { + "pmid": "19066281", + "pubmed": { + "ISODate": "2009-01-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a Rho-GTPase-activating protein (GAP) that is downregulated in various tumor types. In vitro, DLC1 specifically inactivates the small GTPases RhoA, RhoB and RhoC through its GAP domain and this appears to contribute to its tumor suppressor function in vivo. Molecular mechanisms that control DLC1 activity have not so far been investigated. Here, we show that phorbol-ester-induced activation of protein kinase C and protein kinase D stimulates association of DLC1 with the phosphoserine/phosphothreonine-binding 14-3-3 adaptor proteins via recognition motifs that involve Ser327 and Ser431. Association with 14-3-3 proteins inhibits DLC1 GAP activity and facilitates signaling by active Rho. We further show that treatment of cells with phorbol ester or coexpression of 14-3-3 proteins, blocks DLC1 nucleocytoplasmic shuttling, probably by masking a previously unrecognized nuclear localization sequence. The binding to 14-3-3 proteins is thus a newly discovered mechanism by which DLC1 activity is regulated and compartmentalized.", + "authors": { + "abbreviation": "Rolf-Peter Scholz, Jennifer Regner, Anke Theil, ..., Monilola A Olayioye", + "authorList": [ + { + "ForeName": "Rolf-Peter", + "LastName": "Scholz", + "abbrevName": "Scholz RP", + "email": null, + "isCollectiveName": false, + "name": "Rolf-Peter Scholz" + }, + { + "ForeName": "Jennifer", + "LastName": "Regner", + "abbrevName": "Regner J", + "email": null, + "isCollectiveName": false, + "name": "Jennifer Regner" + }, + { + "ForeName": "Anke", + "LastName": "Theil", + "abbrevName": "Theil A", + "email": null, + "isCollectiveName": false, + "name": "Anke Theil" + }, + { + "ForeName": "Patrik", + "LastName": "Erlmann", + "abbrevName": "Erlmann P", + "email": null, + "isCollectiveName": false, + "name": "Patrik Erlmann" + }, + { + "ForeName": "Gerlinde", + "LastName": "Holeiter", + "abbrevName": "Holeiter G", + "email": null, + "isCollectiveName": false, + "name": "Gerlinde Holeiter" + }, + { + "ForeName": "Ruth", + "LastName": "Jähne", + "abbrevName": "Jähne R", + "email": null, + "isCollectiveName": false, + "name": "Ruth Jähne" + }, + { + "ForeName": "Simone", + "LastName": "Schmid", + "abbrevName": "Schmid S", + "email": null, + "isCollectiveName": false, + "name": "Simone Schmid" + }, + { + "ForeName": "Angelika", + "LastName": "Hausser", + "abbrevName": "Hausser A", + "email": null, + "isCollectiveName": false, + "name": "Angelika Hausser" + }, + { + "ForeName": "Monilola", + "LastName": "Olayioye", + "abbrevName": "Olayioye MA", + "email": null, + "isCollectiveName": false, + "name": "Monilola A Olayioye" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.036251", + "pmid": "19066281", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling." + } + }, + { + "pmid": "25277990", + "pubmed": { + "ISODate": "2014-12-01T00:00:00.000Z", + "abstract": "The major mechanical function of talin is to couple the β-integrin cytoplasmic tails to actin filaments. A variety of β-integrin tails contain conserved binding motifs for talin, and recent research shows that β-integrins differ both in affinity to talin and preferences for other cytoplasmic adaptor proteins. While talin predominantly links β3 integrins to actin filaments within the peripheral cell adhesion sites, talin can become replaced by other integrin adaptor proteins through their overlapping binding sites on integrin tails. Although the NPxY motif in the β-integrin tail is important for talin recognition, our simulations suggest considerably smaller contribution of the NPxY motif in the force resistance of the talin-integrin complex than for the residues upstream of the NPxY. It might thus be possible for the NPxY motif to detach from talin and interact with other integrin binding proteins while the β-integrin still remains bound to talin. The epithelial integrin β6 reportedly activates latent TGFβ1, and we propose that its function may involve direct interaction with talin. ", + "authors": { + "abbreviation": "Sampo Kukkurainen, Juha A Määttä, John Saeger, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "abbrevName": "Kukkurainen S", + "email": "vesa.hytonen@uta.fi", + "isCollectiveName": false, + "name": "Sampo Kukkurainen" + }, + { + "ForeName": "Juha", + "LastName": "Määttä", + "abbrevName": "Määttä JA", + "email": null, + "isCollectiveName": false, + "name": "Juha A Määttä" + }, + { + "ForeName": "John", + "LastName": "Saeger", + "abbrevName": "Saeger J", + "email": null, + "isCollectiveName": false, + "name": "John Saeger" + }, + { + "ForeName": "Jarkko", + "LastName": "Valjakka", + "abbrevName": "Valjakka J", + "email": null, + "isCollectiveName": false, + "name": "Jarkko Valjakka" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Sampo", + "LastName": "Kukkurainen", + "email": [ + "vesa.hytonen@uta.fi" + ], + "name": "Sampo Kukkurainen" + } + ] + }, + "doi": "10.1039/c4mb00341a", + "pmid": "25277990", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biosyst 10 2014", + "title": "The talin-integrin interface under mechanical stress." + } + }, + { + "pmid": "24114040", + "pubmed": { + "ISODate": "2014-07-15T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1. ", + "authors": { + "abbreviation": "Frankie Chi Fat Ko, Judy Wai Ping Yam", + "authorList": [ + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Judy", + "LastName": "Ping Yam", + "abbrevName": "Ping Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28505", + "pmid": "24114040", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Cancer 135 2014", + "title": "Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation." + } + }, + { + "pmid": "16951145", + "pubmed": { + "ISODate": "2006-09-01T00:00:00.000Z", + "abstract": "Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell lines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immunoprecipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.", + "authors": { + "abbreviation": "Judy Wai Ping Yam, Frankie Chi Fat Ko, Chung-Yiu Chan, ..., Irene Oi-Lin Ng", + "authorList": [ + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Chung-Yiu", + "LastName": "Chan", + "abbrevName": "Chan CY", + "email": null, + "isCollectiveName": false, + "name": "Chung-Yiu Chan" + }, + { + "ForeName": "Dong-Yan", + "LastName": "Jin", + "abbrevName": "Jin DY", + "email": null, + "isCollectiveName": false, + "name": "Dong-Yan Jin" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + } + ], + "contacts": [] + }, + "doi": "10.1158/0008-5472.CAN-05-2850", + "pmid": "16951145", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Res 66 2006", + "title": "Interaction of deleted in liver cancer 1 with tensin2 in caveolae and implications in tumor suppression." + } + }, + { + "pmid": "22645138", + "pubmed": { + "ISODate": "2012-07-27T00:00:00.000Z", + "abstract": "The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.", + "authors": { + "abbreviation": "Lihong Chen, Changdong Liu, Frankie Chi Fat Ko, ..., Guang Zhu", + "authorList": [ + { + "ForeName": "Lihong", + "LastName": "Chen", + "abbrevName": "Chen L", + "email": null, + "isCollectiveName": false, + "name": "Lihong Chen" + }, + { + "ForeName": "Changdong", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Changdong Liu" + }, + { + "ForeName": "Frankie", + "LastName": "Ko", + "abbrevName": "Ko FC", + "email": null, + "isCollectiveName": false, + "name": "Frankie Chi Fat Ko" + }, + { + "ForeName": "Naining", + "LastName": "Xu", + "abbrevName": "Xu N", + "email": null, + "isCollectiveName": false, + "name": "Naining Xu" + }, + { + "ForeName": "Irene", + "LastName": "Ng", + "abbrevName": "Ng IO", + "email": null, + "isCollectiveName": false, + "name": "Irene Oi-Lin Ng" + }, + { + "ForeName": "Judy", + "LastName": "Yam", + "abbrevName": "Yam JW", + "email": null, + "isCollectiveName": false, + "name": "Judy Wai Ping Yam" + }, + { + "ForeName": "Guang", + "LastName": "Zhu", + "abbrevName": "Zhu G", + "email": null, + "isCollectiveName": false, + "name": "Guang Zhu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.360206", + "pmid": "22645138", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Solution structure of the phosphotyrosine binding (PTB) domain of human tensin2 protein in complex with deleted in liver cancer 1 (DLC1) peptide reveals a novel peptide binding mode." + } + }, + { + "pmid": "28155884", + "pubmed": { + "ISODate": "2017-02-03T00:00:00.000Z", + "abstract": "Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with Cys diminished that of talin2. Further computational modeling analysis shows that talin2 S339 formed a hydrogen bond with E353, which is critical for inducing key hydrogen bonds between talin2 N326 and β1-integrin R760, and between talin2 K327 and β1-integrin D759. Mutation at any of these residues significantly diminished the interaction of talin2 with β1- integrin tails. These hydrogen bonds were not observed in talin1/β1-integrin, but did exist in talin1C336S/β1-integrin complex. These results suggest that talin2 S339 forms a hydrogen bond with E353 to mediate its high affinity to β1-integrin.", + "authors": { + "abbreviation": "Yaxia Yuan, Liqing Li, Yanyan Zhu, ..., Cai Huang", + "authorList": [ + { + "ForeName": "Yaxia", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Yaxia Yuan" + }, + { + "ForeName": "Liqing", + "LastName": "Li", + "abbrevName": "Li L", + "email": null, + "isCollectiveName": false, + "name": "Liqing Li" + }, + { + "ForeName": "Yanyan", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yanyan Zhu" + }, + { + "ForeName": "Lei", + "LastName": "Qi", + "abbrevName": "Qi L", + "email": null, + "isCollectiveName": false, + "name": "Lei Qi" + }, + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Chang-Guo", + "LastName": "Zhan", + "abbrevName": "Zhan CG", + "email": null, + "isCollectiveName": false, + "name": "Chang-Guo Zhan" + }, + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep41989", + "pmid": "28155884", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "The molecular basis of talin2's high affinity toward β1-integrin." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + } + ], + "secret": "read-only", + "type": "binding" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/doct_tests_3.json b/neo4j-test/document/doct_tests_3.json new file mode 100644 index 000000000..a5ac261b9 --- /dev/null +++ b/neo4j-test/document/doct_tests_3.json @@ -0,0 +1,20696 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-02-01T19:40:07.496Z", + "_newestOpId": "c8247685-9229-4c9d-ae57-ffec57f8ebc7", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "ArticleTitle": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, Kent, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rosemarie E", + "Identifier": [], + "Initials": "RE", + "LastName": "Gough" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Matthew C", + "Identifier": [], + "Initials": "MC", + "LastName": "Jones" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Thomas", + "Identifier": [], + "Initials": "T", + "LastName": "Zacharchenko" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Mechanobiology Institute, National University of Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Shimin", + "Identifier": [], + "Initials": "S", + "LastName": "Le" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Mechanobiology Institute, National University of Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Miao", + "Identifier": [], + "Initials": "M", + "LastName": "Yu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Faculty of Science and Engineering, Cell Biology Department, Åbo Akademi University, Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Guillaume", + "Identifier": [], + "Initials": "G", + "LastName": "Jacquemet" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biomedical Sciences, Astbury Centre for Structural Biology, University of Leeds, Leeds, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ste P", + "Identifier": [], + "Initials": "SP", + "LastName": "Muench" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Mechanobiology Institute, National University of Singapore, Singapore; Department of Physics, National University of Singapore, Singapore.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jie", + "Identifier": [], + "Initials": "J", + "LastName": "Yan" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jonathan D", + "Identifier": [], + "Initials": "JD", + "LastName": "Humphries" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Claus", + "Identifier": [], + "Initials": "C", + "LastName": "Jørgensen" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Faculty of Biology, Medicine & Health, Wellcome Centre for Cell-Matrix Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. Electronic address: martin.humphries@manchester.ac.uk.", + "email": [ + "martin.humphries@manchester.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Martin J", + "Identifier": [], + "Initials": "MJ", + "LastName": "Humphries" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, Kent, UK. Electronic address: b.t.goult@kent.ac.uk.", + "email": [ + "b.t.goult@kent.ac.uk" + ] + } + ], + "CollectiveName": null, + "ForeName": "Benjamin T", + "Identifier": [], + "Initials": "BT", + "LastName": "Goult" + } + ], + "Journal": { + "ISOAbbreviation": "J Biol Chem", + "ISSN": { + "IssnType": "Electronic", + "value": "1083-351X" + }, + "JournalIssue": { + "Issue": "1", + "PubDate": { + "Day": null, + "Month": "Jul", + "Year": "2021" + }, + "Volume": "297" + }, + "Title": "The Journal of biological chemistry" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": "D016608", + "value": "Talin" + }, + "RegistryNumber": "0" + }, + { + "NameOfSubstance": { + "UI": "D016203", + "value": "CDC2 Protein Kinase" + }, + "RegistryNumber": "EC 2.7.11.22" + } + ], + "InvestigatorList": [], + "KeywordList": [ + "CDK1", + "adhesion", + "cell cycle", + "cyclin-dependent kinase", + "integrin", + "mechanotransduction", + "talin" + ], + "MeshheadingList": [ + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D020816", + "value": "Amino Acid Motifs" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D000595", + "value": "Amino Acid Sequence" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D000818", + "value": "Animals" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D001665", + "value": "Binding Sites" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D016203", + "value": "CDC2 Protein Kinase" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000737", + "value": "chemistry" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000378", + "value": "metabolism" + } + ] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D002448", + "value": "Cell Adhesion" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D045744", + "value": "Cell Line, Tumor" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D006801", + "value": "Humans" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "Y", + "UI": "D040542", + "value": "Mechanotransduction, Cellular" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D051379", + "value": "Mice" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D008954", + "value": "Models, Biological" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D010766", + "value": "Phosphorylation" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D011485", + "value": "Protein Binding" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D000072417", + "value": "Protein Domains" + }, + "QualifierName": [] + }, + { + "DescriptorName": { + "MajorTopicYN": "N", + "UI": "D016608", + "value": "Talin" + }, + "QualifierName": [ + { + "MajorTopicYN": "N", + "UI": "Q000737", + "value": "chemistry" + }, + { + "MajorTopicYN": "Y", + "UI": "Q000378", + "value": "metabolism" + } + ] + } + ] + }, + "PubmedData": { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "34118235" + }, + { + "IdType": "pmc", + "id": "PMC8260872" + }, + { + "IdType": "doi", + "id": "10.1016/j.jbc.2021.100837" + }, + { + "IdType": "pii", + "id": "S0021-9258(21)00635-9" + } + ], + "History": [ + { + "PubMedPubDate": { + "Day": "20", + "Month": "3", + "Year": "2021" + }, + "PubStatus": "received" + }, + { + "PubMedPubDate": { + "Day": "20", + "Month": "5", + "Year": "2021" + }, + "PubStatus": "revised" + }, + { + "PubMedPubDate": { + "Day": "25", + "Month": "5", + "Year": "2021" + }, + "PubStatus": "accepted" + }, + { + "PubMedPubDate": { + "Day": "13", + "Month": "6", + "Year": "2021" + }, + "PubStatus": "pubmed" + }, + { + "PubMedPubDate": { + "Day": "26", + "Month": "8", + "Year": "2021" + }, + "PubStatus": "medline" + }, + { + "PubMedPubDate": { + "Day": "12", + "Month": "6", + "Year": "2021" + }, + "PubStatus": "entrez" + } + ], + "ReferenceList": [ + { + "Reference": [ + { + "ArticleIdList": [ + { + "IdType": "pmc", + "id": "PMC2132466" + }, + { + "IdType": "pubmed", + "id": "9026502" + } + ], + "Citation": "Assoian R.K. 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I propose that memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix (ECM) adhesions that organise each and every synapse. The MeshCODE framework outlined here represents a unifying theory of data storage in animals, providing read-write storage of both dynamic and persistent information in a binary format. Mechanosensitive proteins that contain force-dependent switches can store information persistently, which can be written or updated using small changes in mechanical force. These mechanosensitive proteins, such as talin, scaffold each synapse, creating a meshwork of switches that together form a code, the so-called MeshCODE. Large signalling complexes assemble on these scaffolds as a function of the switch patterns and these complexes would both stabilise the patterns and coordinate synaptic regulators to dynamically tune synaptic activity. Synaptic transmission and action potential spike trains would operate the cytoskeletal machinery to write and update the synaptic MeshCODEs, thereby propagating this coding throughout the organism. Based on established biophysical principles, such a mechanical basis for memory would provide a physical location for data storage in the brain, with the binary patterns, encoded in the information-storing mechanosensitive molecules in the synaptic scaffolds, and the complexes that form on them, representing the physical location of engrams. Furthermore, the conversion and storage of sensory and temporal inputs into a binary format would constitute an addressable read-write memory system, supporting the view of the mind as an organic supercomputer.", + "authors": { + "abbreviation": "Benjamin T Goult", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [] + }, + "doi": "10.3389/fnmol.2021.592951", + "pmid": "33716664", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Front Mol Neurosci 14 2021", + "title": "The Mechanical Basis of Memory - the MeshCODE Theory." + } + }, + { + "pmid": "33239692", + "pubmed": { + "ISODate": "2020-11-25T00:00:00.000Z", + "abstract": "Comparative genome- and proteome-wide screens yield large amounts of data. To efficiently present such datasets and to simplify the identification of hits, the results are often presented in a type of scatterplot known as a volcano plot, which shows a measure of effect size versus a measure of significance. The data points with the largest effect size and a statistical significance beyond a user-defined threshold are considered as hits. Such hits are usually annotated in the plot by a label with their name. Volcano plots can represent ten thousands of data points, of which typically only a handful is annotated. The information of data that is not annotated is hardly or not accessible. To simplify access to the data and enable its re-use, we have developed an open source and online web tool with R/Shiny. The web app is named VolcaNoseR and it can be used to create, explore, label and share volcano plots ( https://huygens.science.uva.nl/VolcaNoseR ). When the data is stored in an online data repository, the web app can retrieve that data together with user-defined settings to generate a customized, interactive volcano plot. Users can interact with the data, adjust the plot and share their modified plot together with the underlying data. Therefore, VolcaNoseR increases the transparency and re-use of large comparative genome- and proteome-wide datasets.", + "authors": { + "abbreviation": "Joachim Goedhart, Martijn S Luijsterburg", + "authorList": [ + { + "ForeName": "Joachim", + "LastName": "Goedhart", + "abbrevName": "Goedhart J", + "email": "j.goedhart@uva.nl", + "isCollectiveName": false, + "name": "Joachim Goedhart" + }, + { + "ForeName": "Martijn", + "LastName": "Luijsterburg", + "abbrevName": "Luijsterburg MS", + "email": null, + "isCollectiveName": false, + "name": "Martijn S Luijsterburg" + } + ], + "contacts": [ + { + "ForeName": "Joachim", + "LastName": "Goedhart", + "email": [ + "j.goedhart@uva.nl" + ], + "name": "Joachim Goedhart" + } + ] + }, + "doi": "10.1038/s41598-020-76603-3", + "pmid": "33239692", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Sci Rep 10 2020", + "title": "VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots." + } + }, + { + "pmid": "33215380", + "pubmed": { + "ISODate": "2021-01-01T00:00:00.000Z", + "abstract": "More than 250 proteins are associated with the formation of integrin adhesion complexes involving a vast number of complex interactions between them. These interactions enable adhesions to serve as dynamic and diverse mechanosignaling centers. Our laboratory focuses on the biochemical and structural study of these interactions to help unpick this complex network. Here, we describe the general pipeline of biochemical assays and methods we use. The chapter is split into two sections: (1) protein production and characterization and (2) biochemical assays for the characterization of binding between full-length proteins and/or specific regions of proteins with other proteins, peptides, and phospholipids. The suite of assays we use routinely includes circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy for sample quality assessment, prior to biochemical analysis using NMR, fluorescence polarization (FP), microscale thermophoresis (MST), size-exclusion chromatography multiangle light scattering (SEC-MALS), and pulldown/cosedimentation-based approaches. The results of our analysis feed into in vivo studies that allow for the elucidation of the biological role of each interaction.", + "authors": { + "abbreviation": "Rejina B Khan, Lorena Varela, Alana R Cowell, Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rejina", + "LastName": "Khan", + "abbrevName": "Khan RB", + "email": null, + "isCollectiveName": false, + "name": "Rejina B Khan" + }, + { + "ForeName": "Lorena", + "LastName": "Varela", + "abbrevName": "Varela L", + "email": null, + "isCollectiveName": false, + "name": "Lorena Varela" + }, + { + "ForeName": "Alana", + "LastName": "Cowell", + "abbrevName": "Cowell AR", + "email": null, + "isCollectiveName": false, + "name": "Alana R Cowell" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "B.T.Goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "B.T.Goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1007/978-1-0716-0962-0_9", + "pmid": "33215380", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Methods Mol Biol 2217 2021", + "title": "Biochemical Characterization of the Integrin Interactome." + } + }, + { + "pmid": "32585685", + "pubmed": { + "ISODate": "2020-08-03T00:00:00.000Z", + "abstract": "Integrin adhesion complexes (IACs) bridge the extracellular matrix to the actin cytoskeleton and transduce signals in response to both chemical and mechanical cues. The composition, interactions, stoichiometry, and topological organization of proteins within IACs are not fully understood. To address this gap, we used multiplexed proximity biotinylation (BioID) to generate an in situ, proximity-dependent adhesome in mouse pancreatic fibroblasts. Integration of the interactomes of 16 IAC-associated baits revealed a network of 147 proteins with 361 proximity interactions. Candidates with underappreciated roles in adhesion were identified, in addition to established IAC components. Bioinformatic analysis revealed five clusters of IAC baits that link to common groups of prey, and which therefore may represent functional modules. The five clusters, and their spatial associations, are consistent with current models of IAC interaction networks and stratification. This study provides a resource to examine proximal relationships within IACs at a global level.", + "authors": { + "abbreviation": "Megan R Chastney, Craig Lawless, Jonathan D Humphries, ..., Martin J Humphries", + "authorList": [ + { + "ForeName": "Megan", + "LastName": "Chastney", + "abbrevName": "Chastney MR", + "email": null, + "isCollectiveName": false, + "name": "Megan R Chastney" + }, + { + "ForeName": "Craig", + "LastName": "Lawless", + "abbrevName": "Lawless C", + "email": null, + "isCollectiveName": false, + "name": "Craig Lawless" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Stacey", + "LastName": "Warwood", + "abbrevName": "Warwood S", + "email": null, + "isCollectiveName": false, + "name": "Stacey Warwood" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "David", + "LastName": "Knight", + "abbrevName": "Knight D", + "email": null, + "isCollectiveName": false, + "name": "David Knight" + }, + { + "ForeName": "Claus", + "LastName": "Jorgensen", + "abbrevName": "Jorgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jorgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.202003038", + "pmid": "32585685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 219 2020", + "title": "Topological features of integrin adhesion complexes revealed by multiplexed proximity biotinylation." + } + }, + { + "pmid": "31913322", + "pubmed": { + "ISODate": "2020-01-08T00:00:00.000Z", + "abstract": "A large body of literature is available on wound healing in humans. Nonetheless, a standardized ex vivo wound model without disruption of the dermal compartment has not been put forward with compelling justification. Here, we present a novel wound model based on application of negative pressure and its effects for epidermal regeneration and immune cell behaviour. Importantly, the basement membrane remained intact after blister roof removal and keratinocytes were absent in the wounded area. Upon six days of culture, the wound was covered with one to three-cell thick K14+Ki67+ keratinocyte layers, indicating that proliferation and migration were involved in wound closure. After eight to twelve days, a multi-layered epidermis was formed expressing epidermal differentiation markers (K10, filaggrin, DSG-1, CDSN). Investigations about immune cell-specific manners revealed more T cells in the blister roof epidermis compared to normal epidermis. We identified several cell populations in blister roof epidermis and suction blister fluid that are absent in normal epidermis which correlated with their decrease in the dermis, indicating a dermal efflux upon negative pressure. Together, our model recapitulates the main features of epithelial wound regeneration, and can be applied for testing wound healing therapies and investigating underlying mechanisms.", + "authors": { + "abbreviation": "Ana Rakita, Nenad Nikolić, Michael Mildner, ..., Adelheid Elbe-Bürger", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Rakita", + "abbrevName": "Rakita A", + "email": null, + "isCollectiveName": false, + "name": "Ana Rakita" + }, + { + "ForeName": "Nenad", + "LastName": "Nikolić", + "abbrevName": "Nikolić N", + "email": null, + "isCollectiveName": false, + "name": "Nenad Nikolić" + }, + { + "ForeName": "Michael", + "LastName": "Mildner", + "abbrevName": "Mildner M", + "email": null, + "isCollectiveName": false, + "name": "Michael Mildner" + }, + { + "ForeName": "Johannes", + "LastName": "Matiasek", + "abbrevName": "Matiasek J", + "email": null, + "isCollectiveName": false, + "name": "Johannes Matiasek" + }, + { + "ForeName": "Adelheid", + "LastName": "Elbe-Bürger", + "abbrevName": "Elbe-Bürger A", + "email": "adelheid.elbe-buerger@meduniwien.ac.at", + "isCollectiveName": false, + "name": "Adelheid Elbe-Bürger" + } + ], + "contacts": [ + { + "ForeName": "Adelheid", + "LastName": "Elbe-Bürger", + "email": [ + "adelheid.elbe-buerger@meduniwien.ac.at" + ], + "name": "Adelheid Elbe-Bürger" + } + ] + }, + "doi": "10.1038/s41598-019-56847-4", + "pmid": "31913322", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 10 2020", + "title": "Re-epithelialization and immune cell behaviour in an ex vivo human skin model." + } + }, + { + "pmid": "31680160", + "pubmed": { + "ISODate": "2020-01-08T00:00:00.000Z", + "abstract": "The eukaryotic linear motif (ELM) resource is a repository of manually curated experimentally validated short linear motifs (SLiMs). Since the initial release almost 20 years ago, ELM has become an indispensable resource for the molecular biology community for investigating functional regions in many proteins. In this update, we have added 21 novel motif classes, made major revisions to 12 motif classes and added >400 new instances mostly focused on DNA damage, the cytoskeleton, SH2-binding phosphotyrosine motifs and motif mimicry by pathogenic bacterial effector proteins. The current release of the ELM database contains 289 motif classes and 3523 individual protein motif instances manually curated from 3467 scientific publications. ELM is available at: http://elm.eu.org.", + "authors": { + "abbreviation": "Manjeet Kumar, Marc Gouw, Sushama Michael, ..., Toby J Gibson", + "authorList": [ + { + "ForeName": "Manjeet", + "LastName": "Kumar", + "abbrevName": "Kumar M", + "email": null, + "isCollectiveName": false, + "name": "Manjeet Kumar" + }, + { + "ForeName": "Marc", + "LastName": "Gouw", + "abbrevName": "Gouw M", + "email": null, + "isCollectiveName": false, + "name": "Marc Gouw" + }, + { + "ForeName": "Sushama", + "LastName": "Michael", + "abbrevName": "Michael S", + "email": null, + "isCollectiveName": false, + "name": "Sushama Michael" + }, + { + "ForeName": "Hugo", + "LastName": "Sámano-Sánchez", + "abbrevName": "Sámano-Sánchez H", + "email": null, + "isCollectiveName": false, + "name": "Hugo Sámano-Sánchez" + }, + { + "ForeName": "Rita", + "LastName": "Pancsa", + "abbrevName": "Pancsa R", + "email": null, + "isCollectiveName": false, + "name": "Rita Pancsa" + }, + { + "ForeName": "Juliana", + "LastName": "Glavina", + "abbrevName": "Glavina J", + "email": null, + "isCollectiveName": false, + "name": "Juliana Glavina" + }, + { + "ForeName": "Athina", + "LastName": "Diakogianni", + "abbrevName": "Diakogianni A", + "email": null, + "isCollectiveName": false, + "name": "Athina Diakogianni" + }, + { + "ForeName": "Jesús", + "LastName": "Valverde", + "abbrevName": "Valverde JA", + "email": null, + "isCollectiveName": false, + "name": "Jesús Alvarado Valverde" + }, + { + "ForeName": "Dayana", + "LastName": "Bukirova", + "abbrevName": "Bukirova D", + "email": null, + "isCollectiveName": false, + "name": "Dayana Bukirova" + }, + { + "ForeName": "Jelena", + "LastName": "Čalyševa", + "abbrevName": "Čalyševa J", + "email": null, + "isCollectiveName": false, + "name": "Jelena Čalyševa" + }, + { + "ForeName": "Nicolas", + "LastName": "Palopoli", + "abbrevName": "Palopoli N", + "email": null, + "isCollectiveName": false, + "name": "Nicolas Palopoli" + }, + { + "ForeName": "Norman", + "LastName": "Davey", + "abbrevName": "Davey NE", + "email": null, + "isCollectiveName": false, + "name": "Norman E Davey" + }, + { + "ForeName": "Lucía", + "LastName": "Chemes", + "abbrevName": "Chemes LB", + "email": null, + "isCollectiveName": false, + "name": "Lucía B Chemes" + }, + { + "ForeName": "Toby", + "LastName": "Gibson", + "abbrevName": "Gibson TJ", + "email": null, + "isCollectiveName": false, + "name": "Toby J Gibson" + } + ], + "contacts": [] + }, + "doi": "10.1093/nar/gkz1030", + "pmid": "31680160", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 48 2020", + "title": "ELM-the eukaryotic linear motif resource in 2020." + } + }, + { + "pmid": "31588918", + "pubmed": { + "ISODate": "2019-10-01T00:00:00.000Z", + "abstract": "Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.", + "authors": { + "abbreviation": "Dorothee Liebschner, Pavel V Afonine, Matthew L Baker, ..., Paul D Adams", + "authorList": [ + { + "ForeName": "Dorothee", + "LastName": "Liebschner", + "abbrevName": "Liebschner D", + "email": null, + "isCollectiveName": false, + "name": "Dorothee Liebschner" + }, + { + "ForeName": "Pavel", + "LastName": "Afonine", + "abbrevName": "Afonine PV", + "email": null, + "isCollectiveName": false, + "name": "Pavel V Afonine" + }, + { + "ForeName": "Matthew", + "LastName": "Baker", + "abbrevName": "Baker ML", + "email": null, + "isCollectiveName": false, + "name": "Matthew L Baker" + }, + { + "ForeName": "Gábor", + "LastName": "Bunkóczi", + "abbrevName": "Bunkóczi G", + "email": null, + "isCollectiveName": false, + "name": "Gábor Bunkóczi" + }, + { + "ForeName": "Vincent", + "LastName": "Chen", + "abbrevName": "Chen VB", + "email": null, + "isCollectiveName": false, + "name": "Vincent B Chen" + }, + { + "ForeName": "Tristan", + "LastName": "Croll", + "abbrevName": "Croll TI", + "email": null, + "isCollectiveName": false, + "name": "Tristan I Croll" + }, + { + "ForeName": "Bradley", + "LastName": "Hintze", + "abbrevName": "Hintze B", + "email": null, + "isCollectiveName": false, + "name": "Bradley Hintze" + }, + { + "ForeName": "Li", + "LastName": "Hung", + "abbrevName": "Hung LW", + "email": null, + "isCollectiveName": false, + "name": "Li Wei Hung" + }, + { + "ForeName": "Swati", + "LastName": "Jain", + "abbrevName": "Jain S", + "email": null, + "isCollectiveName": false, + "name": "Swati Jain" + }, + { + "ForeName": "Airlie", + "LastName": "McCoy", + "abbrevName": "McCoy AJ", + "email": null, + "isCollectiveName": false, + "name": "Airlie J McCoy" + }, + { + "ForeName": "Nigel", + "LastName": "Moriarty", + "abbrevName": "Moriarty NW", + "email": null, + "isCollectiveName": false, + "name": "Nigel W Moriarty" + }, + { + "ForeName": "Robert", + "LastName": "Oeffner", + "abbrevName": "Oeffner RD", + "email": null, + "isCollectiveName": false, + "name": "Robert D Oeffner" + }, + { + "ForeName": "Billy", + "LastName": "Poon", + "abbrevName": "Poon BK", + "email": null, + "isCollectiveName": false, + "name": "Billy K Poon" + }, + { + "ForeName": "Michael", + "LastName": "Prisant", + "abbrevName": "Prisant MG", + "email": null, + "isCollectiveName": false, + "name": "Michael G Prisant" + }, + { + "ForeName": "Randy", + "LastName": "Read", + "abbrevName": "Read RJ", + "email": null, + "isCollectiveName": false, + "name": "Randy J Read" + }, + { + "ForeName": "Jane", + "LastName": "Richardson", + "abbrevName": "Richardson JS", + "email": null, + "isCollectiveName": false, + "name": "Jane S Richardson" + }, + { + "ForeName": "David", + "LastName": "Richardson", + "abbrevName": "Richardson DC", + "email": null, + "isCollectiveName": false, + "name": "David C Richardson" + }, + { + "ForeName": "Massimo", + "LastName": "Sammito", + "abbrevName": "Sammito MD", + "email": null, + "isCollectiveName": false, + "name": "Massimo D Sammito" + }, + { + "ForeName": "Oleg", + "LastName": "Sobolev", + "abbrevName": "Sobolev OV", + "email": null, + "isCollectiveName": false, + "name": "Oleg V Sobolev" + }, + { + "ForeName": "Duncan", + "LastName": "Stockwell", + "abbrevName": "Stockwell DH", + "email": null, + "isCollectiveName": false, + "name": "Duncan H Stockwell" + }, + { + "ForeName": "Thomas", + "LastName": "Terwilliger", + "abbrevName": "Terwilliger TC", + "email": null, + "isCollectiveName": false, + "name": "Thomas C Terwilliger" + }, + { + "ForeName": "Alexandre", + "LastName": "Urzhumtsev", + "abbrevName": "Urzhumtsev AG", + "email": null, + "isCollectiveName": false, + "name": "Alexandre G Urzhumtsev" + }, + { + "ForeName": "Lizbeth", + "LastName": "Videau", + "abbrevName": "Videau LL", + "email": null, + "isCollectiveName": false, + "name": "Lizbeth L Videau" + }, + { + "ForeName": "Christopher", + "LastName": "Williams", + "abbrevName": "Williams CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J Williams" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + } + ], + "contacts": [] + }, + "doi": "10.1107/S2059798319011471", + "pmid": "31588918", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Acta Crystallogr D Struct Biol 75 2019", + "title": "Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix." + } + }, + { + "pmid": "30395289", + "pubmed": { + "ISODate": "2019-01-08T00:00:00.000Z", + "abstract": "The PRoteomics IDEntifications (PRIDE) database (https://www.ebi.ac.uk/pride/) is the world's largest data repository of mass spectrometry-based proteomics data, and is one of the founding members of the global ProteomeXchange (PX) consortium. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2016. In the last 3 years, public data sharing through PRIDE (as part of PX) has definitely become the norm in the field. In parallel, data re-use of public proteomics data has increased enormously, with multiple applications. We first describe the new architecture of PRIDE Archive, the archival component of PRIDE. PRIDE Archive and the related data submission framework have been further developed to support the increase in submitted data volumes and additional data types. A new scalable and fault tolerant storage backend, Application Programming Interface and web interface have been implemented, as a part of an ongoing process. Additionally, we emphasize the improved support for quantitative proteomics data through the mzTab format. At last, we outline key statistics on the current data contents and volume of downloads, and how PRIDE data are starting to be disseminated to added-value resources including Ensembl, UniProt and Expression Atlas.", + "authors": { + "abbreviation": "Yasset Perez-Riverol, Attila Csordas, Jingwen Bai, ..., Juan Antonio Vizcaíno", + "authorList": [ + { + "ForeName": "Yasset", + "LastName": "Perez-Riverol", + "abbrevName": "Perez-Riverol Y", + "email": null, + "isCollectiveName": false, + "name": "Yasset Perez-Riverol" + }, + { + "ForeName": "Attila", + "LastName": "Csordas", + "abbrevName": "Csordas A", + "email": null, + "isCollectiveName": false, + "name": "Attila Csordas" + }, + { + "ForeName": "Jingwen", + "LastName": "Bai", + "abbrevName": "Bai J", + "email": null, + "isCollectiveName": false, + "name": "Jingwen Bai" + }, + { + "ForeName": "Manuel", + "LastName": "Bernal-Llinares", + "abbrevName": "Bernal-Llinares M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Bernal-Llinares" + }, + { + "ForeName": "Suresh", + "LastName": "Hewapathirana", + "abbrevName": "Hewapathirana S", + "email": null, + "isCollectiveName": false, + "name": "Suresh Hewapathirana" + }, + { + "ForeName": "Deepti", + "LastName": "Kundu", + "abbrevName": "Kundu DJ", + "email": null, + "isCollectiveName": false, + "name": "Deepti J Kundu" + }, + { + "ForeName": "Avinash", + "LastName": "Inuganti", + "abbrevName": "Inuganti A", + "email": null, + "isCollectiveName": false, + "name": "Avinash Inuganti" + }, + { + "ForeName": "Johannes", + "LastName": "Griss", + "abbrevName": "Griss J", + "email": null, + "isCollectiveName": false, + "name": "Johannes Griss" + }, + { + "ForeName": "Gerhard", + "LastName": "Mayer", + "abbrevName": "Mayer G", + "email": null, + "isCollectiveName": false, + "name": "Gerhard Mayer" + }, + { + "ForeName": "Martin", + "LastName": "Eisenacher", + "abbrevName": "Eisenacher M", + "email": null, + "isCollectiveName": false, + "name": "Martin Eisenacher" + }, + { + "ForeName": "Enrique", + "LastName": "Pérez", + "abbrevName": "Pérez E", + "email": null, + "isCollectiveName": false, + "name": "Enrique Pérez" + }, + { + "ForeName": "Julian", + "LastName": "Uszkoreit", + "abbrevName": "Uszkoreit J", + "email": null, + "isCollectiveName": false, + "name": "Julian Uszkoreit" + }, + { + "ForeName": "Julianus", + "LastName": "Pfeuffer", + "abbrevName": "Pfeuffer J", + "email": null, + "isCollectiveName": false, + "name": "Julianus Pfeuffer" + }, + { + "ForeName": "Timo", + "LastName": "Sachsenberg", + "abbrevName": "Sachsenberg T", + "email": null, + "isCollectiveName": false, + "name": "Timo Sachsenberg" + }, + { + "ForeName": "Sule", + "LastName": "Yilmaz", + "abbrevName": "Yilmaz S", + "email": null, + "isCollectiveName": false, + "name": "Sule Yilmaz" + }, + { + "ForeName": "Shivani", + "LastName": "Tiwary", + "abbrevName": "Tiwary S", + "email": null, + "isCollectiveName": false, + "name": "Shivani Tiwary" + }, + { + "ForeName": "Jürgen", + "LastName": "Cox", + "abbrevName": "Cox J", + "email": null, + "isCollectiveName": false, + "name": "Jürgen Cox" + }, + { + "ForeName": "Enrique", + "LastName": "Audain", + "abbrevName": "Audain E", + "email": null, + "isCollectiveName": false, + "name": "Enrique Audain" + }, + { + "ForeName": "Mathias", + "LastName": "Walzer", + "abbrevName": "Walzer M", + "email": null, + "isCollectiveName": false, + "name": "Mathias Walzer" + }, + { + "ForeName": "Andrew", + "LastName": "Jarnuczak", + "abbrevName": "Jarnuczak AF", + "email": null, + "isCollectiveName": false, + "name": "Andrew F Jarnuczak" + }, + { + "ForeName": "Tobias", + "LastName": "Ternent", + "abbrevName": "Ternent T", + "email": null, + "isCollectiveName": false, + "name": "Tobias Ternent" + }, + { + "ForeName": "Alvis", + "LastName": "Brazma", + "abbrevName": "Brazma A", + "email": null, + "isCollectiveName": false, + "name": "Alvis Brazma" + }, + { + "ForeName": "Juan", + "LastName": "Vizcaíno", + "abbrevName": "Vizcaíno JA", + "email": null, + "isCollectiveName": false, + "name": "Juan Antonio Vizcaíno" + } + ], + "contacts": [] + }, + "doi": "10.1093/nar/gky1106", + "pmid": "30395289", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 47 2019", + "title": "The PRIDE database and related tools and resources in 2019: improving support for quantification data." + } + }, + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "29930204", + "pubmed": { + "ISODate": "2018-09-03T00:00:00.000Z", + "abstract": "In most tissues, anchorage-dependent growth and cell cycle progression are dependent on cells engaging extracellular matrices (ECMs) via integrin-receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings before division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell adhesion to the ECM. In this study, we demonstrate that cyclin-dependent kinase 1 (CDK1) mediates this link. CDK1, in complex with cyclin A2, promotes adhesion complex and actin cytoskeleton organization during interphase and mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area decreases in G2, and disassembly occurs several hours before mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1 is therefore the trigger that initiates remodeling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.", + "authors": { + "abbreviation": "Matthew C Jones, Janet A Askari, Jonathan D Humphries, Martin J Humphries", + "authorList": [ + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1083/jcb.201802088", + "pmid": "29930204", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Cell adhesion is regulated by CDK1 during the cell cycle." + } + }, + { + "pmid": "29723415", + "pubmed": { + "ISODate": "2018-06-01T00:00:00.000Z", + "abstract": "Talins are cytoplasmic adapter proteins essential for integrin-mediated cell adhesion to the extracellular matrix. Talins control the activation state of integrins, link integrins to cytoskeletal actin, recruit numerous signalling molecules that mediate integrin signalling and coordinate recruitment of microtubules to adhesion sites via interaction with KANK (kidney ankyrin repeat-containing) proteins. Vertebrates have two talin genes, TLN1 and TLN2. Although talin1 and talin2 share 76% protein sequence identity (88% similarity), they are not functionally redundant, and the differences between the two isoforms are not fully understood. In this Review, we focus on the similarities and differences between the two talins in terms of structure, biochemistry and function, which hint at subtle differences in fine-tuning adhesion signalling.", + "authors": { + "abbreviation": "Rosemarie E Gough, Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [] + }, + "doi": "10.1002/1873-3468.13081", + "pmid": "29723415", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "FEBS Lett 592 2018", + "title": "The tale of two talins - two isoforms to fine-tune integrin signalling." + } + }, + { + "pmid": "29710402", + "pubmed": { + "ISODate": "2018-05-01T00:00:00.000Z", + "abstract": "Vinculin is a central component of mechanosensitive adhesive complexes that form between cells and the extracellular matrix. A myriad of infectious agents mimic vinculin binding sites (VBS), enabling them to hijack the adhesion machinery and facilitate cellular entry. Here, we report the structural and biochemical characterisation of VBS from the chlamydial virulence factor TarP. Whilst the affinities of isolated VBS peptides from TarP and talin for vinculin are similar, their behaviour in larger fragments is markedly different. In talin, VBS are cryptic and require mechanical activation to bind vinculin, whereas the TarP VBS are located in disordered regions, and so are constitutively active. We demonstrate that the TarP VBS can uncouple talin:vinculin complexes, which may lead to adhesion destabilisation.", + "authors": { + "abbreviation": "Austin J Whitewood, Abhimanyu K Singh, David G Brown, Benjamin T Goult", + "authorList": [ + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood AJ", + "email": null, + "isCollectiveName": false, + "name": "Austin J Whitewood" + }, + { + "ForeName": "Abhimanyu", + "LastName": "Singh", + "abbrevName": "Singh AK", + "email": null, + "isCollectiveName": false, + "name": "Abhimanyu K Singh" + }, + { + "ForeName": "David", + "LastName": "Brown", + "abbrevName": "Brown DG", + "email": null, + "isCollectiveName": false, + "name": "David G Brown" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [] + }, + "doi": "10.1002/1873-3468.13074", + "pmid": "29710402", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 592 2018", + "title": "Chlamydial virulence factor TarP mimics talin to disrupt the talin-vinculin complex." + } + }, + { + "pmid": "29516480", + "pubmed": { + "ISODate": "2018-02-21T00:00:00.000Z", + "abstract": "BioID is a unique method to screen for physiologically relevant protein interactions that occur in living cells. This technique harnesses a promiscuous biotin ligase to biotinylate proteins based on proximity. The ligase is fused to a protein of interest and expressed in cells, where it biotinylates proximal endogenous proteins. Because it is a rare protein modification in nature, biotinylation of these endogenous proteins by BioID fusion proteins enables their selective isolation and identification with standard biotin-affinity capture. Proteins identified by BioID are candidate interactors for the protein of interest. BioID can be applied to insoluble proteins, can identify weak and/or transient interactions, and is amenable to temporal regulation. Initially applied to mammalian cells, BioID has potential application in a variety of cell types from diverse species. © 2018 by John Wiley & Sons, Inc.", + "authors": { + "abbreviation": "Kyle J Roux, Dae In Kim, Brian Burke, Danielle G May", + "authorList": [ + { + "ForeName": "Kyle", + "LastName": "Roux", + "abbrevName": "Roux KJ", + "email": null, + "isCollectiveName": false, + "name": "Kyle J Roux" + }, + { + "ForeName": "Dae", + "LastName": "Kim", + "abbrevName": "Kim DI", + "email": null, + "isCollectiveName": false, + "name": "Dae In Kim" + }, + { + "ForeName": "Brian", + "LastName": "Burke", + "abbrevName": "Burke B", + "email": null, + "isCollectiveName": false, + "name": "Brian Burke" + }, + { + "ForeName": "Danielle", + "LastName": "May", + "abbrevName": "May DG", + "email": null, + "isCollectiveName": false, + "name": "Danielle G May" + } + ], + "contacts": [] + }, + "doi": "10.1002/cpps.51", + "pmid": "29516480", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Protoc Protein Sci 91 2018", + "title": "BioID: A Screen for Protein-Protein Interactions." + } + }, + { + "pmid": "28766506", + "pubmed": { + "ISODate": "2017-10-13T00:00:00.000Z", + "abstract": "The mechanical stability of proteins has been extensively studied using AFM as a single-molecule force spectroscopy method. While this has led to many important results, these studies have been mainly limited to fast unfolding at a high-force regime due to the rapid mechanical drift in most AFM stretching experiments. Therefore, there is a gap between the knowledge obtained at a high-force regime and the mechanical properties of proteins at a lower force regime which is often more physiologically relevant. Recent studies have demonstrated that this gap can be addressed by stretching single protein molecules using magnetic tweezers, due to the excellent mechanical stability this technology offers. Here we review magnetic tweezers technology and its current application in studies of the force-dependent stability and interactions of proteins.", + "authors": { + "abbreviation": "Xiaodan Zhao, Xiangjun Zeng, Chen Lu, Jie Yan", + "authorList": [ + { + "ForeName": "Xiaodan", + "LastName": "Zhao", + "abbrevName": "Zhao X", + "email": null, + "isCollectiveName": false, + "name": "Xiaodan Zhao" + }, + { + "ForeName": "Xiangjun", + "LastName": "Zeng", + "abbrevName": "Zeng X", + "email": null, + "isCollectiveName": false, + "name": "Xiangjun Zeng" + }, + { + "ForeName": "Chen", + "LastName": "Lu", + "abbrevName": "Lu C", + "email": null, + "isCollectiveName": false, + "name": "Chen Lu" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1088/1361-6528/aa837e", + "pmid": "28766506", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nanotechnology 28 2017", + "title": "Studying the mechanical responses of proteins using magnetic tweezers." + } + }, + { + "pmid": "28394039", + "pubmed": { + "ISODate": "2017-05-08T00:00:00.000Z", + "abstract": "The giant protein titin plays a critical role in regulating the passive elasticity of muscles, mainly through the stochastic unfolding and refolding of its numerous immunoglobulin domains in the I-band of sarcomeres. The unfolding dynamics of titin immunoglobulin domains at a force range greater than 100 pN has been studied by atomic force microscopy, while that at smaller physiological forces has not been measured before. By using magnetic tweezers, it is found that the titin I27 domain unfolds in a surprising non-monotonic force-dependent manner at forces smaller than 100 pN, with the slowest unfolding rate occurring around 22 pN. We further demonstrate that a model with single unfolding pathway taking into account the elasticity of the transition state can reproduce the experimental results. These results provide important novel insights into the regulation mechanism of the passive elasticity of muscle tissues.", + "authors": { + "abbreviation": "Guohua Yuan, Shimin Le, Mingxi Yao, ..., Hu Chen", + "authorList": [ + { + "ForeName": "Guohua", + "LastName": "Yuan", + "abbrevName": "Yuan G", + "email": null, + "isCollectiveName": false, + "name": "Guohua Yuan" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Hui", + "LastName": "Qian", + "abbrevName": "Qian H", + "email": null, + "isCollectiveName": false, + "name": "Hui Qian" + }, + { + "ForeName": "Xin", + "LastName": "Zhou", + "abbrevName": "Zhou X", + "email": null, + "isCollectiveName": false, + "name": "Xin Zhou" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Hu", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hu Chen" + } + ], + "contacts": [] + }, + "doi": "10.1002/anie.201700411", + "pmid": "28394039", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Angew Chem Int Ed Engl 56 2017", + "title": "Elasticity of the Transition State Leading to an Unexpected Mechanical Stabilization of Titin Immunoglobulin Domains." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "27251275", + "pubmed": { + "ISODate": "2016-06-02T00:00:00.000Z", + "abstract": "Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.", + "authors": { + "abbreviation": "Philipp Mertins, D R Mani, Kelly V Ruggles, ..., NCI CPTAC", + "authorList": [ + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "D", + "LastName": "Mani", + "abbrevName": "Mani DR", + "email": null, + "isCollectiveName": false, + "name": "D R Mani" + }, + { + "ForeName": "Kelly", + "LastName": "Ruggles", + "abbrevName": "Ruggles KV", + "email": null, + "isCollectiveName": false, + "name": "Kelly V Ruggles" + }, + { + "ForeName": "Michael", + "LastName": "Gillette", + "abbrevName": "Gillette MA", + "email": null, + "isCollectiveName": false, + "name": "Michael A Gillette" + }, + { + "ForeName": "Karl", + "LastName": "Clauser", + "abbrevName": "Clauser KR", + "email": null, + "isCollectiveName": false, + "name": "Karl R Clauser" + }, + { + "ForeName": "Pei", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pei Wang" + }, + { + "ForeName": "Xianlong", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xianlong Wang" + }, + { + "ForeName": "Jana", + "LastName": "Qiao", + "abbrevName": "Qiao JW", + "email": null, + "isCollectiveName": false, + "name": "Jana W Qiao" + }, + { + "ForeName": "Song", + "LastName": "Cao", + "abbrevName": "Cao S", + "email": null, + "isCollectiveName": false, + "name": "Song Cao" + }, + { + "ForeName": "Francesca", + "LastName": "Petralia", + "abbrevName": "Petralia F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Petralia" + }, + { + "ForeName": "Emily", + "LastName": "Kawaler", + "abbrevName": "Kawaler E", + "email": null, + "isCollectiveName": false, + "name": "Emily Kawaler" + }, + { + "ForeName": "Filip", + "LastName": "Mundt", + "abbrevName": "Mundt F", + "email": null, + "isCollectiveName": false, + "name": "Filip Mundt" + }, + { + "ForeName": "Karsten", + "LastName": "Krug", + "abbrevName": "Krug K", + "email": null, + "isCollectiveName": false, + "name": "Karsten Krug" + }, + { + "ForeName": "Zhidong", + "LastName": "Tu", + "abbrevName": "Tu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhidong Tu" + }, + { + "ForeName": "Jonathan", + "LastName": "Lei", + "abbrevName": "Lei JT", + "email": null, + "isCollectiveName": false, + "name": "Jonathan T Lei" + }, + { + "ForeName": "Michael", + "LastName": "Gatza", + "abbrevName": "Gatza ML", + "email": null, + "isCollectiveName": false, + "name": "Michael L Gatza" + }, + { + "ForeName": "Matthew", + "LastName": "Wilkerson", + "abbrevName": "Wilkerson M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Wilkerson" + }, + { + "ForeName": "Charles", + "LastName": "Perou", + "abbrevName": "Perou CM", + "email": null, + "isCollectiveName": false, + "name": "Charles M Perou" + }, + { + "ForeName": "Venkata", + "LastName": "Yellapantula", + "abbrevName": "Yellapantula V", + "email": null, + "isCollectiveName": false, + "name": "Venkata Yellapantula" + }, + { + "ForeName": "Kuan-lin", + "LastName": "Huang", + "abbrevName": "Huang KL", + "email": null, + "isCollectiveName": false, + "name": "Kuan-lin Huang" + }, + { + "ForeName": "Chenwei", + "LastName": "Lin", + "abbrevName": "Lin C", + "email": null, + "isCollectiveName": false, + "name": "Chenwei Lin" + }, + { + "ForeName": "Michael", + "LastName": "McLellan", + "abbrevName": "McLellan MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D McLellan" + }, + { + "ForeName": "Ping", + "LastName": "Yan", + "abbrevName": "Yan P", + "email": null, + "isCollectiveName": false, + "name": "Ping Yan" + }, + { + "ForeName": "Sherri", + "LastName": "Davies", + "abbrevName": "Davies SR", + "email": null, + "isCollectiveName": false, + "name": "Sherri R Davies" + }, + { + "ForeName": "R", + "LastName": "Townsend", + "abbrevName": "Townsend RR", + "email": null, + "isCollectiveName": false, + "name": "R Reid Townsend" + }, + { + "ForeName": "Steven", + "LastName": "Skates", + "abbrevName": "Skates SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Skates" + }, + { + "ForeName": "Jing", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jing Wang" + }, + { + "ForeName": "Bing", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bing Zhang" + }, + { + "ForeName": "Christopher", + "LastName": "Kinsinger", + "abbrevName": "Kinsinger CR", + "email": null, + "isCollectiveName": false, + "name": "Christopher R Kinsinger" + }, + { + "ForeName": "Mehdi", + "LastName": "Mesri", + "abbrevName": "Mesri M", + "email": null, + "isCollectiveName": false, + "name": "Mehdi Mesri" + }, + { + "ForeName": "Henry", + "LastName": "Rodriguez", + "abbrevName": "Rodriguez H", + "email": null, + "isCollectiveName": false, + "name": "Henry Rodriguez" + }, + { + "ForeName": "Li", + "LastName": "Ding", + "abbrevName": "Ding L", + "email": null, + "isCollectiveName": false, + "name": "Li Ding" + }, + { + "ForeName": "Amanda", + "LastName": "Paulovich", + "abbrevName": "Paulovich AG", + "email": null, + "isCollectiveName": false, + "name": "Amanda G Paulovich" + }, + { + "ForeName": "David", + "LastName": "Fenyö", + "abbrevName": "Fenyö D", + "email": null, + "isCollectiveName": false, + "name": "David Fenyö" + }, + { + "ForeName": "Matthew", + "LastName": "Ellis", + "abbrevName": "Ellis MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J Ellis" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": null, + "isCollectiveName": false, + "name": "Steven A Carr" + }, + { + "ForeName": null, + "LastName": null, + "abbrevName": "NCI CPTAC", + "email": null, + "isCollectiveName": true, + "name": "NCI CPTAC" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature18003", + "pmid": "27251275", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nature 534 2016", + "title": "Proteogenomics connects somatic mutations to signalling in breast cancer." + } + }, + { + "pmid": "27161398", + "pubmed": { + "ISODate": "2016-05-09T00:00:00.000Z", + "abstract": "Integrin-dependent adhesions are mechanosensitive structures in which talin mediates a linkage to actin filaments either directly or indirectly by recruiting vinculin. Here, we report the development and validation of a talin tension sensor. We find that talin in focal adhesions is under tension, which is higher in peripheral than central adhesions. Tension on talin is increased by vinculin and depends mainly on actin-binding site 2 (ABS2) within the middle of the rod domain, rather than ABS3 at the far C terminus. Unlike vinculin, talin is under lower tension on soft substrates. The difference between central and peripheral adhesions requires ABS3 but not vinculin or ABS2. However, differential stiffness sensing by talin requires ABS2 but not vinculin or ABS3. These results indicate that central versus peripheral adhesions must be organized and regulated differently, and that ABS2 and ABS3 have distinct functions in spatial variations and stiffness sensing. Overall, these results shed new light on talin function and constrain models for cellular mechanosensing.", + "authors": { + "abbreviation": "Abhishek Kumar, Mingxing Ouyang, Koen Van den Dries, ..., Martin A Schwartz", + "authorList": [ + { + "ForeName": "Abhishek", + "LastName": "Kumar", + "abbrevName": "Kumar A", + "email": null, + "isCollectiveName": false, + "name": "Abhishek Kumar" + }, + { + "ForeName": "Mingxing", + "LastName": "Ouyang", + "abbrevName": "Ouyang M", + "email": null, + "isCollectiveName": false, + "name": "Mingxing Ouyang" + }, + { + "ForeName": "Koen", + "LastName": "Van den Dries", + "abbrevName": "Van den Dries K", + "email": null, + "isCollectiveName": false, + "name": "Koen Van den Dries" + }, + { + "ForeName": "Ewan", + "LastName": "McGhee", + "abbrevName": "McGhee EJ", + "email": null, + "isCollectiveName": false, + "name": "Ewan James McGhee" + }, + { + "ForeName": "Keiichiro", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiichiro Tanaka" + }, + { + "ForeName": "Marie", + "LastName": "Anderson", + "abbrevName": "Anderson MD", + "email": null, + "isCollectiveName": false, + "name": "Marie D Anderson" + }, + { + "ForeName": "Alexander", + "LastName": "Groisman", + "abbrevName": "Groisman A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Groisman" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Kurt", + "LastName": "Anderson", + "abbrevName": "Anderson KI", + "email": null, + "isCollectiveName": false, + "name": "Kurt I Anderson" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": "martin.schwartz@yale.edu", + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Schwartz", + "email": [ + "martin.schwartz@yale.edu" + ], + "name": "Martin A Schwartz" + } + ] + }, + "doi": "10.1083/jcb.201510012", + "pmid": "27161398", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 213 2016", + "title": "Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "26515553", + "pubmed": { + "ISODate": "2016-04-10T00:00:00.000Z", + "abstract": "Cell and tissue stiffness have been known to contribute to both developmental and pathological signalling for some time, but the underlying mechanisms remain elusive. Integrins and their associated adhesion signalling complexes (IACs), which form a nexus between the cell cytoskeleton and the extracellular matrix, act as a key force sensing and transducing unit in cells. Accordingly, there has been much interest in obtaining a systems-level understanding of IAC composition. Proteomic approaches have revealed the complexity of IACs and identified a large number of components that are regulated by cytoskeletal force. Here we review the function of the consensus adhesome, an assembly of core IAC proteins that emerged from a meta-analysis of multiple proteomic datasets, in the context of mechanosensing. As IAC components have been linked to a variety of diseases involved with rigidity sensing, the field is now in a position to define the mechanosensing function of individual IAC proteins and elucidate their mechanisms of action.", + "authors": { + "abbreviation": "Edward R Horton, Pablo Astudillo, Martin J Humphries, Jonathan D Humphries", + "authorList": [ + { + "ForeName": "Edward", + "LastName": "Horton", + "abbrevName": "Horton ER", + "email": null, + "isCollectiveName": false, + "name": "Edward R Horton" + }, + { + "ForeName": "Pablo", + "LastName": "Astudillo", + "abbrevName": "Astudillo P", + "email": null, + "isCollectiveName": false, + "name": "Pablo Astudillo" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1016/j.yexcr.2015.10.025", + "pmid": "26515553", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 343 2016", + "title": "Mechanosensitivity of integrin adhesion complexes: role of the consensus adhesome." + } + }, + { + "pmid": "26479319", + "pubmed": { + "ISODate": "2015-12-01T00:00:00.000Z", + "abstract": "Integrin receptor activation initiates the formation of integrin adhesion complexes (IACs) at the cell membrane that transduce adhesion-dependent signals to control a multitude of cellular functions. Proteomic analyses of isolated IACs have revealed an unanticipated molecular complexity; however, a global view of the consensus composition and dynamics of IACs is lacking. Here, we have integrated several IAC proteomes and generated a 2,412-protein integrin adhesome. Analysis of this data set reveals the functional diversity of proteins in IACs and establishes a consensus adhesome of 60 proteins. The consensus adhesome is likely to represent a core cell adhesion machinery, centred around four axes comprising ILK-PINCH-kindlin, FAK-paxillin, talin-vinculin and α-actinin-zyxin-VASP, and includes underappreciated IAC components such as Rsu-1 and caldesmon. Proteomic quantification of IAC assembly and disassembly detailed the compositional dynamics of the core cell adhesion machinery. The definition of this consensus view of integrin adhesome components provides a resource for the research community. ", + "authors": { + "abbreviation": "Edward R Horton, Adam Byron, Janet A Askari, ..., Martin J Humphries", + "authorList": [ + { + "ForeName": "Edward", + "LastName": "Horton", + "abbrevName": "Horton ER", + "email": null, + "isCollectiveName": false, + "name": "Edward R Horton" + }, + { + "ForeName": "Adam", + "LastName": "Byron", + "abbrevName": "Byron A", + "email": null, + "isCollectiveName": false, + "name": "Adam Byron" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Daniel", + "LastName": "Ng", + "abbrevName": "Ng DHJ", + "email": null, + "isCollectiveName": false, + "name": "Daniel H J Ng" + }, + { + "ForeName": "Angélique", + "LastName": "Millon-Frémillon", + "abbrevName": "Millon-Frémillon A", + "email": null, + "isCollectiveName": false, + "name": "Angélique Millon-Frémillon" + }, + { + "ForeName": "Joseph", + "LastName": "Robertson", + "abbrevName": "Robertson J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Robertson" + }, + { + "ForeName": "Ewa", + "LastName": "Koper", + "abbrevName": "Koper EJ", + "email": null, + "isCollectiveName": false, + "name": "Ewa J Koper" + }, + { + "ForeName": "Nikki", + "LastName": "Paul", + "abbrevName": "Paul NR", + "email": null, + "isCollectiveName": false, + "name": "Nikki R Paul" + }, + { + "ForeName": "Stacey", + "LastName": "Warwood", + "abbrevName": "Warwood S", + "email": null, + "isCollectiveName": false, + "name": "Stacey Warwood" + }, + { + "ForeName": "David", + "LastName": "Knight", + "abbrevName": "Knight D", + "email": null, + "isCollectiveName": false, + "name": "David Knight" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3257", + "pmid": "26479319", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 17 2015", + "title": "Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly." + } + }, + { + "pmid": "26318089", + "pubmed": { + "ISODate": "2016-02-01T00:00:00.000Z", + "abstract": "Mechanosensing of the micro-environments has been shown to be essential for cell survival, growth, differentiation and migration. The mechanosensing pathways are mediated by a set of mechanosensitive proteins located at focal adhesion and cell-cell adherens junctions as well as in the cytoskeleton network. Here we review the applications of magnetic tweezers on elucidating the molecular mechanisms of the mechanosensing proteins. The scope of this review includes the principles of the magnetic tweezers technology, theoretical analysis of force-dependent stability and interaction of mechanosensing proteins, and recent findings obtained using magnetic tweezers. ", + "authors": { + "abbreviation": "Shimin Le, Ruchuan Liu, Chwee Teck Lim, Jie Yan", + "authorList": [ + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Ruchuan", + "LastName": "Liu", + "abbrevName": "Liu R", + "email": null, + "isCollectiveName": false, + "name": "Ruchuan Liu" + }, + { + "ForeName": "Chwee", + "LastName": "Lim", + "abbrevName": "Lim CT", + "email": "ctlim@nus.edu.sg", + "isCollectiveName": false, + "name": "Chwee Teck Lim" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": "phyyj@nus.edu.sg", + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [ + { + "ForeName": "Chwee", + "LastName": "Lim", + "email": [ + "ctlim@nus.edu.sg" + ], + "name": "Chwee Teck Lim" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "email": [ + "phyyj@nus.edu.sg" + ], + "name": "Jie Yan" + } + ] + }, + "doi": "10.1016/j.ymeth.2015.08.020", + "pmid": "26318089", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Methods 94 2016", + "title": "Uncovering mechanosensing mechanisms at the single protein level using magnetic tweezers." + } + }, + { + "pmid": "26097520", + "pubmed": { + "ISODate": null, + "abstract": "A fundamental question in mechanobiology is how mechanical stimuli are sensed by mechanosensing proteins and converted into signals that direct cells to adapt to the external environment. A key function of cell adhesion to the extracellular matrix (ECM) is to transduce mechanical forces between cells and their extracellular environment. Talin, a cytoplasmic adapter essential for integrin-mediated adhesion to the ECM, links the actin cytoskeleton to integrin at the plasma membrane. Here, we review recent progress in the understanding of talin-dependent mechanosensing revealed by stretching single talin molecules. Rapid progress in single-molecule force manipulation technologies has made it possible to directly study the impact of mechanical force on talin's conformations and its interactions with other signaling proteins. We also provide our views on how findings from such studies may bring new insights into understanding the principles of mechanobiology on a broader scale, and how such fundamental knowledge may be harnessed for mechanopharmacology.", + "authors": { + "abbreviation": "Jie Yan, Mingxi Yao, Benjamin T Goult, Michael P Sheetz", + "authorList": [ + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + } + ], + "contacts": [] + }, + "doi": "10.1007/s12195-014-0364-5", + "pmid": "26097520", + "pubTypes": [ + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell Mol Bioeng 8", + "title": "Talin Dependent Mechanosensitivity of Cell Focal Adhesions." + } + }, + { + "pmid": "26007651", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "Single-molecule manipulation technologies have been extensively applied to studies of the structures and interactions of DNA and proteins. An important aspect of such studies is to obtain the dynamics of interactions; however the initial binding is often difficult to obtain due to large mechanical perturbation during solution introduction. Here, we report a simple disturbance-free rapid solution exchange method for magnetic tweezers single-molecule manipulation experiments, which is achieved by tethering the molecules inside microwells (typical dimensions-diameter (D): 40-50 μm, height (H): 100 μm; H:D∼2:1). Our simulations and experiments show that the flow speed can be reduced by several orders of magnitude near the bottom of the microwells from that in the flow chamber, effectively eliminating the flow disturbance to molecules tethered in the microwells. We demonstrate a wide scope of applications of this method by measuring the force dependent DNA structural transitions in response to solution condition change, and polymerization dynamics of RecA on ssDNA/SSB-coated ssDNA/dsDNA of various tether lengths under constant forces, as well as the dynamics of vinculin binding to α-catenin at a constant force (< 5 pN) applied to the α-catenin protein. ", + "authors": { + "abbreviation": "Shimin Le, Mingxi Yao, Jin Chen, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Jin", + "LastName": "Chen", + "abbrevName": "Chen J", + "email": null, + "isCollectiveName": false, + "name": "Jin Chen" + }, + { + "ForeName": "Artem", + "LastName": "Efremov", + "abbrevName": "Efremov AK", + "email": null, + "isCollectiveName": false, + "name": "Artem K Efremov" + }, + { + "ForeName": "Sara", + "LastName": "Azimi", + "abbrevName": "Azimi S", + "email": null, + "isCollectiveName": false, + "name": "Sara Azimi" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": "phyyj@nus.edu.sg", + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [ + { + "ForeName": "Jie", + "LastName": "Yan", + "email": [ + "phyyj@nus.edu.sg" + ], + "name": "Jie Yan" + } + ] + }, + "doi": "10.1093/nar/gkv554", + "pmid": "26007651", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 43 2015", + "title": "Disturbance-free rapid solution exchange for magnetic tweezers single-molecule studies." + } + }, + { + "pmid": "25864384", + "pubmed": { + "ISODate": "2015-04-13T00:00:00.000Z", + "abstract": "CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1-Cks1 and CDK1-cyclin B-Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2-cyclin A, CDK1-cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors. ", + "authors": { + "abbreviation": "Nicholas R Brown, Svitlana Korolchuk, Mathew P Martin, ..., Jane A Endicott", + "authorList": [ + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NR", + "email": null, + "isCollectiveName": false, + "name": "Nicholas R Brown" + }, + { + "ForeName": "Svitlana", + "LastName": "Korolchuk", + "abbrevName": "Korolchuk S", + "email": null, + "isCollectiveName": false, + "name": "Svitlana Korolchuk" + }, + { + "ForeName": "Mathew", + "LastName": "Martin", + "abbrevName": "Martin MP", + "email": null, + "isCollectiveName": false, + "name": "Mathew P Martin" + }, + { + "ForeName": "Will", + "LastName": "Stanley", + "abbrevName": "Stanley WA", + "email": null, + "isCollectiveName": false, + "name": "Will A Stanley" + }, + { + "ForeName": "Rouslan", + "LastName": "Moukhametzianov", + "abbrevName": "Moukhametzianov R", + "email": null, + "isCollectiveName": false, + "name": "Rouslan Moukhametzianov" + }, + { + "ForeName": "Martin", + "LastName": "Noble", + "abbrevName": "Noble MEM", + "email": null, + "isCollectiveName": false, + "name": "Martin E M Noble" + }, + { + "ForeName": "Jane", + "LastName": "Endicott", + "abbrevName": "Endicott JA", + "email": null, + "isCollectiveName": false, + "name": "Jane A Endicott" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms7769", + "pmid": "25864384", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "CDK1 structures reveal conserved and unique features of the essential cell cycle CDK." + } + }, + { + "pmid": "25677187", + "pubmed": { + "ISODate": "2015-02-13T00:00:00.000Z", + "abstract": "Cell-extracellular matrix (ECM) adhesion is a fundamental requirement for multicellular existence due to roles in positioning, proliferation and differentiation. Phosphorylation plays a major role in adhesion signalling; however, a full understanding of the phosphorylation events that occur at sites of adhesion is lacking. Here we report a proteomic and phosphoproteomic analysis of adhesion complexes isolated from cells spread on fibronectin. We identify 1,174 proteins, 499 of which are phosphorylated (1,109 phosphorylation sites), including both well-characterized and novel adhesion-regulated phosphorylation events. Immunoblotting suggests that two classes of phosphorylated residues are found at adhesion sites-those induced by adhesion and those constitutively phosphorylated but recruited in response to adhesion. Kinase prediction analysis identifies novel kinases with putative roles in adhesion signalling including CDK1, inhibition of which reduces adhesion complex formation. This phospho-adhesome data set constitutes a valuable resource to improve our understanding of the signalling mechanisms through which cell-ECM interactions control cell behaviour. ", + "authors": { + "abbreviation": "Joseph Robertson, Guillaume Jacquemet, Adam Byron, ..., Martin J Humphries", + "authorList": [ + { + "ForeName": "Joseph", + "LastName": "Robertson", + "abbrevName": "Robertson J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Robertson" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Adam", + "LastName": "Byron", + "abbrevName": "Byron A", + "email": null, + "isCollectiveName": false, + "name": "Adam Byron" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Stacey", + "LastName": "Warwood", + "abbrevName": "Warwood S", + "email": null, + "isCollectiveName": false, + "name": "Stacey Warwood" + }, + { + "ForeName": "Julian", + "LastName": "Selley", + "abbrevName": "Selley JN", + "email": null, + "isCollectiveName": false, + "name": "Julian N Selley" + }, + { + "ForeName": "David", + "LastName": "Knight", + "abbrevName": "Knight D", + "email": null, + "isCollectiveName": false, + "name": "David Knight" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms7265", + "pmid": "25677187", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Defining the phospho-adhesome through the phosphoproteomic analysis of integrin signalling." + } + }, + { + "pmid": "25615869", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "CcpNmr Analysis provides a streamlined pipeline for both NMR chemical shift assignment and structure determination of biological macromolecules. In addition, it encompasses tools to analyse the many additional experiments that make NMR such a pivotal technique for research into complex biological questions. This report describes how CcpNmr Analysis can seamlessly link together all of the tasks in the NMR structure-determination process. It details each of the stages from generating NMR restraints [distance, dihedral, hydrogen bonds and residual dipolar couplings (RDCs)], exporting these to and subsequently re-importing them from structure-calculation software (such as the programs CYANA or ARIA) and analysing and validating the results obtained from the structure calculation to, ultimately, the streamlined deposition of the completed assignments and the refined ensemble of structures into the PDBe repository. Until recently, such solution-structure determination by NMR has been quite a laborious task, requiring multiple stages and programs. However, with the new enhancements to CcpNmr Analysis described here, this process is now much more intuitive and efficient and less error-prone. ", + "authors": { + "abbreviation": "Simon P Skinner, Benjamin T Goult, Rasmus H Fogh, ..., Geerten W Vuister", + "authorList": [ + { + "ForeName": "Simon", + "LastName": "Skinner", + "abbrevName": "Skinner SP", + "email": null, + "isCollectiveName": false, + "name": "Simon P Skinner" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Rasmus", + "LastName": "Fogh", + "abbrevName": "Fogh RH", + "email": null, + "isCollectiveName": false, + "name": "Rasmus H Fogh" + }, + { + "ForeName": "Wayne", + "LastName": "Boucher", + "abbrevName": "Boucher W", + "email": null, + "isCollectiveName": false, + "name": "Wayne Boucher" + }, + { + "ForeName": "Tim", + "LastName": "Stevens", + "abbrevName": "Stevens TJ", + "email": null, + "isCollectiveName": false, + "name": "Tim J Stevens" + }, + { + "ForeName": "Ernest", + "LastName": "Laue", + "abbrevName": "Laue ED", + "email": null, + "isCollectiveName": false, + "name": "Ernest D Laue" + }, + { + "ForeName": "Geerten", + "LastName": "Vuister", + "abbrevName": "Vuister GW", + "email": null, + "isCollectiveName": false, + "name": "Geerten W Vuister" + } + ], + "contacts": [] + }, + "doi": "10.1107/S1399004714026662", + "pmid": "25615869", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D023361", + "value": "Validation Study" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 71 2015", + "title": "Structure calculation, refinement and validation using CcpNmr Analysis." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "25458010", + "pubmed": { + "ISODate": "2014-11-24T00:00:00.000Z", + "abstract": "Cells entering mitosis become rounded, lose attachment to the substrate, and increase their cortical rigidity. Pivotal to these events is the dismantling of focal adhesions (FAs). How mitotic reshaping is linked to commitment to divide is unclear. Here, we show that DEPDC1B, a protein that accumulates in G2, coordinates de-adhesion events and cell-cycle progression at mitosis. DEPDC1B functions as an inhibitor of a RhoA-based signaling complex, which assembles on the FA-associated protein tyrosine phosphatase, receptor type, F (PTPRF) and mediates the integrity of FAs. By competing with RhoA for the interaction with PTPRF, DEPDC1B promotes the dismantling of FAs, which is necessary for the morphological changes preceding mitosis. The circuitry is relevant in whole organisms, as shown by the control exerted by the DEPDC1B/RhoA/PTPRF axis on mitotic dynamics during zebrafish development. Our results uncover an adhesion-dependent signaling mechanism that coordinates adhesion events with the control of cell-cycle progression. ", + "authors": { + "abbreviation": "Stefano Marchesi, Francesca Montani, Gianluca Deflorian, ..., Francesco Nicassio", + "authorList": [ + { + "ForeName": "Stefano", + "LastName": "Marchesi", + "abbrevName": "Marchesi S", + "email": "IIT@SEMM,", + "isCollectiveName": false, + "name": "Stefano Marchesi" + }, + { + "ForeName": "Francesca", + "LastName": "Montani", + "abbrevName": "Montani F", + "email": null, + "isCollectiveName": false, + "name": "Francesca Montani" + }, + { + "ForeName": "Gianluca", + "LastName": "Deflorian", + "abbrevName": "Deflorian G", + "email": null, + "isCollectiveName": false, + "name": "Gianluca Deflorian" + }, + { + "ForeName": "Rocco", + "LastName": "D'Antuono", + "abbrevName": "D'Antuono R", + "email": null, + "isCollectiveName": false, + "name": "Rocco D'Antuono" + }, + { + "ForeName": "Alessandro", + "LastName": "Cuomo", + "abbrevName": "Cuomo A", + "email": null, + "isCollectiveName": false, + "name": "Alessandro Cuomo" + }, + { + "ForeName": "Serena", + "LastName": "Bologna", + "abbrevName": "Bologna S", + "email": null, + "isCollectiveName": false, + "name": "Serena Bologna" + }, + { + "ForeName": "Carmela", + "LastName": "Mazzoccoli", + "abbrevName": "Mazzoccoli C", + "email": null, + "isCollectiveName": false, + "name": "Carmela Mazzoccoli" + }, + { + "ForeName": "Tiziana", + "LastName": "Bonaldi", + "abbrevName": "Bonaldi T", + "email": null, + "isCollectiveName": false, + "name": "Tiziana Bonaldi" + }, + { + "ForeName": "Pier", + "LastName": "Di Fiore", + "abbrevName": "Di Fiore PP", + "email": "pierpaolo.difiore@ieo.eu", + "isCollectiveName": false, + "name": "Pier Paolo Di Fiore" + }, + { + "ForeName": "Francesco", + "LastName": "Nicassio", + "abbrevName": "Nicassio F", + "email": "IIT@SEMM,", + "isCollectiveName": false, + "name": "Francesco Nicassio" + } + ], + "contacts": [ + { + "ForeName": "Stefano", + "LastName": "Marchesi", + "email": [ + "IIT@SEMM," + ], + "name": "Stefano Marchesi" + }, + { + "ForeName": "Pier", + "LastName": "Di Fiore", + "email": [ + "pierpaolo.difiore@ieo.eu" + ], + "name": "Pier Paolo Di Fiore" + }, + { + "ForeName": "Francesco", + "LastName": "Nicassio", + "email": [ + "IIT@SEMM,", + "francesco.nicassio@iit.it" + ], + "name": "Francesco Nicassio" + } + ] + }, + "doi": "10.1016/j.devcel.2014.09.009", + "pmid": "25458010", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 31 2014", + "title": "DEPDC1B coordinates de-adhesion events and cell-cycle progression at mitosis." + } + }, + { + "pmid": "24870021", + "pubmed": { + "ISODate": "2014-06-15T00:00:00.000Z", + "abstract": "LD motifs (leucine-aspartic acid motifs) are short helical protein-protein interaction motifs that have emerged as key players in connecting cell adhesion with cell motility and survival. LD motifs are required for embryogenesis, wound healing and the evolution of multicellularity. LD motifs also play roles in disease, such as in cancer metastasis or viral infection. First described in the paxillin family of scaffolding proteins, LD motifs and similar acidic LXXLL interaction motifs have been discovered in several other proteins, whereas 16 proteins have been reported to contain LDBDs (LD motif-binding domains). Collectively, structural and functional analyses have revealed a surprising multivalency in LD motif interactions and a wide diversity in LDBD architectures. In the present review, we summarize the molecular basis for function, regulation and selectivity of LD motif interactions that has emerged from more than a decade of research. This overview highlights the intricate multi-level regulation and the inherently noisy and heterogeneous nature of signalling through short protein-protein interaction motifs.", + "authors": { + "abbreviation": "Tanvir Alam, Meshari Alazmi, Xin Gao, Stefan T Arold", + "authorList": [ + { + "ForeName": "Tanvir", + "LastName": "Alam", + "abbrevName": "Alam T", + "email": null, + "isCollectiveName": false, + "name": "Tanvir Alam" + }, + { + "ForeName": "Meshari", + "LastName": "Alazmi", + "abbrevName": "Alazmi M", + "email": null, + "isCollectiveName": false, + "name": "Meshari Alazmi" + }, + { + "ForeName": "Xin", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xin Gao" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + } + ], + "contacts": [] + }, + "doi": "10.1042/BJ20140298", + "pmid": "24870021", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochem J 460 2014", + "title": "How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs." + } + }, + { + "pmid": "24780736", + "pubmed": { + "ISODate": "2014-04-28T00:00:00.000Z", + "abstract": "Dividing cells almost always adopt a spherical shape. This is true of most eukaryotic cells lacking a rigid cell wall and is observed in tissue culture and single-celled organisms, as well as in cells dividing inside tissues. While the mechanisms underlying this shape change are now well described, the functional importance of the spherical mitotic cell for the success of cell division has been thus far scarcely addressed. Here we discuss how mitotic rounding contributes to spindle assembly and positioning, as well as the potential consequences of abnormal mitotic cell shape and size on chromosome segregation, tissue growth, and cancer. ", + "authors": { + "abbreviation": "Clotilde Cadart, Ewa Zlotek-Zlotkiewicz, Maël Le Berre, ..., Helen K Matthews", + "authorList": [ + { + "ForeName": "Clotilde", + "LastName": "Cadart", + "abbrevName": "Cadart C", + "email": null, + "isCollectiveName": false, + "name": "Clotilde Cadart" + }, + { + "ForeName": "Ewa", + "LastName": "Zlotek-Zlotkiewicz", + "abbrevName": "Zlotek-Zlotkiewicz E", + "email": null, + "isCollectiveName": false, + "name": "Ewa Zlotek-Zlotkiewicz" + }, + { + "ForeName": "Maël", + "LastName": "Le Berre", + "abbrevName": "Le Berre M", + "email": null, + "isCollectiveName": false, + "name": "Maël Le Berre" + }, + { + "ForeName": "Matthieu", + "LastName": "Piel", + "abbrevName": "Piel M", + "email": "matthieu.piel@curie.fr", + "isCollectiveName": false, + "name": "Matthieu Piel" + }, + { + "ForeName": "Helen", + "LastName": "Matthews", + "abbrevName": "Matthews HK", + "email": "h.matthews@ucl.ac.uk", + "isCollectiveName": false, + "name": "Helen K Matthews" + } + ], + "contacts": [ + { + "ForeName": "Matthieu", + "LastName": "Piel", + "email": [ + "matthieu.piel@curie.fr" + ], + "name": "Matthieu Piel" + }, + { + "ForeName": "Helen", + "LastName": "Matthews", + "email": [ + "h.matthews@ucl.ac.uk" + ], + "name": "Helen K Matthews" + } + ] + }, + "doi": "10.1016/j.devcel.2014.04.009", + "pmid": "24780736", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Dev Cell 29 2014", + "title": "Exploring the function of cell shape and size during mitosis." + } + }, + { + "pmid": "24778310", + "pubmed": { + "ISODate": "2014-04-28T00:00:00.000Z", + "abstract": "Physical forces direct the orientation of the cell division axis for cells cultured on rigid, two-dimensional (2D) substrates. The extent to which physical forces regulate cell division in three-dimensional (3D) environments is not known. Here, we combine live-cell imaging with digital volume correlation to map 3D matrix displacements and identify sites at which cells apply contractile force to the matrix as they divide. Dividing cells embedded in fibrous matrices remained anchored to the matrix by long, thin protrusions. During cell rounding, the cells released adhesive contacts near the cell body while applying tensile forces at the tips of the protrusions to direct the orientation of the cell division axis. After cytokinesis, the daughter cells respread into matrix voids and invaded the matrix while maintaining traction forces at the tips of persistent and newly formed protrusions. Mechanical interactions between cells and the extracellular matrix constitute an important mechanism for regulation of cell division in 3D environments. ", + "authors": { + "abbreviation": "Ayelet Lesman, Jacob Notbohm, David A Tirrell, Guruswami Ravichandran", + "authorList": [ + { + "ForeName": "Ayelet", + "LastName": "Lesman", + "abbrevName": "Lesman A", + "email": null, + "isCollectiveName": false, + "name": "Ayelet Lesman" + }, + { + "ForeName": "Jacob", + "LastName": "Notbohm", + "abbrevName": "Notbohm J", + "email": null, + "isCollectiveName": false, + "name": "Jacob Notbohm" + }, + { + "ForeName": "David", + "LastName": "Tirrell", + "abbrevName": "Tirrell DA", + "email": null, + "isCollectiveName": false, + "name": "David A Tirrell" + }, + { + "ForeName": "Guruswami", + "LastName": "Ravichandran", + "abbrevName": "Ravichandran G", + "email": null, + "isCollectiveName": false, + "name": "Guruswami Ravichandran" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201309029", + "pmid": "24778310", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Contractile forces regulate cell division in three-dimensional environments." + } + }, + { + "pmid": "24719451", + "pubmed": { + "ISODate": "2014-07-01T00:00:00.000Z", + "abstract": "Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. Although the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 min, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation, and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples and motivates reexamination of collection protocols for phosphoprotein analysis. ", + "authors": { + "abbreviation": "Philipp Mertins, Feng Yang, Tao Liu, ..., Steven A Carr", + "authorList": [ + { + "ForeName": "Philipp", + "LastName": "Mertins", + "abbrevName": "Mertins P", + "email": "scarr@broad.mit.edu", + "isCollectiveName": false, + "name": "Philipp Mertins" + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang" + }, + { + "ForeName": "Tao", + "LastName": "Liu", + "abbrevName": "Liu T", + "email": null, + "isCollectiveName": false, + "name": "Tao Liu" + }, + { + "ForeName": "D", + "LastName": "Mani", + "abbrevName": "Mani DR", + "email": null, + "isCollectiveName": false, + "name": "D R Mani" + }, + { + "ForeName": "Vladislav", + "LastName": "Petyuk", + "abbrevName": "Petyuk VA", + "email": null, + "isCollectiveName": false, + "name": "Vladislav A Petyuk" + }, + { + "ForeName": "Michael", + "LastName": "Gillette", + "abbrevName": "Gillette MA", + "email": null, + "isCollectiveName": false, + "name": "Michael A Gillette" + }, + { + "ForeName": "Karl", + "LastName": "Clauser", + "abbrevName": "Clauser KR", + "email": null, + "isCollectiveName": false, + "name": "Karl R Clauser" + }, + { + "ForeName": "Jana", + "LastName": "Qiao", + "abbrevName": "Qiao JW", + "email": null, + "isCollectiveName": false, + "name": "Jana W Qiao" + }, + { + "ForeName": "Marina", + "LastName": "Gritsenko", + "abbrevName": "Gritsenko MA", + "email": null, + "isCollectiveName": false, + "name": "Marina A Gritsenko" + }, + { + "ForeName": "Ronald", + "LastName": "Moore", + "abbrevName": "Moore RJ", + "email": null, + "isCollectiveName": false, + "name": "Ronald J Moore" + }, + { + "ForeName": "Douglas", + "LastName": "Levine", + "abbrevName": "Levine DA", + "email": null, + "isCollectiveName": false, + "name": "Douglas A Levine" + }, + { + "ForeName": "Reid", + "LastName": "Townsend", + "abbrevName": "Townsend R", + "email": null, + "isCollectiveName": false, + "name": "Reid Townsend" + }, + { + "ForeName": "Petra", + "LastName": "Erdmann-Gilmore", + "abbrevName": "Erdmann-Gilmore P", + "email": null, + "isCollectiveName": false, + "name": "Petra Erdmann-Gilmore" + }, + { + "ForeName": "Jacqueline", + "LastName": "Snider", + "abbrevName": "Snider JE", + "email": null, + "isCollectiveName": false, + "name": "Jacqueline E Snider" + }, + { + "ForeName": "Sherri", + "LastName": "Davies", + "abbrevName": "Davies SR", + "email": null, + "isCollectiveName": false, + "name": "Sherri R Davies" + }, + { + "ForeName": "Kelly", + "LastName": "Ruggles", + "abbrevName": "Ruggles KV", + "email": null, + "isCollectiveName": false, + "name": "Kelly V Ruggles" + }, + { + "ForeName": "David", + "LastName": "Fenyo", + "abbrevName": "Fenyo D", + "email": null, + "isCollectiveName": false, + "name": "David Fenyo" + }, + { + "ForeName": "R", + "LastName": "Kitchens", + "abbrevName": "Kitchens RT", + "email": null, + "isCollectiveName": false, + "name": "R Thomas Kitchens" + }, + { + "ForeName": "Shunqiang", + "LastName": "Li", + "abbrevName": "Li S", + "email": null, + "isCollectiveName": false, + "name": "Shunqiang Li" + }, + { + "ForeName": "Narciso", + "LastName": "Olvera", + "abbrevName": "Olvera N", + "email": null, + "isCollectiveName": false, + "name": "Narciso Olvera" + }, + { + "ForeName": "Fanny", + "LastName": "Dao", + "abbrevName": "Dao F", + "email": null, + "isCollectiveName": false, + "name": "Fanny Dao" + }, + { + "ForeName": "Henry", + "LastName": "Rodriguez", + "abbrevName": "Rodriguez H", + "email": null, + "isCollectiveName": false, + "name": "Henry Rodriguez" + }, + { + "ForeName": "Daniel", + "LastName": "Chan", + "abbrevName": "Chan DW", + "email": null, + "isCollectiveName": false, + "name": "Daniel W Chan" + }, + { + "ForeName": "Daniel", + "LastName": "Liebler", + "abbrevName": "Liebler D", + "email": null, + "isCollectiveName": false, + "name": "Daniel Liebler" + }, + { + "ForeName": "Forest", + "LastName": "White", + "abbrevName": "White F", + "email": null, + "isCollectiveName": false, + "name": "Forest White" + }, + { + "ForeName": "Karin", + "LastName": "Rodland", + "abbrevName": "Rodland KD", + "email": null, + "isCollectiveName": false, + "name": "Karin D Rodland" + }, + { + "ForeName": "Gordon", + "LastName": "Mills", + "abbrevName": "Mills GB", + "email": null, + "isCollectiveName": false, + "name": "Gordon B Mills" + }, + { + "ForeName": "Richard", + "LastName": "Smith", + "abbrevName": "Smith RD", + "email": null, + "isCollectiveName": false, + "name": "Richard D Smith" + }, + { + "ForeName": "Amanda", + "LastName": "Paulovich", + "abbrevName": "Paulovich AG", + "email": null, + "isCollectiveName": false, + "name": "Amanda G Paulovich" + }, + { + "ForeName": "Matthew", + "LastName": "Ellis", + "abbrevName": "Ellis M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Ellis" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "abbrevName": "Carr SA", + "email": "scarr@broad.mit.edu", + "isCollectiveName": false, + "name": "Steven A Carr" + } + ], + "contacts": [ + { + "ForeName": "Philipp", + "LastName": "Mertins", + "email": [ + "scarr@broad.mit.edu", + "pmertins@broadinstitute.org" + ], + "name": "Philipp Mertins" + }, + { + "ForeName": "Steven", + "LastName": "Carr", + "email": [ + "scarr@broad.mit.edu", + "pmertins@broadinstitute.org" + ], + "name": "Steven A Carr" + } + ] + }, + "doi": "10.1074/mcp.M113.036392", + "pmid": "24719451", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Proteomics 13 2014", + "title": "Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels." + } + }, + { + "pmid": "24651544", + "pubmed": { + "ISODate": "2014-04-01T00:00:00.000Z", + "abstract": "The adhesive interactions of cells with their environment through the integrin family of transmembrane receptors have key roles in regulating multiple aspects of cellular physiology, including cell proliferation, viability, differentiation and migration. Consequently, failure to establish functional cell adhesions, and thus the assembly of associated cytoplasmic scaffolding and signalling networks, can have severe pathological effects. The roles of specific constituents of integrin-mediated adhesions, which are collectively known as the 'integrin adhesome', in diverse pathological states are becoming clear. Indeed, the prominence of mutations in specific adhesome molecules in various human diseases is now appreciated, and experimental as well as in silico approaches provide insights into the molecular mechanisms underlying these pathological conditions.", + "authors": { + "abbreviation": "Sabina E Winograd-Katz, Reinhard Fässler, Benjamin Geiger, Kyle R Legate", + "authorList": [ + { + "ForeName": "Sabina", + "LastName": "Winograd-Katz", + "abbrevName": "Winograd-Katz SE", + "email": null, + "isCollectiveName": false, + "name": "Sabina E Winograd-Katz" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Benjamin", + "LastName": "Geiger", + "abbrevName": "Geiger B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Geiger" + }, + { + "ForeName": "Kyle", + "LastName": "Legate", + "abbrevName": "Legate KR", + "email": null, + "isCollectiveName": false, + "name": "Kyle R Legate" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm3769", + "pmid": "24651544", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 15 2014", + "title": "The integrin adhesome: from genes and proteins to human disease." + } + }, + { + "pmid": "24607328", + "pubmed": { + "ISODate": "2014-10-01T00:00:00.000Z", + "abstract": "Cell division requires the wholesale reorganization of cell architecture. At the same time as the microtubule network is remodelled to generate a bipolar spindle, animal cells entering mitosis replace their interphase actin cytoskeleton with a contractile mitotic actomyosin cortex that is tightly coupled to the plasma membrane--driving mitotic cell rounding. Here, we consider how these two processes are coordinated to couple chromosome segregation and cell division. In doing so we explore the relative roles of cell shape and the actin cortex in spindle morphogenesis, orientation and positioning.", + "authors": { + "abbreviation": "Oscar M Lancaster, Buzz Baum", + "authorList": [ + { + "ForeName": "Oscar", + "LastName": "Lancaster", + "abbrevName": "Lancaster OM", + "email": "oscar.lancaster@kcl.ac.uk", + "isCollectiveName": false, + "name": "Oscar M Lancaster" + }, + { + "ForeName": "Buzz", + "LastName": "Baum", + "abbrevName": "Baum B", + "email": "b.baum@ucl.ac.uk", + "isCollectiveName": false, + "name": "Buzz Baum" + } + ], + "contacts": [ + { + "ForeName": "Oscar", + "LastName": "Lancaster", + "email": [ + "oscar.lancaster@kcl.ac.uk" + ], + "name": "Oscar M Lancaster" + }, + { + "ForeName": "Buzz", + "LastName": "Baum", + "email": [ + "b.baum@ucl.ac.uk" + ], + "name": "Buzz Baum" + } + ] + }, + "doi": "10.1016/j.semcdb.2014.02.015", + "pmid": "24607328", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Semin Cell Dev Biol 34 2014", + "title": "Shaping up to divide: coordinating actin and microtubule cytoskeletal remodelling during mitosis." + } + }, + { + "pmid": "24275569", + "pubmed": { + "ISODate": "2014-01-16T00:00:00.000Z", + "abstract": "Protein phosphorylation is one of the most common post-translational modifications. It plays key roles in regulating diverse biological processes of liver tissues. To better understand the role of protein phosphorylation in liver functions, it is essential to perform in-depth phosphoproteome analysis of human liver. Here, an enzyme assisted reversed-phase-reversed-phase liquid chromatography (RP-RPLC) approach with both RPLC separations operated with optimized acidic mobile phase was developed. High orthogonal separation was achieved by trypsin digestion of the Glu-C generated peptides in the fractions collected from the first RPLC separation. The phosphoproteome coverage was further improved by using two types of instruments, i.e. TripleTOF 5600 and LTQ Orbitrap Velos. A total of 22,446 phosphorylation sites, corresponding to 6526 nonredundant phosphoproteins were finally identified from normal human liver tissues. Of these sites, 15,229 sites were confidently localized with Ascore≥13. This dataset was the largest phosphoproteome dataset of human liver. It can be a public resource for the liver research community and holds promise for further biology studies. BIOLOGICAL SIGNIFICANCE: The enzyme assisted approach enabled the two RPLC separations operated both with optimized acidic mobile phases. The identifications from TripleTOF 5600 and Orbitrap Velos are highly complementary. The largest phosphoproteome dataset of human liver was generated.", + "authors": { + "abbreviation": "Yangyang Bian, Chunxia Song, Kai Cheng, ..., Hanfa Zou", + "authorList": [ + { + "ForeName": "Yangyang", + "LastName": "Bian", + "abbrevName": "Bian Y", + "email": null, + "isCollectiveName": false, + "name": "Yangyang Bian" + }, + { + "ForeName": "Chunxia", + "LastName": "Song", + "abbrevName": "Song C", + "email": null, + "isCollectiveName": false, + "name": "Chunxia Song" + }, + { + "ForeName": "Kai", + "LastName": "Cheng", + "abbrevName": "Cheng K", + "email": null, + "isCollectiveName": false, + "name": "Kai Cheng" + }, + { + "ForeName": "Mingming", + "LastName": "Dong", + "abbrevName": "Dong M", + "email": null, + "isCollectiveName": false, + "name": "Mingming Dong" + }, + { + "ForeName": "Fangjun", + "LastName": "Wang", + "abbrevName": "Wang F", + "email": null, + "isCollectiveName": false, + "name": "Fangjun Wang" + }, + { + "ForeName": "Junfeng", + "LastName": "Huang", + "abbrevName": "Huang J", + "email": null, + "isCollectiveName": false, + "name": "Junfeng Huang" + }, + { + "ForeName": "Deguang", + "LastName": "Sun", + "abbrevName": "Sun D", + "email": null, + "isCollectiveName": false, + "name": "Deguang Sun" + }, + { + "ForeName": "Liming", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Liming Wang" + }, + { + "ForeName": "Mingliang", + "LastName": "Ye", + "abbrevName": "Ye M", + "email": "mingliang@dicp.ac.cn", + "isCollectiveName": false, + "name": "Mingliang Ye" + }, + { + "ForeName": "Hanfa", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": "hanfazou@dicp.ac.cn", + "isCollectiveName": false, + "name": "Hanfa Zou" + } + ], + "contacts": [ + { + "ForeName": "Mingliang", + "LastName": "Ye", + "email": [ + "mingliang@dicp.ac.cn" + ], + "name": "Mingliang Ye" + }, + { + "ForeName": "Hanfa", + "LastName": "Zou", + "email": [ + "hanfazou@dicp.ac.cn" + ], + "name": "Hanfa Zou" + } + ] + }, + "doi": "10.1016/j.jprot.2013.11.014", + "pmid": "24275569", + "pubTypes": [ + { + "UI": "D016430", + "value": "Clinical Trial" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Proteomics 96 2014", + "title": "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome." + } + }, + { + "pmid": "24186063", + "pubmed": { + "ISODate": "2013-12-01T00:00:00.000Z", + "abstract": "Cks is an evolutionarily conserved protein that regulates cyclin-dependent kinase (CDK) activity. Clarifying the underlying mechanisms and cellular contexts of Cks function is critical because Cks is essential for proper cell growth, and its overexpression has been linked to cancer. We observe that budding-yeast Cks associates with select phosphorylated sequences in cell cycle-regulatory proteins. We characterize the molecular interactions responsible for this specificity and demonstrate that Cks enhances CDK activity in response to specific priming phosphosites. Identification of the binding consensus sequence allows us to identify putative Cks-directed CDK substrates and binding partners. We characterize new Cks-binding sites in the mitotic regulator Wee1 and discover a new role for Cks in regulating CDK activity at mitotic entry. Together, our results portray Cks as a multifunctional phosphoadaptor that serves as a specificity factor for CDK activity. ", + "authors": { + "abbreviation": "Denise A McGrath, Eva Rose M Balog, Mardo Kõivomägi, ..., Seth M Rubin", + "authorList": [ + { + "ForeName": "Denise", + "LastName": "McGrath", + "abbrevName": "McGrath DA", + "email": null, + "isCollectiveName": false, + "name": "Denise A McGrath" + }, + { + "ForeName": "Eva", + "LastName": "Balog", + "abbrevName": "Balog ER", + "email": null, + "isCollectiveName": false, + "name": "Eva Rose M Balog" + }, + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "abbrevName": "Kõivomägi M", + "email": null, + "isCollectiveName": false, + "name": "Mardo Kõivomägi" + }, + { + "ForeName": "Rafael", + "LastName": "Lucena", + "abbrevName": "Lucena R", + "email": null, + "isCollectiveName": false, + "name": "Rafael Lucena" + }, + { + "ForeName": "Michelle", + "LastName": "Mai", + "abbrevName": "Mai MV", + "email": null, + "isCollectiveName": false, + "name": "Michelle V Mai" + }, + { + "ForeName": "Alexander", + "LastName": "Hirschi", + "abbrevName": "Hirschi A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Hirschi" + }, + { + "ForeName": "Douglas", + "LastName": "Kellogg", + "abbrevName": "Kellogg DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Kellogg" + }, + { + "ForeName": "Mart", + "LastName": "Loog", + "abbrevName": "Loog M", + "email": null, + "isCollectiveName": false, + "name": "Mart Loog" + }, + { + "ForeName": "Seth", + "LastName": "Rubin", + "abbrevName": "Rubin SM", + "email": null, + "isCollectiveName": false, + "name": "Seth M Rubin" + } + ], + "contacts": [] + }, + "doi": "10.1038/nsmb.2707", + "pmid": "24186063", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Struct Mol Biol 20 2013", + "title": "Cks confers specificity to phosphorylation-dependent CDK signaling pathways." + } + }, + { + "pmid": "23861057", + "pubmed": { + "ISODate": "2013-08-01T00:00:00.000Z", + "abstract": "Cyclin-dependent kinases (Cdks) are serine/threonine kinases and their catalytic activities are modulated by interactions with cyclins and Cdk inhibitors (CKIs). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that mammalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis. Even more remarkably, they can accomplish some of these tasks individually, without the need for Cdk/cyclin complex formation or kinase activity. In this Review, we discuss the latest revelations about Cdks, cyclins and CKIs with the goal of showcasing their functional diversity beyond cell cycle regulation and their impact on development and disease in mammals. ", + "authors": { + "abbreviation": "Shuhui Lim, Philipp Kaldis", + "authorList": [ + { + "ForeName": "Shuhui", + "LastName": "Lim", + "abbrevName": "Lim S", + "email": null, + "isCollectiveName": false, + "name": "Shuhui Lim" + }, + { + "ForeName": "Philipp", + "LastName": "Kaldis", + "abbrevName": "Kaldis P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Kaldis" + } + ], + "contacts": [] + }, + "doi": "10.1242/dev.091744", + "pmid": "23861057", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Development 140 2013", + "title": "Cdks, cyclins and CKIs: roles beyond cell cycle regulation." + } + }, + { + "pmid": "23623611", + "pubmed": { + "ISODate": "2013-05-13T00:00:00.000Z", + "abstract": "Accurate animal cell division requires precise coordination of changes in the structure of the microtubule-based spindle and the actin-based cell cortex. Here, we use a series of perturbation experiments to dissect the relative roles of actin, cortical mechanics, and cell shape in spindle formation. We find that, whereas the actin cortex is largely dispensable for rounding and timely mitotic progression in isolated cells, it is needed to drive rounding to enable unperturbed spindle morphogenesis under conditions of confinement. Using different methods to limit mitotic cell height, we show that a failure to round up causes defects in spindle assembly, pole splitting, and a delay in mitotic progression. These defects can be rescued by increasing microtubule lengths and therefore appear to be a direct consequence of the limited reach of mitotic centrosome-nucleated microtubules. These findings help to explain why most animal cells round up as they enter mitosis.", + "authors": { + "abbreviation": "Oscar M Lancaster, Maël Le Berre, Andrea Dimitracopoulos, ..., Buzz Baum", + "authorList": [ + { + "ForeName": "Oscar", + "LastName": "Lancaster", + "abbrevName": "Lancaster OM", + "email": null, + "isCollectiveName": false, + "name": "Oscar M Lancaster" + }, + { + "ForeName": "Maël", + "LastName": "Le Berre", + "abbrevName": "Le Berre M", + "email": null, + "isCollectiveName": false, + "name": "Maël Le Berre" + }, + { + "ForeName": "Andrea", + "LastName": "Dimitracopoulos", + "abbrevName": "Dimitracopoulos A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Dimitracopoulos" + }, + { + "ForeName": "Daria", + "LastName": "Bonazzi", + "abbrevName": "Bonazzi D", + "email": null, + "isCollectiveName": false, + "name": "Daria Bonazzi" + }, + { + "ForeName": "Ewa", + "LastName": "Zlotek-Zlotkiewicz", + "abbrevName": "Zlotek-Zlotkiewicz E", + "email": null, + "isCollectiveName": false, + "name": "Ewa Zlotek-Zlotkiewicz" + }, + { + "ForeName": "Remigio", + "LastName": "Picone", + "abbrevName": "Picone R", + "email": null, + "isCollectiveName": false, + "name": "Remigio Picone" + }, + { + "ForeName": "Thomas", + "LastName": "Duke", + "abbrevName": "Duke T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Duke" + }, + { + "ForeName": "Matthieu", + "LastName": "Piel", + "abbrevName": "Piel M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Piel" + }, + { + "ForeName": "Buzz", + "LastName": "Baum", + "abbrevName": "Baum B", + "email": null, + "isCollectiveName": false, + "name": "Buzz Baum" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2013.03.014", + "pmid": "23623611", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 25 2013", + "title": "Mitotic rounding alters cell geometry to ensure efficient bipolar spindle formation." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "22552143", + "pubmed": { + "ISODate": "2012-05-02T00:00:00.000Z", + "abstract": "Cytokinesis is the process by which mitotic cells physically split in two following chromosome segregation. Dividing animal cells first ingress a cytokinetic furrow and then separate the plasma membrane by abscission. The general cytological events and several conserved molecular factors involved in cytokinesis have been known for many years. However, recent progress in microscopy, chemical genetics, biochemical reconstitution and biophysical methodology has tremendously increased our understanding of the underlying molecular mechanisms. We discuss how recent insights have led to refined models of the distinct steps of animal cell cytokinesis, including anaphase spindle reorganization, division plane specification, actomyosin ring assembly and contraction, and abscission. We highlight how molecular signalling pathways coordinate the individual events to ensure faithful partitioning of the genome to emerging daughter cells.", + "authors": { + "abbreviation": "Juan Pablo Fededa, Daniel W Gerlich", + "authorList": [ + { + "ForeName": "Juan", + "LastName": "Fededa", + "abbrevName": "Fededa JP", + "email": null, + "isCollectiveName": false, + "name": "Juan Pablo Fededa" + }, + { + "ForeName": "Daniel", + "LastName": "Gerlich", + "abbrevName": "Gerlich DW", + "email": null, + "isCollectiveName": false, + "name": "Daniel W Gerlich" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2482", + "pmid": "22552143", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Cell Biol 14 2012", + "title": "Molecular control of animal cell cytokinesis." + } + }, + { + "pmid": "22412018", + "pubmed": { + "ISODate": "2012-03-19T00:00:00.000Z", + "abstract": "We have developed a new technique for proximity-dependent labeling of proteins in eukaryotic cells. Named BioID for proximity-dependent biotin identification, this approach is based on fusion of a promiscuous Escherichia coli biotin protein ligase to a targeting protein. BioID features proximity-dependent biotinylation of proteins that are near-neighbors of the fusion protein. Biotinylated proteins may be isolated by affinity capture and identified by mass spectrometry. We apply BioID to lamin-A (LaA), a well-characterized intermediate filament protein that is a constituent of the nuclear lamina, an important structural element of the nuclear envelope (NE). We identify multiple proteins that associate with and/or are proximate to LaA in vivo. The most abundant of these include known interactors of LaA that are localized to the NE, as well as a new NE-associated protein named SLAP75. Our results suggest BioID is a useful and generally applicable method to screen for both interacting and neighboring proteins in their native cellular environment.", + "authors": { + "abbreviation": "Kyle J Roux, Dae In Kim, Manfred Raida, Brian Burke", + "authorList": [ + { + "ForeName": "Kyle", + "LastName": "Roux", + "abbrevName": "Roux KJ", + "email": "Kyle.Roux@sanfordhealth.org", + "isCollectiveName": false, + "name": "Kyle J Roux" + }, + { + "ForeName": "Dae", + "LastName": "Kim", + "abbrevName": "Kim DI", + "email": null, + "isCollectiveName": false, + "name": "Dae In Kim" + }, + { + "ForeName": "Manfred", + "LastName": "Raida", + "abbrevName": "Raida M", + "email": null, + "isCollectiveName": false, + "name": "Manfred Raida" + }, + { + "ForeName": "Brian", + "LastName": "Burke", + "abbrevName": "Burke B", + "email": null, + "isCollectiveName": false, + "name": "Brian Burke" + } + ], + "contacts": [ + { + "ForeName": "Kyle", + "LastName": "Roux", + "email": [ + "Kyle.Roux@sanfordhealth.org" + ], + "name": "Kyle J Roux" + } + ] + }, + "doi": "10.1083/jcb.201112098", + "pmid": "22412018", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 196 2012", + "title": "A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells." + } + }, + { + "pmid": "22366317", + "pubmed": { + "ISODate": "2012-03-20T00:00:00.000Z", + "abstract": "Protein interactions with peptides generally have low thermodynamic and mechanical stability. Streptococcus pyogenes fibronectin-binding protein FbaB contains a domain with a spontaneous isopeptide bond between Lys and Asp. By splitting this domain and rational engineering of the fragments, we obtained a peptide (SpyTag) which formed an amide bond to its protein partner (SpyCatcher) in minutes. Reaction occurred in high yield simply upon mixing and amidst diverse conditions of pH, temperature, and buffer. SpyTag could be fused at either terminus or internally and reacted specifically at the mammalian cell surface. Peptide binding was not reversed by boiling or competing peptide. Single-molecule dynamic force spectroscopy showed that SpyTag did not separate from SpyCatcher until the force exceeded 1 nN, where covalent bonds snap. The robust reaction conditions and irreversible linkage of SpyTag shed light on spontaneous isopeptide bond formation and should provide a targetable lock in cells and a stable module for new protein architectures.", + "authors": { + "abbreviation": "Bijan Zakeri, Jacob O Fierer, Emrah Celik, ..., Mark Howarth", + "authorList": [ + { + "ForeName": "Bijan", + "LastName": "Zakeri", + "abbrevName": "Zakeri B", + "email": null, + "isCollectiveName": false, + "name": "Bijan Zakeri" + }, + { + "ForeName": "Jacob", + "LastName": "Fierer", + "abbrevName": "Fierer JO", + "email": null, + "isCollectiveName": false, + "name": "Jacob O Fierer" + }, + { + "ForeName": "Emrah", + "LastName": "Celik", + "abbrevName": "Celik E", + "email": null, + "isCollectiveName": false, + "name": "Emrah Celik" + }, + { + "ForeName": "Emily", + "LastName": "Chittock", + "abbrevName": "Chittock EC", + "email": null, + "isCollectiveName": false, + "name": "Emily C Chittock" + }, + { + "ForeName": "Ulrich", + "LastName": "Schwarz-Linek", + "abbrevName": "Schwarz-Linek U", + "email": null, + "isCollectiveName": false, + "name": "Ulrich Schwarz-Linek" + }, + { + "ForeName": "Vincent", + "LastName": "Moy", + "abbrevName": "Moy VT", + "email": null, + "isCollectiveName": false, + "name": "Vincent T Moy" + }, + { + "ForeName": "Mark", + "LastName": "Howarth", + "abbrevName": "Howarth M", + "email": null, + "isCollectiveName": false, + "name": "Mark Howarth" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1115485109", + "pmid": "22366317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 109 2012", + "title": "Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin." + } + }, + { + "pmid": "21244848", + "pubmed": { + "ISODate": "2011-01-19T00:00:00.000Z", + "abstract": "Although magnetic tweezers have many unique advantages in terms of specificity, throughput, and force stability, this tool has had limited application on short tethers because accurate measurement of force has been difficult for short tethers under large tension. Here, we report a method that allows us to apply magnetic tweezers to stretch short biomolecules with accurate force calibration over a wide range of up to 100 pN. We demonstrate the use of the method by overstretching of a short DNA and unfolding/refolding a protein of filamin A immunoglobulin domains 1-8. Other potential applications of this method are also discussed.", + "authors": { + "abbreviation": "Hu Chen, Hongxia Fu, Xiaoying Zhu, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Hu", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hu Chen" + }, + { + "ForeName": "Hongxia", + "LastName": "Fu", + "abbrevName": "Fu H", + "email": null, + "isCollectiveName": false, + "name": "Hongxia Fu" + }, + { + "ForeName": "Xiaoying", + "LastName": "Zhu", + "abbrevName": "Zhu X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoying Zhu" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Fumihiko", + "LastName": "Nakamura", + "abbrevName": "Nakamura F", + "email": null, + "isCollectiveName": false, + "name": "Fumihiko Nakamura" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bpj.2010.12.3700", + "pmid": "21244848", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biophys J 100 2011", + "title": "Improved high-force magnetic tweezers for stretching and refolding of proteins and short DNA." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "20383002", + "pubmed": { + "ISODate": "2010-04-01T00:00:00.000Z", + "abstract": "Coot is a molecular-graphics application for model building and validation of biological macromolecules. The program displays electron-density maps and atomic models and allows model manipulations such as idealization, real-space refinement, manual rotation/translation, rigid-body fitting, ligand search, solvation, mutations, rotamers and Ramachandran idealization. Furthermore, tools are provided for model validation as well as interfaces to external programs for refinement, validation and graphics. The software is designed to be easy to learn for novice users, which is achieved by ensuring that tools for common tasks are 'discoverable' through familiar user-interface elements (menus and toolbars) or by intuitive behaviour (mouse controls). Recent developments have focused on providing tools for expert users, with customisable key bindings, extensions and an extensive scripting interface. The software is under rapid development, but has already achieved very widespread use within the crystallographic community. The current state of the software is presented, with a description of the facilities available and of some of the underlying methods employed.", + "authors": { + "abbreviation": "P Emsley, B Lohkamp, W G Scott, K Cowtan", + "authorList": [ + { + "ForeName": "P", + "LastName": "Emsley", + "abbrevName": "Emsley P", + "email": "paul.emsley@bioch.ox.ac.uk", + "isCollectiveName": false, + "name": "P Emsley" + }, + { + "ForeName": "B", + "LastName": "Lohkamp", + "abbrevName": "Lohkamp B", + "email": null, + "isCollectiveName": false, + "name": "B Lohkamp" + }, + { + "ForeName": "W", + "LastName": "Scott", + "abbrevName": "Scott WG", + "email": null, + "isCollectiveName": false, + "name": "W G Scott" + }, + { + "ForeName": "K", + "LastName": "Cowtan", + "abbrevName": "Cowtan K", + "email": null, + "isCollectiveName": false, + "name": "K Cowtan" + } + ], + "contacts": [ + { + "ForeName": "P", + "LastName": "Emsley", + "email": [ + "paul.emsley@bioch.ox.ac.uk" + ], + "name": "P Emsley" + } + ] + }, + "doi": "10.1107/S0907444910007493", + "pmid": "20383002", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 66 2010", + "title": "Features and development of Coot." + } + }, + { + "pmid": "19798053", + "pubmed": { + "ISODate": "2009-11-18T00:00:00.000Z", + "abstract": "Fundamental to cell adhesion and migration, integrins are large heterodimeric membrane proteins that uniquely mediate inside-out signal transduction, whereby adhesion to the extracellular matrix is activated from within the cell by direct binding of talin to the cytoplasmic tail of the beta integrin subunit. Here, we report the first structure of talin bound to an authentic full-length beta integrin tail. Using biophysical and whole cell measurements, we show that a specific ionic interaction between the talin F3 domain and the membrane-proximal helix of the beta tail disrupts an integrin alpha/beta salt bridge that helps maintain the integrin inactive state. Second, we identify a positively charged surface on the talin F2 domain that precisely orients talin to disrupt the heterodimeric integrin transmembrane (TM) complex. These results show key structural features that explain the ability of talin to mediate inside-out TM signalling.", + "authors": { + "abbreviation": "Nicholas J Anthis, Kate L Wegener, Feng Ye, ..., Iain D Campbell", + "authorList": [ + { + "ForeName": "Nicholas", + "LastName": "Anthis", + "abbrevName": "Anthis NJ", + "email": "nick.anthis@gmail.com", + "isCollectiveName": false, + "name": "Nicholas J Anthis" + }, + { + "ForeName": "Kate", + "LastName": "Wegener", + "abbrevName": "Wegener KL", + "email": null, + "isCollectiveName": false, + "name": "Kate L Wegener" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Chungho", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chungho Kim" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Edward", + "LastName": "Lowe", + "abbrevName": "Lowe ED", + "email": null, + "isCollectiveName": false, + "name": "Edward D Lowe" + }, + { + "ForeName": "Ioannis", + "LastName": "Vakonakis", + "abbrevName": "Vakonakis I", + "email": null, + "isCollectiveName": false, + "name": "Ioannis Vakonakis" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Anthis", + "email": [ + "nick.anthis@gmail.com" + ], + "name": "Nicholas J Anthis" + } + ] + }, + "doi": "10.1038/emboj.2009.287", + "pmid": "19798053", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 28 2009", + "title": "The structure of an integrin/talin complex reveals the basis of inside-out signal transduction." + } + }, + { + "pmid": "19738201", + "pubmed": { + "ISODate": "2009-09-08T00:00:00.000Z", + "abstract": "The binding of integrin adhesion receptors to their extracellular matrix ligands controls cell morphology, movement, survival, and differentiation in various developmental, homeostatic, and disease processes. Here, we report a methodology to isolate complexes associated with integrin adhesion receptors, which, like other receptor-associated signaling complexes, have been refractory to proteomic analysis. Quantitative, comparative analyses of the proteomes of two receptor-ligand pairs, alpha(4)beta(1)-vascular cell adhesion molecule-1 and alpha(5)beta(1)-fibronectin, defined both core and receptor-specific components. Regulator of chromosome condensation-2 (RCC2) was detected in the alpha(5)beta(1)-fibronectin signaling network at an intersection between the Rac1 and adenosine 5'-diphosphate ribosylation factor 6 (Arf6) subnetworks. RCC2 knockdown enhanced fibronectin-induced activation of both Rac1 and Arf6 and accelerated cell spreading, suggesting that RCC2 limits the signaling required for membrane protrusion and delivery. Dysregulation of Rac1 and Arf6 function by RCC2 knockdown also abolished persistent migration along fibronectin fibers, indicating a functional role for RCC2 in directional cell movement. This proteomics workflow now opens the way to further dissection and systems-level analyses of adhesion signaling.", + "authors": { + "abbreviation": "Jonathan D Humphries, Adam Byron, Mark D Bass, ..., Martin J Humphries", + "authorList": [ + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Adam", + "LastName": "Byron", + "abbrevName": "Byron A", + "email": null, + "isCollectiveName": false, + "name": "Adam Byron" + }, + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Sue", + "LastName": "Craig", + "abbrevName": "Craig SE", + "email": null, + "isCollectiveName": false, + "name": "Sue E Craig" + }, + { + "ForeName": "John", + "LastName": "Pinney", + "abbrevName": "Pinney JW", + "email": null, + "isCollectiveName": false, + "name": "John W Pinney" + }, + { + "ForeName": "David", + "LastName": "Knight", + "abbrevName": "Knight D", + "email": null, + "isCollectiveName": false, + "name": "David Knight" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [] + }, + "doi": "10.1126/scisignal.2000396", + "pmid": "19738201", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Sci Signal 2 2009", + "title": "Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6." + } + }, + { + "pmid": "19638416", + "pubmed": { + "ISODate": "2009-08-15T00:00:00.000Z", + "abstract": "At the onset of mitosis, most adherent cells undergo cell retraction characterised by the disassembly of focal adhesions and actin stress fibres. Mitosis takes place in rounded cells, and the two daughter cells spread again after cytokinesis. Because of the well-documented ability of the small GTPase Rap1 to stimulate integrin-dependent adhesion and spreading, we assessed its role during mitosis. We show that Rap1 activity is regulated during this process. Changes in Rap1 activity play an essential role in regulating cell retraction and spreading, respectively, before and after mitosis of HeLa cells. Indeed, endogenous Rap1 is inhibited at the onset of mitosis; conversely, constitutive activation of Rap1 inhibits the disassembly of premitotic focal adhesions and of the actin cytoskeleton, leading to delayed mitosis and to cytokinesis defects. Rap1 activity slowly increases after mitosis ends; inhibition of Rap1 activation by the ectopic expression of the dominant-negative Rap1[S17A] mutant prevents the rounded cells from spreading after mitosis. For the first time, we provide evidence for the direct regulation of adhesion processes during mitosis via the activity of the Rap1 GTPase.", + "authors": { + "abbreviation": "Vi Thuy Dao, Aurélien Guy Dupuy, Olivier Gavet, ..., Jean de Gunzburg", + "authorList": [ + { + "ForeName": "Vi", + "LastName": "Dao", + "abbrevName": "Dao VT", + "email": null, + "isCollectiveName": false, + "name": "Vi Thuy Dao" + }, + { + "ForeName": "Aurélien", + "LastName": "Dupuy", + "abbrevName": "Dupuy AG", + "email": null, + "isCollectiveName": false, + "name": "Aurélien Guy Dupuy" + }, + { + "ForeName": "Olivier", + "LastName": "Gavet", + "abbrevName": "Gavet O", + "email": null, + "isCollectiveName": false, + "name": "Olivier Gavet" + }, + { + "ForeName": "Emmanuelle", + "LastName": "Caron", + "abbrevName": "Caron E", + "email": null, + "isCollectiveName": false, + "name": "Emmanuelle Caron" + }, + { + "ForeName": "Jean", + "LastName": "de Gunzburg", + "abbrevName": "de Gunzburg J", + "email": null, + "isCollectiveName": false, + "name": "Jean de Gunzburg" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.041301", + "pmid": "19638416", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 122 2009", + "title": "Dynamic changes in Rap1 activity are required for cell retraction and spreading during mitosis." + } + }, + { + "pmid": "19461840", + "pubmed": { + "ISODate": "2007-08-01T00:00:00.000Z", + "abstract": "Phaser is a program for phasing macromolecular crystal structures by both molecular replacement and experimental phasing methods. The novel phasing algorithms implemented in Phaser have been developed using maximum likelihood and multivariate statistics. For molecular replacement, the new algorithms have proved to be significantly better than traditional methods in discriminating correct solutions from noise, and for single-wavelength anomalous dispersion experimental phasing, the new algorithms, which account for correlations between F(+) and F(-), give better phases (lower mean phase error with respect to the phases given by the refined structure) than those that use mean F and anomalous differences DeltaF. One of the design concepts of Phaser was that it be capable of a high degree of automation. To this end, Phaser (written in C++) can be called directly from Python, although it can also be called using traditional CCP4 keyword-style input. Phaser is a platform for future development of improved phasing methods and their release, including source code, to the crystallographic community.", + "authors": { + "abbreviation": "Airlie J McCoy, Ralf W Grosse-Kunstleve, Paul D Adams, ..., Randy J Read", + "authorList": [ + { + "ForeName": "Airlie", + "LastName": "McCoy", + "abbrevName": "McCoy AJ", + "email": null, + "isCollectiveName": false, + "name": "Airlie J McCoy" + }, + { + "ForeName": "Ralf", + "LastName": "Grosse-Kunstleve", + "abbrevName": "Grosse-Kunstleve RW", + "email": null, + "isCollectiveName": false, + "name": "Ralf W Grosse-Kunstleve" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + }, + { + "ForeName": "Martyn", + "LastName": "Winn", + "abbrevName": "Winn MD", + "email": null, + "isCollectiveName": false, + "name": "Martyn D Winn" + }, + { + "ForeName": "Laurent", + "LastName": "Storoni", + "abbrevName": "Storoni LC", + "email": null, + "isCollectiveName": false, + "name": "Laurent C Storoni" + }, + { + "ForeName": "Randy", + "LastName": "Read", + "abbrevName": "Read RJ", + "email": null, + "isCollectiveName": false, + "name": "Randy J Read" + } + ], + "contacts": [] + }, + "doi": "10.1107/S0021889807021206", + "pmid": "19461840", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Appl Crystallogr 40 2007", + "title": "Phaser crystallographic software." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "17654475", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "The orientation of mitotic spindles, which determines the plane of cell division, is tightly regulated in polarized cells such as epithelial cells, but it has been unclear whether there is a mechanism regulating spindle orientation in non-polarized cultured cells. In adherent cultured cells, spindles are positioned at the center of the cells and the axis of the spindle lies in the longest axis of the cell. Thus, cell geometry is thought to be one of cues for spindle orientation and positioning in cultured cells because this defines the center and the long axis of the cell. Recent work provides a new insight into the spindle orientation in cultured cells; spindles are aligned along the axis parallel to the cell-substrate adhesion plane. Concomitantly, integrin-mediated cell adhesion to the extracellular matrix (ECM), rather than gravitation, cell-cell adhesion or cell geometry, has shown to be essential for this mechanism of spindle orientation. Several independent lines of evidence confirm the involvement of cell-ECM adhesion in spindle orientation in both cultured cells and in developing organisms. The important future challenge is to identify a molecular mechanism(s) that links integrin and spindles in the control of spindle axis.", + "authors": { + "abbreviation": "Fumiko Toyoshima, Eisuke Nishida", + "authorList": [ + { + "ForeName": "Fumiko", + "LastName": "Toyoshima", + "abbrevName": "Toyoshima F", + "email": "ftoyoshima@lif.kyoto-u.ac.jp", + "isCollectiveName": false, + "name": "Fumiko Toyoshima" + }, + { + "ForeName": "Eisuke", + "LastName": "Nishida", + "abbrevName": "Nishida E", + "email": null, + "isCollectiveName": false, + "name": "Eisuke Nishida" + } + ], + "contacts": [ + { + "ForeName": "Fumiko", + "LastName": "Toyoshima", + "email": [ + "ftoyoshima@lif.kyoto-u.ac.jp" + ], + "name": "Fumiko Toyoshima" + } + ] + }, + "doi": "10.1002/jcp.21227", + "pmid": "17654475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Physiol 213 2007", + "title": "Spindle orientation in animal cell mitosis: roles of integrin in the control of spindle axis." + } + }, + { + "pmid": "16258726", + "pubmed": { + "ISODate": "2005-09-01T00:00:00.000Z", + "abstract": "Integrins and growth factor receptors coordinately regulate proliferation in nontransformed cells. Coordinate signaling from these receptors controls the activation of the G1 phase cyclin-dependent kinases, largely by regulating levels of cyclin D1 and p27(kip1). Induction of cyclin D1 is one of the best understood examples of an integrin/growth factor receptor-regulated G1 phase target. This review focuses on the integrin-dependent signal transduction events that regulate the expression of cyclin D1 during G1 phase.", + "authors": { + "abbreviation": "Janice L Walker, Richard K Assoian", + "authorList": [ + { + "ForeName": "Janice", + "LastName": "Walker", + "abbrevName": "Walker JL", + "email": null, + "isCollectiveName": false, + "name": "Janice L Walker" + }, + { + "ForeName": "Richard", + "LastName": "Assoian", + "abbrevName": "Assoian RK", + "email": null, + "isCollectiveName": false, + "name": "Richard K Assoian" + } + ], + "contacts": [] + }, + "doi": "10.1007/s10555-005-5130-7", + "pmid": "16258726", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cancer Metastasis Rev 24 2005", + "title": "Integrin-dependent signal transduction regulating cyclin D1 expression and G1 phase cell cycle progression." + } + }, + { + "pmid": "16179950", + "pubmed": { + "ISODate": "2005-10-01T00:00:00.000Z", + "abstract": "The cell division axis determines the future positions of daughter cells and is therefore critical for cell fate. The positioning of the division axis has been mostly studied in systems such as embryos or yeasts, in which cell shape is well defined. In these cases, cell shape anisotropy and cell polarity affect spindle orientation. It remains unclear whether cell geometry or cortical cues are determinants for spindle orientation in mammalian cultured cells. The cell environment is composed of an extracellular matrix (ECM), which is connected to the intracellular actin cytoskeleton via transmembrane proteins. We used micro-contact printing to control the spatial distribution of the ECM on the substrate and demonstrated that it has a role in determining the orientation of the division axis of HeLa cells. On the basis of our analysis of the average distributions of actin-binding proteins in interphase and mitosis, we propose that the ECM controls the location of actin dynamics at the membrane, and thus the segregation of cortical components in interphase. This segregation is further maintained on the cortex of mitotic cells and used for spindle orientation.", + "authors": { + "abbreviation": "Manuel Théry, Victor Racine, Anne Pépin, ..., Michel Bornens", + "authorList": [ + { + "ForeName": "Manuel", + "LastName": "Théry", + "abbrevName": "Théry M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Théry" + }, + { + "ForeName": "Victor", + "LastName": "Racine", + "abbrevName": "Racine V", + "email": null, + "isCollectiveName": false, + "name": "Victor Racine" + }, + { + "ForeName": "Anne", + "LastName": "Pépin", + "abbrevName": "Pépin A", + "email": null, + "isCollectiveName": false, + "name": "Anne Pépin" + }, + { + "ForeName": "Matthieu", + "LastName": "Piel", + "abbrevName": "Piel M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Piel" + }, + { + "ForeName": "Yong", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Chen" + }, + { + "ForeName": "Jean-Baptiste", + "LastName": "Sibarita", + "abbrevName": "Sibarita JB", + "email": null, + "isCollectiveName": false, + "name": "Jean-Baptiste Sibarita" + }, + { + "ForeName": "Michel", + "LastName": "Bornens", + "abbrevName": "Bornens M", + "email": null, + "isCollectiveName": false, + "name": "Michel Bornens" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1307", + "pmid": "16179950", + "pubTypes": [ + { + "UI": "D016422", + "value": "Letter" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 7 2005", + "title": "The extracellular matrix guides the orientation of the cell division axis." + } + }, + { + "pmid": "14527389", + "pubmed": { + "ISODate": "2003-10-01T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are large submembrane signaling complexes formed at sites of cellular attachment to the extracellular matrix. The interaction of LD motifs with their targets plays an important role in the assembly of FAs. We have determined the molecular basis for the recognition of two paxillin LD motifs by the FA targeting (FAT) domain of FA kinase using a combination of X-ray crystallography, solution NMR, and homology modeling. The four-helix FAT domain displays two LD binding sites on opposite sites of the molecule that bind LD peptides in a helical conformation. Threading studies suggest that the LD-interacting domain of p95PKL shares a common four-helical core with the FAT domain and the tail of vinculin, defining a structural family of LD motif binding modules.", + "authors": { + "abbreviation": "Maria K Hoellerer, Martin E M Noble, Gilles Labesse, ..., Stefan T Arold", + "authorList": [ + { + "ForeName": "Maria", + "LastName": "Hoellerer", + "abbrevName": "Hoellerer MK", + "email": null, + "isCollectiveName": false, + "name": "Maria K Hoellerer" + }, + { + "ForeName": "Martin", + "LastName": "Noble", + "abbrevName": "Noble ME", + "email": null, + "isCollectiveName": false, + "name": "Martin E M Noble" + }, + { + "ForeName": "Gilles", + "LastName": "Labesse", + "abbrevName": "Labesse G", + "email": null, + "isCollectiveName": false, + "name": "Gilles Labesse" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "Jörn", + "LastName": "Werner", + "abbrevName": "Werner JM", + "email": null, + "isCollectiveName": false, + "name": "Jörn M Werner" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2003.08.010", + "pmid": "14527389", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 11 2003", + "title": "Molecular recognition of paxillin LD motifs by the focal adhesion targeting domain." + } + }, + { + "pmid": "14526080", + "pubmed": { + "ISODate": "2003-10-03T00:00:00.000Z", + "abstract": "Control of integrin affinity for ligands (integrin activation) is essential for normal cell adhesion, migration, and assembly of an extracellular matrix. Integrin activation is usually mediated through the integrin beta subunit cytoplasmic tail and can be regulated by many different biochemical signaling pathways. We report that specific binding of the cytoskeletal protein talin to integrin beta subunit cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that increase their affinity. Thus, regulated binding of talin to integrin beta tails is a final common element of cellular signaling cascades that control integrin activation.", + "authors": { + "abbreviation": "Seiji Tadokoro, Sanford J Shattil, Koji Eto, ..., David A Calderwood", + "authorList": [ + { + "ForeName": "Seiji", + "LastName": "Tadokoro", + "abbrevName": "Tadokoro S", + "email": null, + "isCollectiveName": false, + "name": "Seiji Tadokoro" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Koji", + "LastName": "Eto", + "abbrevName": "Eto K", + "email": null, + "isCollectiveName": false, + "name": "Koji Eto" + }, + { + "ForeName": "Vera", + "LastName": "Tai", + "abbrevName": "Tai V", + "email": null, + "isCollectiveName": false, + "name": "Vera Tai" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Jose", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "Jose M de Pereda" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1086652", + "pmid": "14526080", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Science 302 2003", + "title": "Talin binding to integrin beta tails: a final common step in integrin activation." + } + }, + { + "pmid": "12535520", + "pubmed": { + "ISODate": "2003-01-01T00:00:00.000Z", + "abstract": "The binding of cytoplasmic proteins, such as talin, to the cytoplasmic domains of integrin adhesion receptors mediates bidirectional signal transduction. Here we report the crystal structure of the principal integrin binding and activating fragment of talin, alone and in complex with fragments of the beta 3 integrin tail. The FERM (four point one, ezrin, radixin, and moesin) domain of talin engages integrins via a novel variant of the canonical phosphotyrosine binding (PTB) domain-NPxY ligand interaction that may be a prototype for FERM domain recognition of transmembrane receptors. In combination with NMR and mutational analysis, our studies reveal the critical interacting elements of both talin and the integrin beta 3 tail, providing structural paradigms for integrin linkage to the cell interior.", + "authors": { + "abbreviation": "Begoña García-Alvarez, José M de Pereda, David A Calderwood, ..., Robert C Liddington", + "authorList": [ + { + "ForeName": "Begoña", + "LastName": "García-Alvarez", + "abbrevName": "García-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña García-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Tobias", + "LastName": "Ulmer", + "abbrevName": "Ulmer TS", + "email": null, + "isCollectiveName": false, + "name": "Tobias S Ulmer" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley D", + "email": null, + "isCollectiveName": false, + "name": "David Critchley" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + } + ], + "contacts": [] + }, + "doi": "10.1016/s1097-2765(02)00823-7", + "pmid": "12535520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Cell 11 2003", + "title": "Structural determinants of integrin recognition by talin." + } + }, + { + "pmid": "10497155", + "pubmed": { + "ISODate": "1999-10-01T00:00:00.000Z", + "abstract": "The beta subunit cytoplasmic domains of integrin adhesion receptors are necessary for the connection of these receptors to the actin cytoskeleton. The cytoplasmic protein, talin, binds to beta integrin cytoplasmic tails and actin filaments, hence forming an integrin-cytoskeletal linkage. We used recombinant structural mimics of beta(1)A, beta(1)D and beta(3) integrin cytoplasmic tails to characterize integrin-binding sites within talin. Here we report that an integrin-binding site is localized within the N-terminal talin head domain. The binding of the talin head domain to integrin beta tails is specific in that it is abrogated by a single point mutation that disrupts integrin localization to talin-rich focal adhesions. Integrin-cytoskeletal interactions regulate integrin affinity for ligands (activation). Overexpression of a fragment of talin containing the head domain led to activation of integrin alpha(IIb)beta(3); activation was dependent on the presence of both the talin head domain and the integrin beta(3) cytoplasmic tail. The head domain of talin thus binds to integrins to form a link to the actin cytoskeleton and can thus regulate integrin function.", + "authors": { + "abbreviation": "D A Calderwood, R Zent, R Grant, ..., M H Ginsberg", + "authorList": [ + { + "ForeName": "D", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "D A Calderwood" + }, + { + "ForeName": "R", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "R Zent" + }, + { + "ForeName": "R", + "LastName": "Grant", + "abbrevName": "Grant R", + "email": null, + "isCollectiveName": false, + "name": "R Grant" + }, + { + "ForeName": "D", + "LastName": "Rees", + "abbrevName": "Rees DJ", + "email": null, + "isCollectiveName": false, + "name": "D J Rees" + }, + { + "ForeName": "R", + "LastName": "Hynes", + "abbrevName": "Hynes RO", + "email": null, + "isCollectiveName": false, + "name": "R O Hynes" + }, + { + "ForeName": "M", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "M H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.274.40.28071", + "pmid": "10497155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 274 1999", + "title": "The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation." + } + }, + { + "pmid": "9699628", + "pubmed": { + "ISODate": "1998-08-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "M C Brown, M S Curtis, C E Turner", + "authorList": [ + { + "ForeName": "M", + "LastName": "Brown", + "abbrevName": "Brown MC", + "email": "Brownm@vax.cs.hscsyr.edu", + "isCollectiveName": false, + "name": "M C Brown" + }, + { + "ForeName": "M", + "LastName": "Curtis", + "abbrevName": "Curtis MS", + "email": null, + "isCollectiveName": false, + "name": "M S Curtis" + }, + { + "ForeName": "C", + "LastName": "Turner", + "abbrevName": "Turner CE", + "email": null, + "isCollectiveName": false, + "name": "C E Turner" + } + ], + "contacts": [ + { + "ForeName": "M", + "LastName": "Brown", + "email": [ + "Brownm@vax.cs.hscsyr.edu" + ], + "name": "M C Brown" + } + ] + }, + "doi": "10.1038/1370", + "pmid": "9699628", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Struct Biol 5 1998", + "title": "Paxillin LD motifs may define a new family of protein recognition domains." + } + }, + { + "pmid": "9330874", + "pubmed": { + "ISODate": "1997-10-01T00:00:00.000Z", + "abstract": "The loss of integrin-mediated cell-matrix contact induces apoptosis ('anoikis') in certain cell types. Recently it has been shown that protein kinase signaling pathways control anoikis both positively and negatively. Focal adhesion kinase, when activated by integrins, can suppress anoikis. Phosphatidylinositol 3-kinase and the AKT oncoprotein may mediate the anoikis-suppressing effects of focal adhesion kinase. Conversely, the stress-activated protein kinase/Jun amino-terminal kinase pathway promotes anoikis. Latest results indicate that caspase-mediated cleavage of the first component of this latter pathway, MEKK-1, may trigger activation of this pathway in anoikis. In addition, certain integrins may regulate bcl-2 expression levels, possibly adjusting the threshold for anoikis.", + "authors": { + "abbreviation": "S M Frisch, E Ruoslahti", + "authorList": [ + { + "ForeName": "S", + "LastName": "Frisch", + "abbrevName": "Frisch SM", + "email": "sfrisch@ljcrf.edu", + "isCollectiveName": false, + "name": "S M Frisch" + }, + { + "ForeName": "E", + "LastName": "Ruoslahti", + "abbrevName": "Ruoslahti E", + "email": null, + "isCollectiveName": false, + "name": "E Ruoslahti" + } + ], + "contacts": [ + { + "ForeName": "S", + "LastName": "Frisch", + "email": [ + "sfrisch@ljcrf.edu" + ], + "name": "S M Frisch" + } + ] + }, + "doi": "10.1016/s0955-0674(97)80124-x", + "pmid": "9330874", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 9 1997", + "title": "Integrins and anoikis." + } + }, + { + "pmid": "9159132", + "pubmed": { + "ISODate": "1997-05-27T00:00:00.000Z", + "abstract": "Talin is an actin-binding protein involved in integrin-mediated cell adhesion and spreading. The C-terminal 197 amino acids of vertebrate talin are 45% similar to the C-terminal residues of Sla2, a yeast protein implicated in polarized assembly of the yeast actin cytoskeleton. Talin is also homologous in this region to nematode talin, cellular slime mold filopodin, and an Sla2 homolog from nematode. Analysis of the conserved C-terminal sequences of these five proteins with BLOCK MAKER reveals a series of four blocks, which we name the I/LWEQ module after the conserved initial residues in each block. Experiments presented here show that the conserved protein domain represented by the I/LWEQ module competes quantitatively with native talin for binding to F-actin in vitro. Furthermore, the corresponding domain of Sla2 binds to both yeast and vertebrate F-actin in vitro. Mutation of one of the conserved residues in the fourth conserved block abolishes the interaction of the Sla2 I/LWEQ module with F-actin. These results establish the location of an F-actin binding domain in native talin, demonstrate that direct interaction of Sla2 with actin is a possible basis for its effect on the actin cytoskeleton in vivo, and define the I/LWEQ consensus as a new actin-binding motif.", + "authors": { + "abbreviation": "R O McCann, S W Craig", + "authorList": [ + { + "ForeName": "R", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "R O McCann" + }, + { + "ForeName": "S", + "LastName": "Craig", + "abbrevName": "Craig SW", + "email": null, + "isCollectiveName": false, + "name": "S W Craig" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.94.11.5679", + "pmid": "9159132", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 94 1997", + "title": "The I/LWEQ module: a conserved sequence that signifies F-actin binding in functionally diverse proteins from yeast to mammals." + } + }, + { + "pmid": "9026502", + "pubmed": { + "ISODate": "1997-01-13T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "R K Assoian", + "authorList": [ + { + "ForeName": "R", + "LastName": "Assoian", + "abbrevName": "Assoian RK", + "email": null, + "isCollectiveName": false, + "name": "R K Assoian" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.136.1.1", + "pmid": "9026502", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 136 1997", + "title": "Anchorage-dependent cell cycle progression." + } + }, + { + "pmid": "8937989", + "pubmed": { + "ISODate": "1996-11-01T00:00:00.000Z", + "abstract": "We have determined the sequence of chicken talin (2,541 amino acids, M(r) 271,881) which is very similar (89% identity) to that of the mouse protein. Alignments with the Caenorhabditis elegans and Dictyostelium discoideum talin sequences show that the N- and C-terminal regions of the protein are conserved whereas the central part of the molecule is more divergent. By expressing overlapping talin polypeptides as fusion proteins, we have identified at least three regions of the protein which can bind F-actin: residues 102-497, 951-1,327 and 2,269-2,541. The N-terminal binding site contains a region with homology to the ERM family of actin-binding proteins, and the C-terminal site is homologous to the yeast actin-binding protein Sla2p. Each of the actin-binding sites is close to, but distinct from a binding site for vinculin, a protein which also binds actin. The Pro1176 to Thr substitution found in talin from Wistar-Furth rats does not destroy the capacity of this region of the protein to bind actin or vinculin. Microinjection studies showed that a fusion protein containing the N-terminal actin-binding site localised weakly to stress fibres, whereas one containing the C-terminal site initially localised predominantly to focal adhesions. The former was readily solubilised, and the latter was resistant to Triton extraction. The N-terminal talin polypeptide eventually disrupted actin stress fibres whereas the C-terminal polypeptide was without effect. However, a larger C-terminal fusion protein also containing a vinculin-binding site did disrupt stress fibres and focal adhesions. The results suggest that, although both the N- and C-terminal regions of talin bind actin, the properties of these two regions of the protein are distinct.", + "authors": { + "abbreviation": "L Hemmings, D J Rees, V Ohanian, ..., D R Critchley", + "authorList": [ + { + "ForeName": "L", + "LastName": "Hemmings", + "abbrevName": "Hemmings L", + "email": null, + "isCollectiveName": false, + "name": "L Hemmings" + }, + { + "ForeName": "D", + "LastName": "Rees", + "abbrevName": "Rees DJ", + "email": null, + "isCollectiveName": false, + "name": "D J Rees" + }, + { + "ForeName": "V", + "LastName": "Ohanian", + "abbrevName": "Ohanian V", + "email": null, + "isCollectiveName": false, + "name": "V Ohanian" + }, + { + "ForeName": "S", + "LastName": "Bolton", + "abbrevName": "Bolton SJ", + "email": null, + "isCollectiveName": false, + "name": "S J Bolton" + }, + { + "ForeName": "A", + "LastName": "Gilmore", + "abbrevName": "Gilmore AP", + "email": null, + "isCollectiveName": false, + "name": "A P Gilmore" + }, + { + "ForeName": "B", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "B Patel" + }, + { + "ForeName": "H", + "LastName": "Priddle", + "abbrevName": "Priddle H", + "email": null, + "isCollectiveName": false, + "name": "H Priddle" + }, + { + "ForeName": "J", + "LastName": "Trevithick", + "abbrevName": "Trevithick JE", + "email": null, + "isCollectiveName": false, + "name": "J E Trevithick" + }, + { + "ForeName": "R", + "LastName": "Hynes", + "abbrevName": "Hynes RO", + "email": null, + "isCollectiveName": false, + "name": "R O Hynes" + }, + { + "ForeName": "D", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "D R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.109.11.2715", + "pmid": "8937989", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Sci 109 ( Pt 11) 1996", + "title": "Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site." + } + }, + { + "pmid": "8257797", + "pubmed": { + "ISODate": "1993-09-01T00:00:00.000Z", + "abstract": "Programmed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. In many cases, PCD is induced by the withdrawal of specific hormones or growth factors that function as survival factors. In this study, we have investigated the potential role of the extracellular matrix (ECM) as a cell survival factor. Our results indicate that in the absence of any ECM interactions, human endothelial cells rapidly undergo PCD, as determined by cell morphology, nuclei fragmentation, DNA degradation, protein cross-linking, and the expression of the PCD-specific gene TRPM-2. PCD was blocked by plating cells on an immobilized integrin beta 1 antibody but not by antibodies to either the class I histocompatibility antigen (HLA) or vascular cell adhesion molecule-1 (VCAM-1), suggesting that integrin-mediated signals were required for maintaining cell viability. Treatment of the cells in suspension with the tyrosine phosphatase inhibitor sodium orthovanadate also blocked PCD. When other cell types were examined, some, but not all, underwent rapid cell death when deprived of adhesion to the ECM. These results suggest that in addition to regulating cell growth and differentiation, the ECM also functions as a survival factor for many cell types.", + "authors": { + "abbreviation": "J E Meredith, B Fazeli, M A Schwartz", + "authorList": [ + { + "ForeName": "J", + "LastName": "Meredith", + "abbrevName": "Meredith JE", + "email": null, + "isCollectiveName": false, + "name": "J E Meredith" + }, + { + "ForeName": "B", + "LastName": "Fazeli", + "abbrevName": "Fazeli B", + "email": null, + "isCollectiveName": false, + "name": "B Fazeli" + }, + { + "ForeName": "M", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "M A Schwartz" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.4.9.953", + "pmid": "8257797", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 4 1993", + "title": "The extracellular matrix as a cell survival factor." + } + }, + { + "pmid": "7799941", + "pubmed": { + "ISODate": "1995-01-01T00:00:00.000Z", + "abstract": "The cyclin-dependent protein kinases (CDKs) are activated by association with cyclins and by phosphorylation at a conserved threonine residue by the CDK-activating kinase (CAK). We have studied the binding of various human CDK and cyclin subunits in vitro, using purified proteins derived from baculovirus-infected insect cells. We find that most CDK-cyclin complexes known to exist in human cells (CDC2-cyclin B, CDK2-cyclin A, and CDK2-cyclin E) form with high affinity in the absence of phosphorylation or other cellular components. One complex (CDC2-cyclin A) forms with high affinity only after CAK-mediated phosphorylation of CDC2 at the activating threonine residue. CDC2 does not bind with high affinity to cyclin E in vitro, even after phosphorylation of the CDC2 subunit. Thus, phosphorylation is of varying importance in the formation of high-affinity CDK-cyclin complexes.", + "authors": { + "abbreviation": "D Desai, H C Wessling, R P Fisher, D O Morgan", + "authorList": [ + { + "ForeName": "D", + "LastName": "Desai", + "abbrevName": "Desai D", + "email": null, + "isCollectiveName": false, + "name": "D Desai" + }, + { + "ForeName": "H", + "LastName": "Wessling", + "abbrevName": "Wessling HC", + "email": null, + "isCollectiveName": false, + "name": "H C Wessling" + }, + { + "ForeName": "R", + "LastName": "Fisher", + "abbrevName": "Fisher RP", + "email": null, + "isCollectiveName": false, + "name": "R P Fisher" + }, + { + "ForeName": "D", + "LastName": "Morgan", + "abbrevName": "Morgan DO", + "email": null, + "isCollectiveName": false, + "name": "D O Morgan" + } + ], + "contacts": [] + }, + "doi": "10.1128/MCB.15.1.345", + "pmid": "7799941", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Cell Biol 15 1995", + "title": "Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2." + } + } + ], + "relatedPapers": [ + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "29930204", + "pubmed": { + "ISODate": "2018-09-03T00:00:00.000Z", + "abstract": "In most tissues, anchorage-dependent growth and cell cycle progression are dependent on cells engaging extracellular matrices (ECMs) via integrin-receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings before division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell adhesion to the ECM. In this study, we demonstrate that cyclin-dependent kinase 1 (CDK1) mediates this link. CDK1, in complex with cyclin A2, promotes adhesion complex and actin cytoskeleton organization during interphase and mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area decreases in G2, and disassembly occurs several hours before mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1 is therefore the trigger that initiates remodeling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.", + "authors": { + "abbreviation": "Matthew C Jones, Janet A Askari, Jonathan D Humphries, Martin J Humphries", + "authorList": [ + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1083/jcb.201802088", + "pmid": "29930204", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Cell adhesion is regulated by CDK1 during the cell cycle." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "28701514", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and Drosophila to present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.", + "authors": { + "abbreviation": "Benjamin Klapholz, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": "nb117@cam.ac.uk", + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Brown", + "email": [ + "nb117@cam.ac.uk" + ], + "name": "Nicholas H Brown" + } + ] + }, + "doi": "10.1242/jcs.190991", + "pmid": "28701514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "Talin - the master of integrin adhesions." + } + }, + { + "pmid": "22496808", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Talin is a large (∼2540 residues) dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs), where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell.", + "authors": { + "abbreviation": "Neil Bate, Alexandre R Gingras, Alexia Bachir, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir A", + "email": null, + "isCollectiveName": false, + "name": "Alexia Bachir" + }, + { + "ForeName": "Rick", + "LastName": "Horwitz", + "abbrevName": "Horwitz R", + "email": null, + "isCollectiveName": false, + "name": "Rick Horwitz" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0034461", + "pmid": "22496808", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "30254158", + "pubmed": { + "ISODate": "2018-10-09T00:00:00.000Z", + "abstract": "Multicellular organisms have well-defined, tightly regulated mechanisms for cell adhesion. Heterodimeric αβ integrin receptors play central roles in this function and regulate processes for normal cell functions, including signaling, cell migration, and development, binding to the extracellular matrix, and senescence. They are involved in hemostasis and the immune response, participate in leukocyte function, and have biological implications in angiogenesis and cancer. Proper control of integrin activation for cellular communication with the external environment requires several physiological processes. Perturbation of these equilibria may lead to constitutive integrin activation that results in bleeding disorders. Furthermore, integrins play key roles in cancer progression and metastasis in which certain tumor types exhibit higher levels of various integrins. Thus, the integrin-associated signaling complex is important for cancer therapy development. During inside-out signaling, the cytoskeletal protein talin plays a key role in regulating integrin affinity whereby the talin head domain activates integrin by binding to the cytoplasmic tail of β-integrin and acidic membrane phospholipids. To understand the mechanism of integrin activation by talin, we determined the crystal structure of the talin head domain bound to the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), allowing us to design a lipid-binding-deficient talin mutant. Our confocal microscopy with talin knockout cells suggests that the talin-cell membrane interaction seems essential for focal adhesion formation and stabilization. Basal integrin activation in Chinese hamster ovary cells suggests that the lipid-binding-deficient talin mutant inhibits integrin activation. Thus, membrane attachment of talin seems necessary for integrin activation and focal adhesion formation.", + "authors": { + "abbreviation": "Krishna Chinthalapudi, Erumbi S Rangarajan, Tina Izard", + "authorList": [ + { + "ForeName": "Krishna", + "LastName": "Chinthalapudi", + "abbrevName": "Chinthalapudi K", + "email": null, + "isCollectiveName": false, + "name": "Krishna Chinthalapudi" + }, + { + "ForeName": "Erumbi", + "LastName": "Rangarajan", + "abbrevName": "Rangarajan ES", + "email": null, + "isCollectiveName": false, + "name": "Erumbi S Rangarajan" + }, + { + "ForeName": "Tina", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": "cmorrow@scripps.edu", + "isCollectiveName": false, + "name": "Tina Izard" + } + ], + "contacts": [ + { + "ForeName": "Tina", + "LastName": "Izard", + "email": [ + "cmorrow@scripps.edu" + ], + "name": "Tina Izard" + } + ] + }, + "doi": "10.1073/pnas.1806275115", + "pmid": "30254158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation." + } + }, + { + "pmid": "34708856", + "pubmed": { + "ISODate": "2021-10-15T00:00:00.000Z", + "abstract": "Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches - proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.", + "authors": { + "abbreviation": "Benjamin T Goult, Nicholas H Brown, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.258749", + "pmid": "34708856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 134 2021", + "title": "Talin in mechanotransduction and mechanomemory at a glance." + } + }, + { + "pmid": "27252130", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellular matrix (ECM) via its connection with the actin cytoskeleton and membrane integrins. It is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the field of mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as well as its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival. New data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states.-Haining, A. W. M., Lieberthal, T. J., del Río Hernández, A. Talin: a mechanosensitive molecule in health and disease.", + "authors": { + "abbreviation": "Alexander W M Haining, Tyler J Lieberthal, Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AW", + "email": null, + "isCollectiveName": false, + "name": "Alexander W M Haining" + }, + { + "ForeName": "Tyler", + "LastName": "Lieberthal", + "abbrevName": "Lieberthal TJ", + "email": null, + "isCollectiveName": false, + "name": "Tyler J Lieberthal" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": "a.del-rio-hernandez@imperial.ac.uk", + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [ + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "email": [ + "a.del-rio-hernandez@imperial.ac.uk" + ], + "name": "Armando Del Río Hernández" + } + ] + }, + "doi": "10.1096/fj.201500080R", + "pmid": "27252130", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FASEB J 30 2016", + "title": "Talin: a mechanosensitive molecule in health and disease." + } + }, + { + "pmid": "19948488", + "pubmed": { + "ISODate": "2009-11-30T00:00:00.000Z", + "abstract": "Integrin-dependent adhesion sites consist of clustered integrins that transmit mechanical forces and provide signaling required for cell survival and morphogenesis. Despite their importance, the regulation of integrin clustering by the cytoplasmic adapter protein talin (Tal) and phosphatidylinositol (PI)-4,5-biphosphate (PI(4,5)P(2)) lipids nor their dynamic coupling to the actin cytoskeleton is fully understood. By using a Tal-dependent integrin clustering assay in intact cells, we identified a PI(4,5)P(2)-binding basic ridge spanning across the F2 and F3 domains of the Tal head that regulates integrin clustering. Clustering requires a new PI(4,5)P(2)-binding site in F2 and is negatively regulated by autoinhibitory interactions between F3 and the Tal rod (Tal-R). The release of the Tal-R exposes a new beta3-integrin-binding site in F3, enabling interaction with a membrane proximal acidic motif, which involves the formation of salt bridges between K(316) and K(324) with E(726) and D(723), respectively. This interaction shields the beta-integrin tail from reassociation with its alpha subunit, thereby maintaining the integrin in a substrate-binding and clustering-competent form.", + "authors": { + "abbreviation": "Frédéric Saltel, Eva Mortier, Vesa P Hytönen, ..., Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Frédéric", + "LastName": "Saltel", + "abbrevName": "Saltel F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Saltel" + }, + { + "ForeName": "Eva", + "LastName": "Mortier", + "abbrevName": "Mortier E", + "email": null, + "isCollectiveName": false, + "name": "Eva Mortier" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Marie-Claude", + "LastName": "Jacquier", + "abbrevName": "Jacquier MC", + "email": null, + "isCollectiveName": false, + "name": "Marie-Claude Jacquier" + }, + { + "ForeName": "Pascale", + "LastName": "Zimmermann", + "abbrevName": "Zimmermann P", + "email": null, + "isCollectiveName": false, + "name": "Pascale Zimmermann" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": null, + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200908134", + "pmid": "19948488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 187 2009", + "title": "New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering." + } + }, + { + "pmid": "18550856", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Leukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (K(d), 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (K(d), 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated beta2 integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion.", + "authors": { + "abbreviation": "Heikki Takala, Elisa Nurminen, Susanna M Nurmi, ..., Susanna C Fagerholm", + "authorList": [ + { + "ForeName": "Heikki", + "LastName": "Takala", + "abbrevName": "Takala H", + "email": null, + "isCollectiveName": false, + "name": "Heikki Takala" + }, + { + "ForeName": "Elisa", + "LastName": "Nurminen", + "abbrevName": "Nurminen E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Nurminen" + }, + { + "ForeName": "Susanna", + "LastName": "Nurmi", + "abbrevName": "Nurmi SM", + "email": null, + "isCollectiveName": false, + "name": "Susanna M Nurmi" + }, + { + "ForeName": "Maria", + "LastName": "Aatonen", + "abbrevName": "Aatonen M", + "email": null, + "isCollectiveName": false, + "name": "Maria Aatonen" + }, + { + "ForeName": "Tomas", + "LastName": "Strandin", + "abbrevName": "Strandin T", + "email": null, + "isCollectiveName": false, + "name": "Tomas Strandin" + }, + { + "ForeName": "Maarit", + "LastName": "Takatalo", + "abbrevName": "Takatalo M", + "email": null, + "isCollectiveName": false, + "name": "Maarit Takatalo" + }, + { + "ForeName": "Tiila", + "LastName": "Kiema", + "abbrevName": "Kiema T", + "email": null, + "isCollectiveName": false, + "name": "Tiila Kiema" + }, + { + "ForeName": "Carl", + "LastName": "Gahmberg", + "abbrevName": "Gahmberg CG", + "email": null, + "isCollectiveName": false, + "name": "Carl G Gahmberg" + }, + { + "ForeName": "Jari", + "LastName": "Ylänne", + "abbrevName": "Ylänne J", + "email": null, + "isCollectiveName": false, + "name": "Jari Ylänne" + }, + { + "ForeName": "Susanna", + "LastName": "Fagerholm", + "abbrevName": "Fagerholm SC", + "email": null, + "isCollectiveName": false, + "name": "Susanna C Fagerholm" + } + ], + "contacts": [] + }, + "doi": "10.1182/blood-2007-12-127795", + "pmid": "18550856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Blood 112 2008", + "title": "Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding." + } + }, + { + "pmid": "15031296", + "pubmed": { + "ISODate": "2004-05-21T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which provides a direct link between integrins and actin filaments, has been shown to contain two distinct binding sites for integrin beta subunits. Here, we report the precise delimitation and a first functional analysis of the talin rod domain integrin-binding site. Partially overlapping cDNAs covering the entire human talin gene were transiently expressed as DsRed fusion proteins in Chinese hamster ovary cells expressing alpha(IIb)beta(3), linked to green fluorescent protein (GFP). Two-color fluorescence analysis of the transfected cells, spread on fibrinogen, revealed distinct subcellular staining patterns including focal adhesion, actin filament, and granular labeling for different talin fragments. The rod domain fragment G (residues 1984-2344), devoid of any known actin- or vinculin-binding sites, colocalized with beta(3)-GFP in focal adhesions. Direct in vitro interaction of fragment G with native platelet integrin alpha(IIb)beta(3) or with the recombinant wild type, but not the Y747A mutant beta(3) cytoplasmic tail, linked to glutathione S-transferase, was demonstrated by surface plasmon resonance analysis and pull-down assays, respectively. Here, we demonstrate for the first time the in vivo relevance of this interaction by fluorescence resonance energy transfer between beta(3)-GFP and DsRed-talin fragment G. Further in vitro pull-down studies allowed us to map out the integrin-binding site within fragment G to a stretch of 130 residues (fragment J, residues 1984-2113) that also localized to focal adhesions. Finally, we show by a cell biology approach that this integrin-binding site within the talin rod domain is important for beta(3)-cytoskeletal interactions but does not participate in alpha(IIb)beta(3) activation.", + "authors": { + "abbreviation": "Laurent Tremuth, Stephanie Kreis, Chantal Melchior, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Stephanie", + "LastName": "Kreis", + "abbrevName": "Kreis S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kreis" + }, + { + "ForeName": "Chantal", + "LastName": "Melchior", + "abbrevName": "Melchior C", + "email": null, + "isCollectiveName": false, + "name": "Chantal Melchior" + }, + { + "ForeName": "Johan", + "LastName": "Hoebeke", + "abbrevName": "Hoebeke J", + "email": null, + "isCollectiveName": false, + "name": "Johan Hoebeke" + }, + { + "ForeName": "Philippe", + "LastName": "Rondé", + "abbrevName": "Rondé P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Rondé" + }, + { + "ForeName": "Sébastien", + "LastName": "Plançon", + "abbrevName": "Plançon S", + "email": null, + "isCollectiveName": false, + "name": "Sébastien Plançon" + }, + { + "ForeName": "Kenneth", + "LastName": "Takeda", + "abbrevName": "Takeda K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Takeda" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M400947200", + "pmid": "15031296", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A fluorescence cell biology approach to map the second integrin-binding site of talin to a 130-amino acid sequence within the rod domain." + } + }, + { + "pmid": "17430904", + "pubmed": { + "ISODate": "2007-06-08T00:00:00.000Z", + "abstract": "Talin1 is a large cytoskeletal protein that links integrins to actin filaments through two distinct integrin binding sites, one present in the talin head domain (IBS1) necessary for integrin activation and a second (IBS2) that we have previously mapped to talin residues 1984-2113 (fragment J) of the talin rod domain (1 Tremuth, L., Kreis, S., Melchior, C., Hoebeke, J., Ronde, P., Plancon, S., Takeda, K., and Kieffer, N. (2004) J. Biol. Chem. 279, 22258-22266), but whose functional role is still elusive. Using a bioinformatics and cell biology approach, we have determined the minimal structure of IBS2 and show that this integrin binding site corresponds to 23 residues located in alpha helix 50 of the talin rod domain (residues 2077-2099). Alanine mutation of 2 highly conserved residues (L2094A/I2095A) within this alpha helix, which disrupted the alpha-helical structure of IBS2 as demonstrated by infrared spectroscopy and limited trypsin proteolysis, was sufficient to prevent in vivo talin fragment J targeting to alphaIIbbeta3 integrin in focal adhesions and to inhibit in vitro this association as shown by an alphaIIbbeta3 pulldown assay. Moreover, expression of a full-length mouse green fluorescent protein-talin LI/AA mutant in mouse talin1(-/-) cells was unable to rescue the inability of these cells to assemble focal adhesions (in contrast to green fluorescent protein-talin wild type) despite the presence of IBS1. Our data provide the first direct evidence that IBS2 in the talin rod is essential to link integrins to the cytoskeleton.", + "authors": { + "abbreviation": "Michèle Moes, Sophie Rodius, Stacey J Coleman, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Michèle", + "LastName": "Moes", + "abbrevName": "Moes M", + "email": null, + "isCollectiveName": false, + "name": "Michèle Moes" + }, + { + "ForeName": "Sophie", + "LastName": "Rodius", + "abbrevName": "Rodius S", + "email": null, + "isCollectiveName": false, + "name": "Sophie Rodius" + }, + { + "ForeName": "Stacey", + "LastName": "Coleman", + "abbrevName": "Coleman SJ", + "email": null, + "isCollectiveName": false, + "name": "Stacey J Coleman" + }, + { + "ForeName": "Susan", + "LastName": "Monkley", + "abbrevName": "Monkley SJ", + "email": null, + "isCollectiveName": false, + "name": "Susan J Monkley" + }, + { + "ForeName": "Erik", + "LastName": "Goormaghtigh", + "abbrevName": "Goormaghtigh E", + "email": null, + "isCollectiveName": false, + "name": "Erik Goormaghtigh" + }, + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Corinne", + "LastName": "Kox", + "abbrevName": "Kox C", + "email": null, + "isCollectiveName": false, + "name": "Corinne Kox" + }, + { + "ForeName": "Patrick", + "LastName": "van der Holst", + "abbrevName": "van der Holst PP", + "email": null, + "isCollectiveName": false, + "name": "Patrick P G van der Holst" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M611846200", + "pmid": "17430904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 282 2007", + "title": "The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin beta subunits to the cytoskeleton." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "31539492", + "pubmed": { + "ISODate": "2019-09-19T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.", + "authors": { + "abbreviation": "Dirk Dedden, Stephanie Schumacher, Charlotte F Kelley, ..., Naoko Mizuno", + "authorList": [ + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Stephanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Schumacher" + }, + { + "ForeName": "Charlotte", + "LastName": "Kelley", + "abbrevName": "Kelley CF", + "email": null, + "isCollectiveName": false, + "name": "Charlotte F Kelley" + }, + { + "ForeName": "Martin", + "LastName": "Zacharias", + "abbrevName": "Zacharias M", + "email": null, + "isCollectiveName": false, + "name": "Martin Zacharias" + }, + { + "ForeName": "Christian", + "LastName": "Biertümpfel", + "abbrevName": "Biertümpfel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Biertümpfel" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": "mizuno@biochem.mpg.de", + "isCollectiveName": false, + "name": "Naoko Mizuno" + } + ], + "contacts": [ + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "email": [ + "mizuno@biochem.mpg.de" + ], + "name": "Naoko Mizuno" + } + ] + }, + "doi": "10.1016/j.cell.2019.08.034", + "pmid": "31539492", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell 179 2019", + "title": "The Architecture of Talin1 Reveals an Autoinhibition Mechanism." + } + }, + { + "pmid": "16081423", + "pubmed": { + "ISODate": "2005-09-23T00:00:00.000Z", + "abstract": "Previous experiments with peptide fusion proteins suggested that cyclin A/Cdk1 and Cdk2 might exhibit similar yet distinct phosphorylation specificities. Using a physiological substrate, CDP/Cux, our study confirms this notion. Proteolytic processing of CDP/Cux by cathepsin L generates the CDP/Cux p110 isoform at the beginning of S phase. CDP/Cux p110 makes stable interactions with DNA during S phase but is inhibited in G2 following the phosphorylation of serine 1237 by cyclin A/Cdk1. In this study, we propose that differential phosphorylation by cyclin A/Cdk1 and cyclin A/Cdk2 enables CDP/Cux p110 to exert its function as a transcriptional regulator specifically during S phase. We found that like cyclin A/Cdk1, cyclin A/Cdk2 interacted efficiently with recombinant CDP/Cux proteins that contain the Cut homeodomain and an adjacent cyclin-binding motif (Cy). In contrast to cyclin A/Cdk1, however, cyclin A/Cdk2 did not efficiently phosphorylate CDP/Cux p110 on serine 1237 and did not inhibit its DNA binding activity in vitro. Accordingly, co-expression with cyclin A/Cdk2 in cells did not inhibit the DNA binding and transcriptional activities of CDP/Cux p110. To confirm that the sequence surrounding serine 1237 was responsible for the differential regulation by Cdk1 and Cdk2, we replaced 4 amino acids flanking the phosphorylation site to mimic a known Cdk2 phosphorylation site present in the Cdc6 protein. Both cyclin A/Cdk2 and Cdk1 efficiently phosphorylated the CDP/Cux(Cdc6) mutant and inhibited its DNA binding activity. Altogether our results help explain why the DNA binding activity of CDP/Cux p110 is maximal during S phase and decreases in G2 phase.", + "authors": { + "abbreviation": "Marianne Santaguida, Alain Nepveu", + "authorList": [ + { + "ForeName": "Marianne", + "LastName": "Santaguida", + "abbrevName": "Santaguida M", + "email": null, + "isCollectiveName": false, + "name": "Marianne Santaguida" + }, + { + "ForeName": "Alain", + "LastName": "Nepveu", + "abbrevName": "Nepveu A", + "email": null, + "isCollectiveName": false, + "name": "Alain Nepveu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M505417200", + "pmid": "16081423", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Differential regulation of CDP/Cux p110 by cyclin A/Cdk2 and cyclin A/Cdk1." + } + }, + { + "pmid": "16135522", + "pubmed": { + "ISODate": "2005-11-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. Three vinculin binding sites (VBS1-3) have previously been identified in the talin rod using a yeast two-hybrid assay. To extend these studies, we spot-synthesized a series of peptides spanning all the alpha-helical regions predicted for the talin rod and identified eight additional VBSs, two of which overlap key functional regions of the rod, including the integrin binding site and C-terminal actin binding site. The talin VBS alpha-helices bind to a hydrophobic cleft in the N-terminal vinculin Vd1 domain. We have defined the specificity of this interaction by spot-synthesizing a series of 25-mer talin VBS1 peptides containing substitutions with all the commonly occurring amino acids. The consensus for recognition is LXXAAXXVAXX- VXXLIXXA with distinct classes of hydrophobic side chains at positions 1, 4, 5, 8, 9, 12, 15, and 16 required for vinculin binding. Positions 1, 8, 12, 15, and 16 require an aliphatic residue and will not tolerate alanine, whereas positions 4, 5, and 9 are less restrictive. These preferences are common to all 11 VBS sequences with a minor variation occurring in one case. A crystal structure of this variant VBS peptide in complex with the vinculin Vd1 domain reveals a subtly different mode of vinculin binding.", + "authors": { + "abbreviation": "Alexandre R Gingras, Wolfgang H Ziegler, Ronald Frank, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M508060200", + "pmid": "16135522", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod." + } + }, + { + "pmid": "7622520", + "pubmed": { + "ISODate": "1995-07-14T00:00:00.000Z", + "abstract": "The interaction of cells with extracellular matrix proteins plays a critical role in a variety of biological processes. Recent studies suggest that cell-matrix interactions mediated by integrins can transduce biochemical signals to the cell interior that regulate cell proliferation and differentiation. These studies have placed the focal adhesion kinase (FAK), an intracellular protein tyrosine kinase, in a central position in integrin-initiated signal transduction pathways (Zachary, I., and Rozengurt, E. (1992) Cell 71, 891-894; Schaller, M., and Parsons, J. T. (1993) Trends Cell Biol. 3, 258-262). Here, we report data suggesting a possible association of FAK with the cytoskeletal protein talin in NIH 3T3 cells. We have identified a 48-amino acid sequence in the carboxyl-terminal domain of FAK necessary for talin binding in vitro. Furthermore, we have correlated the ability of integrin to induce FAK phosphorylation with its ability to bind talin using a mutant integrin lacking the carboxyl-terminal 13 amino acids. These studies suggest talin may be a mediator for FAK activation in signaling initiated by integrins and may provide an explanation for the dependence on the integrity of actin-cytoskeleton of multiple intracellular signaling pathways converging to FAK activation and autophosphorylation.", + "authors": { + "abbreviation": "H C Chen, P A Appeddu, J T Parsons, ..., J L Guan", + "authorList": [ + { + "ForeName": "H", + "LastName": "Chen", + "abbrevName": "Chen HC", + "email": null, + "isCollectiveName": false, + "name": "H C Chen" + }, + { + "ForeName": "P", + "LastName": "Appeddu", + "abbrevName": "Appeddu PA", + "email": null, + "isCollectiveName": false, + "name": "P A Appeddu" + }, + { + "ForeName": "J", + "LastName": "Parsons", + "abbrevName": "Parsons JT", + "email": null, + "isCollectiveName": false, + "name": "J T Parsons" + }, + { + "ForeName": "J", + "LastName": "Hildebrand", + "abbrevName": "Hildebrand JD", + "email": null, + "isCollectiveName": false, + "name": "J D Hildebrand" + }, + { + "ForeName": "M", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "M D Schaller" + }, + { + "ForeName": "J", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "J L Guan" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.270.28.16995", + "pmid": "7622520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 270 1995", + "title": "Interaction of focal adhesion kinase with cytoskeletal protein talin." + } + }, + { + "pmid": "11591813", + "pubmed": { + "ISODate": "2001-09-01T00:00:00.000Z", + "abstract": "Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.", + "authors": { + "abbreviation": "C R Carlson, O Witczak, L Vossebein, ..., K Taskén", + "authorList": [ + { + "ForeName": "C", + "LastName": "Carlson", + "abbrevName": "Carlson CR", + "email": "cathrine.carlson@basalmed.uio.no", + "isCollectiveName": false, + "name": "C R Carlson" + }, + { + "ForeName": "O", + "LastName": "Witczak", + "abbrevName": "Witczak O", + "email": null, + "isCollectiveName": false, + "name": "O Witczak" + }, + { + "ForeName": "L", + "LastName": "Vossebein", + "abbrevName": "Vossebein L", + "email": null, + "isCollectiveName": false, + "name": "L Vossebein" + }, + { + "ForeName": "J", + "LastName": "Labbé", + "abbrevName": "Labbé JC", + "email": null, + "isCollectiveName": false, + "name": "J C Labbé" + }, + { + "ForeName": "B", + "LastName": "Skålhegg", + "abbrevName": "Skålhegg BS", + "email": null, + "isCollectiveName": false, + "name": "B S Skålhegg" + }, + { + "ForeName": "G", + "LastName": "Keryer", + "abbrevName": "Keryer G", + "email": null, + "isCollectiveName": false, + "name": "G Keryer" + }, + { + "ForeName": "F", + "LastName": "Herberg", + "abbrevName": "Herberg FW", + "email": null, + "isCollectiveName": false, + "name": "F W Herberg" + }, + { + "ForeName": "P", + "LastName": "Collas", + "abbrevName": "Collas P", + "email": null, + "isCollectiveName": false, + "name": "P Collas" + }, + { + "ForeName": "K", + "LastName": "Taskén", + "abbrevName": "Taskén K", + "email": null, + "isCollectiveName": false, + "name": "K Taskén" + } + ], + "contacts": [ + { + "ForeName": "C", + "LastName": "Carlson", + "email": [ + "cathrine.carlson@basalmed.uio.no" + ], + "name": "C R Carlson" + } + ] + }, + "doi": "10.1242/jcs.114.18.3243", + "pmid": "11591813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 114 2001", + "title": "CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis." + } + }, + { + "pmid": "16648844", + "pubmed": { + "ISODate": "2006-06-01T00:00:00.000Z", + "abstract": "Transmembrane adhesion receptors, such as integrins, mediate cell adhesion by interacting with intracellular proteins that connect to the cytoskeleton. Talin, one such linker protein, is thought to have two roles: mediating inside-out activation of integrins, and connecting extracellular matrix (ECM)-bound integrins to the cytoskeleton. Talin's amino-terminal head, which consists of a FERM domain, binds an NPxY motif within the cytoplasmic tail of most integrin beta subunits. This is consistent with the role of FERM domains in recruiting other proteins to the plasma membrane. We tested the role of the talin-head-NPxY interaction in integrin function in Drosophila. We found that introduction of a mutation that perturbs this binding in vitro into the isolated talin head disrupts its recruitment by integrins in vivo. Surprisingly, when engineered into the full-length talin, this mutation did not disrupt talin recruitment by integrins nor its ability to connect integrins to the cytoskeleton. However, it reduced the ability of talin to strengthen integrin adhesion to the ECM, indicating that the function of the talin-head-NPxY interaction is solely to regulate integrin adhesion.", + "authors": { + "abbreviation": "Guy Tanentzapf, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": null, + "isCollectiveName": false, + "name": "Guy Tanentzapf" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1411", + "pmid": "16648844", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 8 2006", + "title": "An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton." + } + }, + { + "pmid": "16460027", + "pubmed": { + "ISODate": "2006-02-14T00:00:00.000Z", + "abstract": "Talin is a key protein involved in linking integrins to the actin cytoskeleton. The long flexible talin rod domain contains a number of binding sites for vinculin, a cytoskeletal protein important in stabilizing integrin-mediated cell-matrix junctions. Here we report the solution structure of a talin rod polypeptide (residues 1843-1973) which contains a single vinculin binding site (VBS; residues 1944-1969). Like other talin rod polypeptides, it consists of a helical bundle, in this case a four-helix bundle with a right-handed topology. The residues in the VBS important for vinculin binding were identified by studying the binding of a series of VBS-related peptides to the vinculin Vd1 domain. The key binding determinants are buried in the interior of the helical bundle, suggesting that a substantial structural change in the talin polypeptide is required for vinculin binding. Direct evidence for this was obtained by NMR and EPR spectroscopy. [1H,15N]-HSQC spectra of the talin fragment indicate that vinculin binding caused approximately two-thirds of the protein to adopt a flexible random coil. For EPR spectroscopy, nitroxide spin labels were attached to the talin polypeptide via appropriately located cysteine residues. Measurements of inter-nitroxide distances in doubly spin-labeled protein showed clearly that the helical bundle is disrupted and the mobility of the helices, except for the VBS helix, is markedly increased. Binding of vinculin to talin is thus a clear example of the unusual phenomenon of protein unfolding being required for protein/protein interaction.", + "authors": { + "abbreviation": "Alexandre R Gingras, Klaus-Peter Vogel, Heinz-Jürgen Steinhoff, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Klaus-Peter", + "LastName": "Vogel", + "abbrevName": "Vogel KP", + "email": null, + "isCollectiveName": false, + "name": "Klaus-Peter Vogel" + }, + { + "ForeName": "Heinz-Jürgen", + "LastName": "Steinhoff", + "abbrevName": "Steinhoff HJ", + "email": null, + "isCollectiveName": false, + "name": "Heinz-Jürgen Steinhoff" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi052136l", + "pmid": "16460027", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 45 2006", + "title": "Structural and dynamic characterization of a vinculin binding site in the talin rod." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "20150896", + "pubmed": { + "ISODate": "2010-03-17T00:00:00.000Z", + "abstract": "Talin is a 270-kDa protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM domain comprised of F1, F2 and F3 domains, but it is atypical in that F1 contains a large insert and is preceded by an extra domain F0. Although F3 contains the binding site for beta-integrin tails, F0 and F1 are also required for activation of beta1-integrins. Here, we report the solution structures of F0, F1 and of the F0F1 double domain. Both F0 and F1 have ubiquitin-like folds joined in a novel fixed orientation by an extensive charged interface. The F1 insert forms a loop with helical propensity, and basic residues predicted to reside on one surface of the helix are required for binding to acidic phospholipids and for talin-mediated activation of beta1-integrins. This and the fact that basic residues on F2 and F3 are also essential for integrin activation suggest that extensive interactions between the talin FERM domain and acidic membrane phospholipids are required to orientate the FERM domain such that it can activate integrins.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, Paul R Elliott, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1038/emboj.2010.4", + "pmid": "20150896", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 29 2010", + "title": "Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation." + } + }, + { + "pmid": "10497223", + "pubmed": { + "ISODate": "1999-10-01T00:00:00.000Z", + "abstract": "Following platelet aggregation, integrin alpha(IIb)beta(3) becomes associated with the platelet cytoskeleton. The conserved NPLY sequence represents a potential beta-turn motif in the beta(3) cytoplasmic tail and has been suggested to mediate the interaction of beta(3) integrins with talin. In the present study, we performed a double mutation (N744Q/P745A) in the integrin beta(3) subunit to test the functional significance of this beta-turn motif. Chinese hamster ovary cells were co-transfected with cDNA constructs encoding mutant beta(3) and wild type alpha(IIb). Cells expressing either wild type (A5) or mutant (D4) alpha(IIb)beta(3) adhered to fibrinogen; however, as opposed to control A5 cells, adherent D4 cells failed to spread, form focal adhesions, or initiate protein tyrosine phosphorylation. To investigate the role of the NPLY motif in talin binding, we examined the ability of the mutant alpha(IIb)beta(3) to interact with talin in a solid phase binding assay. Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin. Additionally, purified talin failed to interact with peptides containing the AKWDTANNPLYK sequence indicating that the talin binding domain in the integrin beta(3) subunit does not reside in the NPLY motif. In contrast, specific binding of talin to peptides containing the membrane-proximal HDRKEFAKFEEERARAK sequence of the beta(3) cytoplasmic tail was observed, and this interaction was blocked by a recombinant protein fragment corresponding to the 47-kDa N-terminal head domain of talin (rTalin-N). In addition, RGD affinity purified platelet alpha(IIb)beta(3) bound dose-dependently to immobilized rTalin-N, indicating that an integrin-binding site is present in the talin N-terminal head domain. Collectively, these studies demonstrate that the NPLY beta-turn motif regulates post-ligand binding functions of alpha(IIb)beta(3) in a manner independent of talin interaction. Moreover, talin was shown to bind through its N-terminal head domain to the membrane-proximal sequence of the beta(3) cytoplasmic tail.", + "authors": { + "abbreviation": "S Patil, A Jedsadayanmata, J D Wencel-Drake, ..., S C Lam", + "authorList": [ + { + "ForeName": "S", + "LastName": "Patil", + "abbrevName": "Patil S", + "email": null, + "isCollectiveName": false, + "name": "S Patil" + }, + { + "ForeName": "A", + "LastName": "Jedsadayanmata", + "abbrevName": "Jedsadayanmata A", + "email": null, + "isCollectiveName": false, + "name": "A Jedsadayanmata" + }, + { + "ForeName": "J", + "LastName": "Wencel-Drake", + "abbrevName": "Wencel-Drake JD", + "email": null, + "isCollectiveName": false, + "name": "J D Wencel-Drake" + }, + { + "ForeName": "W", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "W Wang" + }, + { + "ForeName": "I", + "LastName": "Knezevic", + "abbrevName": "Knezevic I", + "email": null, + "isCollectiveName": false, + "name": "I Knezevic" + }, + { + "ForeName": "S", + "LastName": "Lam", + "abbrevName": "Lam SC", + "email": null, + "isCollectiveName": false, + "name": "S C Lam" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.274.40.28575", + "pmid": "10497223", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 274 1999", + "title": "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail." + } + }, + { + "pmid": "31393109", + "pubmed": { + "ISODate": "2019-11-26T00:00:00.000Z", + "abstract": "Mechanotransduction from the extracellular matrix into the cell is primarily supervised by a transmembrane receptor, integrin, and a cytosolic protein, talin. Integrin binds ligands on the extracellular side, whereas talin couples integrin receptors to the actin cytoskeleton and later acts as a \"force buffer\". Talin and integrin together form a mechanosensitive signaling hub that regulates crucial cellular processes and pathways, including cell signaling and formation of focal adhesion complexes, which help cells to sense their mechano-environment and transduce the signal accordingly. Although both proteins function in tandem, most literature focuses on them individually. Here, we provide a focused review of the talin-integrin mechano-interactome network in light of its role in the process of mechanotransduction and its connection to diseases. While working under force, these proteins drive numerous biomolecular interactions and form adhesion complexes, which in turn control many physiological processes such as cell migration; thus, they are invariably associated with several diseases from leukocyte adhesion deficiency to cancer. Gaining insights into their role in the occurrence of these pathological disorders might lead us to establish treatment methods and therapeutic techniques.", + "authors": { + "abbreviation": "Soham Chakraborty, Souradeep Banerjee, Manasven Raina, Shubhasis Haldar", + "authorList": [ + { + "ForeName": "Soham", + "LastName": "Chakraborty", + "abbrevName": "Chakraborty S", + "email": null, + "isCollectiveName": false, + "name": "Soham Chakraborty" + }, + { + "ForeName": "Souradeep", + "LastName": "Banerjee", + "abbrevName": "Banerjee S", + "email": null, + "isCollectiveName": false, + "name": "Souradeep Banerjee" + }, + { + "ForeName": "Manasven", + "LastName": "Raina", + "abbrevName": "Raina M", + "email": null, + "isCollectiveName": false, + "name": "Manasven Raina" + }, + { + "ForeName": "Shubhasis", + "LastName": "Haldar", + "abbrevName": "Haldar S", + "email": null, + "isCollectiveName": false, + "name": "Shubhasis Haldar" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.biochem.9b00442", + "pmid": "31393109", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochemistry 58 2019", + "title": "Force-Directed \"Mechanointeractome\" of Talin-Integrin." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "27603133", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The p17 protein of avian reovirus (ARV) causes cell cycle retardation in a variety of cell lines; however, the underlying mechanism(s) by which p17 regulates the cell cycle remains largely unknown. We demonstrate for the first time that p17 interacts with CDK1 and vimentin as revealed by reciprocal co-immunoprecipitation and GST pull-down assays. Both in vitro and in vivo studies indicated that direct interaction of p17 and CDK1/vimentin was mapped within the amino terminus (aa 1-60) of p17 and central region (aa 27-118) of CDK1/vimentin. Furthermore, p17 was found to occupy the Plk1-binding site within the vimentin, thereby blocking Plk1 recruitment to CDK1-induced vimentin phosphorylation at Ser 56. Interaction of p17 to CDK1 or vimentin interferes with CDK1-catalyzed phosphorylation of vimentin at Ser 56 and subsequently vimentin phosphorylation at Ser 82 by Plk1. Furthermore, we have identified upstream signaling pathways and cellular factor(s) targeted by p17 and found that p17 regulates inhibitory phosphorylation of CDK1 and blocks vimentin phosphorylation at Ser 56 and Ser 82. The p17-mediated inactivation of CDK1 is dependent on several mechanisms, which include direct interaction with CDK1, p17-mediated suppression of Plk1 by activating the Tpr/p53 and ATM/Chk1/PP2A pathways, and p17-mediated cdc25C degradation via an ubiquitin- proteasome pathway. Additionally, depletion of p53 with a shRNA as well as inhibition of ATM and vimentin by inhibitors diminished virus yield while Tpr and CDK1 knockdown increased virus yield. Taken together, results demonstrate that p17 suppresses both CDK1 and Plk1functions, disrupts vimentin phosphorylation, causes G2/M cell cycle arrest and thus benefits virus replication. ", + "authors": { + "abbreviation": "Hung-Chuan Chiu, Wei-Ru Huang, Tsai-Ling Liao, ..., Hung-Jen Liu", + "authorList": [ + { + "ForeName": "Hung-Chuan", + "LastName": "Chiu", + "abbrevName": "Chiu HC", + "email": null, + "isCollectiveName": false, + "name": "Hung-Chuan Chiu" + }, + { + "ForeName": "Wei-Ru", + "LastName": "Huang", + "abbrevName": "Huang WR", + "email": null, + "isCollectiveName": false, + "name": "Wei-Ru Huang" + }, + { + "ForeName": "Tsai-Ling", + "LastName": "Liao", + "abbrevName": "Liao TL", + "email": null, + "isCollectiveName": false, + "name": "Tsai-Ling Liao" + }, + { + "ForeName": "Hung-Yi", + "LastName": "Wu", + "abbrevName": "Wu HY", + "email": null, + "isCollectiveName": false, + "name": "Hung-Yi Wu" + }, + { + "ForeName": "Muhammad", + "LastName": "Munir", + "abbrevName": "Munir M", + "email": null, + "isCollectiveName": false, + "name": "Muhammad Munir" + }, + { + "ForeName": "Wing-Ling", + "LastName": "Shih", + "abbrevName": "Shih WL", + "email": null, + "isCollectiveName": false, + "name": "Wing-Ling Shih" + }, + { + "ForeName": "Hung-Jen", + "LastName": "Liu", + "abbrevName": "Liu HJ", + "email": null, + "isCollectiveName": false, + "name": "Hung-Jen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0162356", + "pmid": "27603133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 11 2016", + "title": "Suppression of Vimentin Phosphorylation by the Avian Reovirus p17 through Inhibition of CDK1 and Plk1 Impacting the G2/M Phase of the Cell Cycle." + } + }, + { + "pmid": "21658602", + "pubmed": { + "ISODate": "2011-06-10T00:00:00.000Z", + "abstract": "Cdk specificity is determined by the intrinsic selectivity of the active site and by substrate docking sites on the cyclin subunit. There is a long-standing debate about the relative importance of these factors in the timing of Cdk1 substrate phosphorylation. We analyzed major budding yeast cyclins (the G1/S-cyclin Cln2, S-cyclin Clb5, G2/M-cyclin Clb3, and M-cyclin Clb2) and found that the activity of Cdk1 toward the consensus motif increased gradually in the sequence Cln2-Clb5-Clb3-Clb2, in parallel with cell cycle progression. Further, we identified a docking element that compensates for the weak intrinsic specificity of Cln2 toward G1-specific targets. In addition, Cln2-Cdk1 showed distinct consensus site specificity, suggesting that cyclins do not merely activate Cdk1 but also modulate its active-site specificity. Finally, we identified several Cln2-, Clb3-, and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1.", + "authors": { + "abbreviation": "Mardo Kõivomägi, Ervin Valk, Rainis Venta, ..., Mart Loog", + "authorList": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "abbrevName": "Kõivomägi M", + "email": "mart.loog@ut.ee", + "isCollectiveName": false, + "name": "Mardo Kõivomägi" + }, + { + "ForeName": "Ervin", + "LastName": "Valk", + "abbrevName": "Valk E", + "email": null, + "isCollectiveName": false, + "name": "Ervin Valk" + }, + { + "ForeName": "Rainis", + "LastName": "Venta", + "abbrevName": "Venta R", + "email": null, + "isCollectiveName": false, + "name": "Rainis Venta" + }, + { + "ForeName": "Anna", + "LastName": "Iofik", + "abbrevName": "Iofik A", + "email": null, + "isCollectiveName": false, + "name": "Anna Iofik" + }, + { + "ForeName": "Martin", + "LastName": "Lepiku", + "abbrevName": "Lepiku M", + "email": null, + "isCollectiveName": false, + "name": "Martin Lepiku" + }, + { + "ForeName": "David", + "LastName": "Morgan", + "abbrevName": "Morgan DO", + "email": null, + "isCollectiveName": false, + "name": "David O Morgan" + }, + { + "ForeName": "Mart", + "LastName": "Loog", + "abbrevName": "Loog M", + "email": null, + "isCollectiveName": false, + "name": "Mart Loog" + } + ], + "contacts": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "email": [ + "mart.loog@ut.ee" + ], + "name": "Mardo Kõivomägi" + } + ] + }, + "doi": "10.1016/j.molcel.2011.05.016", + "pmid": "21658602", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Dynamics of Cdk1 substrate specificity during the cell cycle." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": true + } + ], + "element": [ + { + "_creationTimestamp": "2022-02-01T19:42:45.182Z", + "_newestOpId": "c66549e8-c309-452d-adf8-5bddd0d2486b", + "_ops": [], + "association": "phosphorylation", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "e70f848c-4670-460b-932c-0cc788d0b5d5" + }, + { + "group": "unsigned", + "id": "65414935-0004-44be-9c0a-3e8945acde43" + } + ], + "id": "3e7c85db-c2a3-4a1f-b96e-6d187c6ab93b", + "liveId": "05bd36fe-08e5-41a8-9663-9a3d0591c9d6", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": -246.01265822784816, + "y": -79.83122362869202 + }, + "relatedPapers": [ + { + "pmid": "10497223", + "pubmed": { + "ISODate": "1999-10-01T00:00:00.000Z", + "abstract": "Following platelet aggregation, integrin alpha(IIb)beta(3) becomes associated with the platelet cytoskeleton. The conserved NPLY sequence represents a potential beta-turn motif in the beta(3) cytoplasmic tail and has been suggested to mediate the interaction of beta(3) integrins with talin. In the present study, we performed a double mutation (N744Q/P745A) in the integrin beta(3) subunit to test the functional significance of this beta-turn motif. Chinese hamster ovary cells were co-transfected with cDNA constructs encoding mutant beta(3) and wild type alpha(IIb). Cells expressing either wild type (A5) or mutant (D4) alpha(IIb)beta(3) adhered to fibrinogen; however, as opposed to control A5 cells, adherent D4 cells failed to spread, form focal adhesions, or initiate protein tyrosine phosphorylation. To investigate the role of the NPLY motif in talin binding, we examined the ability of the mutant alpha(IIb)beta(3) to interact with talin in a solid phase binding assay. Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin. Additionally, purified talin failed to interact with peptides containing the AKWDTANNPLYK sequence indicating that the talin binding domain in the integrin beta(3) subunit does not reside in the NPLY motif. In contrast, specific binding of talin to peptides containing the membrane-proximal HDRKEFAKFEEERARAK sequence of the beta(3) cytoplasmic tail was observed, and this interaction was blocked by a recombinant protein fragment corresponding to the 47-kDa N-terminal head domain of talin (rTalin-N). In addition, RGD affinity purified platelet alpha(IIb)beta(3) bound dose-dependently to immobilized rTalin-N, indicating that an integrin-binding site is present in the talin N-terminal head domain. Collectively, these studies demonstrate that the NPLY beta-turn motif regulates post-ligand binding functions of alpha(IIb)beta(3) in a manner independent of talin interaction. Moreover, talin was shown to bind through its N-terminal head domain to the membrane-proximal sequence of the beta(3) cytoplasmic tail.", + "authors": { + "abbreviation": "S Patil, A Jedsadayanmata, J D Wencel-Drake, ..., S C Lam", + "authorList": [ + { + "ForeName": "S", + "LastName": "Patil", + "abbrevName": "Patil S", + "email": null, + "isCollectiveName": false, + "name": "S Patil" + }, + { + "ForeName": "A", + "LastName": "Jedsadayanmata", + "abbrevName": "Jedsadayanmata A", + "email": null, + "isCollectiveName": false, + "name": "A Jedsadayanmata" + }, + { + "ForeName": "J", + "LastName": "Wencel-Drake", + "abbrevName": "Wencel-Drake JD", + "email": null, + "isCollectiveName": false, + "name": "J D Wencel-Drake" + }, + { + "ForeName": "W", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "W Wang" + }, + { + "ForeName": "I", + "LastName": "Knezevic", + "abbrevName": "Knezevic I", + "email": null, + "isCollectiveName": false, + "name": "I Knezevic" + }, + { + "ForeName": "S", + "LastName": "Lam", + "abbrevName": "Lam SC", + "email": null, + "isCollectiveName": false, + "name": "S C Lam" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.274.40.28575", + "pmid": "10497223", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 274 1999", + "title": "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail." + } + }, + { + "pmid": "17430904", + "pubmed": { + "ISODate": "2007-06-08T00:00:00.000Z", + "abstract": "Talin1 is a large cytoskeletal protein that links integrins to actin filaments through two distinct integrin binding sites, one present in the talin head domain (IBS1) necessary for integrin activation and a second (IBS2) that we have previously mapped to talin residues 1984-2113 (fragment J) of the talin rod domain (1 Tremuth, L., Kreis, S., Melchior, C., Hoebeke, J., Ronde, P., Plancon, S., Takeda, K., and Kieffer, N. (2004) J. Biol. Chem. 279, 22258-22266), but whose functional role is still elusive. Using a bioinformatics and cell biology approach, we have determined the minimal structure of IBS2 and show that this integrin binding site corresponds to 23 residues located in alpha helix 50 of the talin rod domain (residues 2077-2099). Alanine mutation of 2 highly conserved residues (L2094A/I2095A) within this alpha helix, which disrupted the alpha-helical structure of IBS2 as demonstrated by infrared spectroscopy and limited trypsin proteolysis, was sufficient to prevent in vivo talin fragment J targeting to alphaIIbbeta3 integrin in focal adhesions and to inhibit in vitro this association as shown by an alphaIIbbeta3 pulldown assay. Moreover, expression of a full-length mouse green fluorescent protein-talin LI/AA mutant in mouse talin1(-/-) cells was unable to rescue the inability of these cells to assemble focal adhesions (in contrast to green fluorescent protein-talin wild type) despite the presence of IBS1. Our data provide the first direct evidence that IBS2 in the talin rod is essential to link integrins to the cytoskeleton.", + "authors": { + "abbreviation": "Michèle Moes, Sophie Rodius, Stacey J Coleman, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Michèle", + "LastName": "Moes", + "abbrevName": "Moes M", + "email": null, + "isCollectiveName": false, + "name": "Michèle Moes" + }, + { + "ForeName": "Sophie", + "LastName": "Rodius", + "abbrevName": "Rodius S", + "email": null, + "isCollectiveName": false, + "name": "Sophie Rodius" + }, + { + "ForeName": "Stacey", + "LastName": "Coleman", + "abbrevName": "Coleman SJ", + "email": null, + "isCollectiveName": false, + "name": "Stacey J Coleman" + }, + { + "ForeName": "Susan", + "LastName": "Monkley", + "abbrevName": "Monkley SJ", + "email": null, + "isCollectiveName": false, + "name": "Susan J Monkley" + }, + { + "ForeName": "Erik", + "LastName": "Goormaghtigh", + "abbrevName": "Goormaghtigh E", + "email": null, + "isCollectiveName": false, + "name": "Erik Goormaghtigh" + }, + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Corinne", + "LastName": "Kox", + "abbrevName": "Kox C", + "email": null, + "isCollectiveName": false, + "name": "Corinne Kox" + }, + { + "ForeName": "Patrick", + "LastName": "van der Holst", + "abbrevName": "van der Holst PP", + "email": null, + "isCollectiveName": false, + "name": "Patrick P G van der Holst" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M611846200", + "pmid": "17430904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 282 2007", + "title": "The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin beta subunits to the cytoskeleton." + } + }, + { + "pmid": "16081423", + "pubmed": { + "ISODate": "2005-09-23T00:00:00.000Z", + "abstract": "Previous experiments with peptide fusion proteins suggested that cyclin A/Cdk1 and Cdk2 might exhibit similar yet distinct phosphorylation specificities. Using a physiological substrate, CDP/Cux, our study confirms this notion. Proteolytic processing of CDP/Cux by cathepsin L generates the CDP/Cux p110 isoform at the beginning of S phase. CDP/Cux p110 makes stable interactions with DNA during S phase but is inhibited in G2 following the phosphorylation of serine 1237 by cyclin A/Cdk1. In this study, we propose that differential phosphorylation by cyclin A/Cdk1 and cyclin A/Cdk2 enables CDP/Cux p110 to exert its function as a transcriptional regulator specifically during S phase. We found that like cyclin A/Cdk1, cyclin A/Cdk2 interacted efficiently with recombinant CDP/Cux proteins that contain the Cut homeodomain and an adjacent cyclin-binding motif (Cy). In contrast to cyclin A/Cdk1, however, cyclin A/Cdk2 did not efficiently phosphorylate CDP/Cux p110 on serine 1237 and did not inhibit its DNA binding activity in vitro. Accordingly, co-expression with cyclin A/Cdk2 in cells did not inhibit the DNA binding and transcriptional activities of CDP/Cux p110. To confirm that the sequence surrounding serine 1237 was responsible for the differential regulation by Cdk1 and Cdk2, we replaced 4 amino acids flanking the phosphorylation site to mimic a known Cdk2 phosphorylation site present in the Cdc6 protein. Both cyclin A/Cdk2 and Cdk1 efficiently phosphorylated the CDP/Cux(Cdc6) mutant and inhibited its DNA binding activity. Altogether our results help explain why the DNA binding activity of CDP/Cux p110 is maximal during S phase and decreases in G2 phase.", + "authors": { + "abbreviation": "Marianne Santaguida, Alain Nepveu", + "authorList": [ + { + "ForeName": "Marianne", + "LastName": "Santaguida", + "abbrevName": "Santaguida M", + "email": null, + "isCollectiveName": false, + "name": "Marianne Santaguida" + }, + { + "ForeName": "Alain", + "LastName": "Nepveu", + "abbrevName": "Nepveu A", + "email": null, + "isCollectiveName": false, + "name": "Alain Nepveu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M505417200", + "pmid": "16081423", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Differential regulation of CDP/Cux p110 by cyclin A/Cdk2 and cyclin A/Cdk1." + } + }, + { + "pmid": "20150896", + "pubmed": { + "ISODate": "2010-03-17T00:00:00.000Z", + "abstract": "Talin is a 270-kDa protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM domain comprised of F1, F2 and F3 domains, but it is atypical in that F1 contains a large insert and is preceded by an extra domain F0. Although F3 contains the binding site for beta-integrin tails, F0 and F1 are also required for activation of beta1-integrins. Here, we report the solution structures of F0, F1 and of the F0F1 double domain. Both F0 and F1 have ubiquitin-like folds joined in a novel fixed orientation by an extensive charged interface. The F1 insert forms a loop with helical propensity, and basic residues predicted to reside on one surface of the helix are required for binding to acidic phospholipids and for talin-mediated activation of beta1-integrins. This and the fact that basic residues on F2 and F3 are also essential for integrin activation suggest that extensive interactions between the talin FERM domain and acidic membrane phospholipids are required to orientate the FERM domain such that it can activate integrins.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, Paul R Elliott, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1038/emboj.2010.4", + "pmid": "20150896", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 29 2010", + "title": "Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation." + } + }, + { + "pmid": "18550856", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Leukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (K(d), 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (K(d), 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated beta2 integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion.", + "authors": { + "abbreviation": "Heikki Takala, Elisa Nurminen, Susanna M Nurmi, ..., Susanna C Fagerholm", + "authorList": [ + { + "ForeName": "Heikki", + "LastName": "Takala", + "abbrevName": "Takala H", + "email": null, + "isCollectiveName": false, + "name": "Heikki Takala" + }, + { + "ForeName": "Elisa", + "LastName": "Nurminen", + "abbrevName": "Nurminen E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Nurminen" + }, + { + "ForeName": "Susanna", + "LastName": "Nurmi", + "abbrevName": "Nurmi SM", + "email": null, + "isCollectiveName": false, + "name": "Susanna M Nurmi" + }, + { + "ForeName": "Maria", + "LastName": "Aatonen", + "abbrevName": "Aatonen M", + "email": null, + "isCollectiveName": false, + "name": "Maria Aatonen" + }, + { + "ForeName": "Tomas", + "LastName": "Strandin", + "abbrevName": "Strandin T", + "email": null, + "isCollectiveName": false, + "name": "Tomas Strandin" + }, + { + "ForeName": "Maarit", + "LastName": "Takatalo", + "abbrevName": "Takatalo M", + "email": null, + "isCollectiveName": false, + "name": "Maarit Takatalo" + }, + { + "ForeName": "Tiila", + "LastName": "Kiema", + "abbrevName": "Kiema T", + "email": null, + "isCollectiveName": false, + "name": "Tiila Kiema" + }, + { + "ForeName": "Carl", + "LastName": "Gahmberg", + "abbrevName": "Gahmberg CG", + "email": null, + "isCollectiveName": false, + "name": "Carl G Gahmberg" + }, + { + "ForeName": "Jari", + "LastName": "Ylänne", + "abbrevName": "Ylänne J", + "email": null, + "isCollectiveName": false, + "name": "Jari Ylänne" + }, + { + "ForeName": "Susanna", + "LastName": "Fagerholm", + "abbrevName": "Fagerholm SC", + "email": null, + "isCollectiveName": false, + "name": "Susanna C Fagerholm" + } + ], + "contacts": [] + }, + "doi": "10.1182/blood-2007-12-127795", + "pmid": "18550856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Blood 112 2008", + "title": "Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding." + } + }, + { + "pmid": "29930204", + "pubmed": { + "ISODate": "2018-09-03T00:00:00.000Z", + "abstract": "In most tissues, anchorage-dependent growth and cell cycle progression are dependent on cells engaging extracellular matrices (ECMs) via integrin-receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings before division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell adhesion to the ECM. In this study, we demonstrate that cyclin-dependent kinase 1 (CDK1) mediates this link. CDK1, in complex with cyclin A2, promotes adhesion complex and actin cytoskeleton organization during interphase and mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area decreases in G2, and disassembly occurs several hours before mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1 is therefore the trigger that initiates remodeling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.", + "authors": { + "abbreviation": "Matthew C Jones, Janet A Askari, Jonathan D Humphries, Martin J Humphries", + "authorList": [ + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1083/jcb.201802088", + "pmid": "29930204", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Cell adhesion is regulated by CDK1 during the cell cycle." + } + }, + { + "pmid": "11591813", + "pubmed": { + "ISODate": "2001-09-01T00:00:00.000Z", + "abstract": "Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.", + "authors": { + "abbreviation": "C R Carlson, O Witczak, L Vossebein, ..., K Taskén", + "authorList": [ + { + "ForeName": "C", + "LastName": "Carlson", + "abbrevName": "Carlson CR", + "email": "cathrine.carlson@basalmed.uio.no", + "isCollectiveName": false, + "name": "C R Carlson" + }, + { + "ForeName": "O", + "LastName": "Witczak", + "abbrevName": "Witczak O", + "email": null, + "isCollectiveName": false, + "name": "O Witczak" + }, + { + "ForeName": "L", + "LastName": "Vossebein", + "abbrevName": "Vossebein L", + "email": null, + "isCollectiveName": false, + "name": "L Vossebein" + }, + { + "ForeName": "J", + "LastName": "Labbé", + "abbrevName": "Labbé JC", + "email": null, + "isCollectiveName": false, + "name": "J C Labbé" + }, + { + "ForeName": "B", + "LastName": "Skålhegg", + "abbrevName": "Skålhegg BS", + "email": null, + "isCollectiveName": false, + "name": "B S Skålhegg" + }, + { + "ForeName": "G", + "LastName": "Keryer", + "abbrevName": "Keryer G", + "email": null, + "isCollectiveName": false, + "name": "G Keryer" + }, + { + "ForeName": "F", + "LastName": "Herberg", + "abbrevName": "Herberg FW", + "email": null, + "isCollectiveName": false, + "name": "F W Herberg" + }, + { + "ForeName": "P", + "LastName": "Collas", + "abbrevName": "Collas P", + "email": null, + "isCollectiveName": false, + "name": "P Collas" + }, + { + "ForeName": "K", + "LastName": "Taskén", + "abbrevName": "Taskén K", + "email": null, + "isCollectiveName": false, + "name": "K Taskén" + } + ], + "contacts": [ + { + "ForeName": "C", + "LastName": "Carlson", + "email": [ + "cathrine.carlson@basalmed.uio.no" + ], + "name": "C R Carlson" + } + ] + }, + "doi": "10.1242/jcs.114.18.3243", + "pmid": "11591813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 114 2001", + "title": "CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "27252130", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellular matrix (ECM) via its connection with the actin cytoskeleton and membrane integrins. It is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the field of mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as well as its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival. New data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states.-Haining, A. W. M., Lieberthal, T. J., del Río Hernández, A. Talin: a mechanosensitive molecule in health and disease.", + "authors": { + "abbreviation": "Alexander W M Haining, Tyler J Lieberthal, Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AW", + "email": null, + "isCollectiveName": false, + "name": "Alexander W M Haining" + }, + { + "ForeName": "Tyler", + "LastName": "Lieberthal", + "abbrevName": "Lieberthal TJ", + "email": null, + "isCollectiveName": false, + "name": "Tyler J Lieberthal" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": "a.del-rio-hernandez@imperial.ac.uk", + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [ + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "email": [ + "a.del-rio-hernandez@imperial.ac.uk" + ], + "name": "Armando Del Río Hernández" + } + ] + }, + "doi": "10.1096/fj.201500080R", + "pmid": "27252130", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FASEB J 30 2016", + "title": "Talin: a mechanosensitive molecule in health and disease." + } + }, + { + "pmid": "31393109", + "pubmed": { + "ISODate": "2019-11-26T00:00:00.000Z", + "abstract": "Mechanotransduction from the extracellular matrix into the cell is primarily supervised by a transmembrane receptor, integrin, and a cytosolic protein, talin. Integrin binds ligands on the extracellular side, whereas talin couples integrin receptors to the actin cytoskeleton and later acts as a \"force buffer\". Talin and integrin together form a mechanosensitive signaling hub that regulates crucial cellular processes and pathways, including cell signaling and formation of focal adhesion complexes, which help cells to sense their mechano-environment and transduce the signal accordingly. Although both proteins function in tandem, most literature focuses on them individually. Here, we provide a focused review of the talin-integrin mechano-interactome network in light of its role in the process of mechanotransduction and its connection to diseases. While working under force, these proteins drive numerous biomolecular interactions and form adhesion complexes, which in turn control many physiological processes such as cell migration; thus, they are invariably associated with several diseases from leukocyte adhesion deficiency to cancer. Gaining insights into their role in the occurrence of these pathological disorders might lead us to establish treatment methods and therapeutic techniques.", + "authors": { + "abbreviation": "Soham Chakraborty, Souradeep Banerjee, Manasven Raina, Shubhasis Haldar", + "authorList": [ + { + "ForeName": "Soham", + "LastName": "Chakraborty", + "abbrevName": "Chakraborty S", + "email": null, + "isCollectiveName": false, + "name": "Soham Chakraborty" + }, + { + "ForeName": "Souradeep", + "LastName": "Banerjee", + "abbrevName": "Banerjee S", + "email": null, + "isCollectiveName": false, + "name": "Souradeep Banerjee" + }, + { + "ForeName": "Manasven", + "LastName": "Raina", + "abbrevName": "Raina M", + "email": null, + "isCollectiveName": false, + "name": "Manasven Raina" + }, + { + "ForeName": "Shubhasis", + "LastName": "Haldar", + "abbrevName": "Haldar S", + "email": null, + "isCollectiveName": false, + "name": "Shubhasis Haldar" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.biochem.9b00442", + "pmid": "31393109", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochemistry 58 2019", + "title": "Force-Directed \"Mechanointeractome\" of Talin-Integrin." + } + }, + { + "pmid": "27603133", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The p17 protein of avian reovirus (ARV) causes cell cycle retardation in a variety of cell lines; however, the underlying mechanism(s) by which p17 regulates the cell cycle remains largely unknown. We demonstrate for the first time that p17 interacts with CDK1 and vimentin as revealed by reciprocal co-immunoprecipitation and GST pull-down assays. Both in vitro and in vivo studies indicated that direct interaction of p17 and CDK1/vimentin was mapped within the amino terminus (aa 1-60) of p17 and central region (aa 27-118) of CDK1/vimentin. Furthermore, p17 was found to occupy the Plk1-binding site within the vimentin, thereby blocking Plk1 recruitment to CDK1-induced vimentin phosphorylation at Ser 56. Interaction of p17 to CDK1 or vimentin interferes with CDK1-catalyzed phosphorylation of vimentin at Ser 56 and subsequently vimentin phosphorylation at Ser 82 by Plk1. Furthermore, we have identified upstream signaling pathways and cellular factor(s) targeted by p17 and found that p17 regulates inhibitory phosphorylation of CDK1 and blocks vimentin phosphorylation at Ser 56 and Ser 82. The p17-mediated inactivation of CDK1 is dependent on several mechanisms, which include direct interaction with CDK1, p17-mediated suppression of Plk1 by activating the Tpr/p53 and ATM/Chk1/PP2A pathways, and p17-mediated cdc25C degradation via an ubiquitin- proteasome pathway. Additionally, depletion of p53 with a shRNA as well as inhibition of ATM and vimentin by inhibitors diminished virus yield while Tpr and CDK1 knockdown increased virus yield. Taken together, results demonstrate that p17 suppresses both CDK1 and Plk1functions, disrupts vimentin phosphorylation, causes G2/M cell cycle arrest and thus benefits virus replication. ", + "authors": { + "abbreviation": "Hung-Chuan Chiu, Wei-Ru Huang, Tsai-Ling Liao, ..., Hung-Jen Liu", + "authorList": [ + { + "ForeName": "Hung-Chuan", + "LastName": "Chiu", + "abbrevName": "Chiu HC", + "email": null, + "isCollectiveName": false, + "name": "Hung-Chuan Chiu" + }, + { + "ForeName": "Wei-Ru", + "LastName": "Huang", + "abbrevName": "Huang WR", + "email": null, + "isCollectiveName": false, + "name": "Wei-Ru Huang" + }, + { + "ForeName": "Tsai-Ling", + "LastName": "Liao", + "abbrevName": "Liao TL", + "email": null, + "isCollectiveName": false, + "name": "Tsai-Ling Liao" + }, + { + "ForeName": "Hung-Yi", + "LastName": "Wu", + "abbrevName": "Wu HY", + "email": null, + "isCollectiveName": false, + "name": "Hung-Yi Wu" + }, + { + "ForeName": "Muhammad", + "LastName": "Munir", + "abbrevName": "Munir M", + "email": null, + "isCollectiveName": false, + "name": "Muhammad Munir" + }, + { + "ForeName": "Wing-Ling", + "LastName": "Shih", + "abbrevName": "Shih WL", + "email": null, + "isCollectiveName": false, + "name": "Wing-Ling Shih" + }, + { + "ForeName": "Hung-Jen", + "LastName": "Liu", + "abbrevName": "Liu HJ", + "email": null, + "isCollectiveName": false, + "name": "Hung-Jen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0162356", + "pmid": "27603133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 11 2016", + "title": "Suppression of Vimentin Phosphorylation by the Avian Reovirus p17 through Inhibition of CDK1 and Plk1 Impacting the G2/M Phase of the Cell Cycle." + } + }, + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "16648844", + "pubmed": { + "ISODate": "2006-06-01T00:00:00.000Z", + "abstract": "Transmembrane adhesion receptors, such as integrins, mediate cell adhesion by interacting with intracellular proteins that connect to the cytoskeleton. Talin, one such linker protein, is thought to have two roles: mediating inside-out activation of integrins, and connecting extracellular matrix (ECM)-bound integrins to the cytoskeleton. Talin's amino-terminal head, which consists of a FERM domain, binds an NPxY motif within the cytoplasmic tail of most integrin beta subunits. This is consistent with the role of FERM domains in recruiting other proteins to the plasma membrane. We tested the role of the talin-head-NPxY interaction in integrin function in Drosophila. We found that introduction of a mutation that perturbs this binding in vitro into the isolated talin head disrupts its recruitment by integrins in vivo. Surprisingly, when engineered into the full-length talin, this mutation did not disrupt talin recruitment by integrins nor its ability to connect integrins to the cytoskeleton. However, it reduced the ability of talin to strengthen integrin adhesion to the ECM, indicating that the function of the talin-head-NPxY interaction is solely to regulate integrin adhesion.", + "authors": { + "abbreviation": "Guy Tanentzapf, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": null, + "isCollectiveName": false, + "name": "Guy Tanentzapf" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1411", + "pmid": "16648844", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 8 2006", + "title": "An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "15031296", + "pubmed": { + "ISODate": "2004-05-21T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which provides a direct link between integrins and actin filaments, has been shown to contain two distinct binding sites for integrin beta subunits. Here, we report the precise delimitation and a first functional analysis of the talin rod domain integrin-binding site. Partially overlapping cDNAs covering the entire human talin gene were transiently expressed as DsRed fusion proteins in Chinese hamster ovary cells expressing alpha(IIb)beta(3), linked to green fluorescent protein (GFP). Two-color fluorescence analysis of the transfected cells, spread on fibrinogen, revealed distinct subcellular staining patterns including focal adhesion, actin filament, and granular labeling for different talin fragments. The rod domain fragment G (residues 1984-2344), devoid of any known actin- or vinculin-binding sites, colocalized with beta(3)-GFP in focal adhesions. Direct in vitro interaction of fragment G with native platelet integrin alpha(IIb)beta(3) or with the recombinant wild type, but not the Y747A mutant beta(3) cytoplasmic tail, linked to glutathione S-transferase, was demonstrated by surface plasmon resonance analysis and pull-down assays, respectively. Here, we demonstrate for the first time the in vivo relevance of this interaction by fluorescence resonance energy transfer between beta(3)-GFP and DsRed-talin fragment G. Further in vitro pull-down studies allowed us to map out the integrin-binding site within fragment G to a stretch of 130 residues (fragment J, residues 1984-2113) that also localized to focal adhesions. Finally, we show by a cell biology approach that this integrin-binding site within the talin rod domain is important for beta(3)-cytoskeletal interactions but does not participate in alpha(IIb)beta(3) activation.", + "authors": { + "abbreviation": "Laurent Tremuth, Stephanie Kreis, Chantal Melchior, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Stephanie", + "LastName": "Kreis", + "abbrevName": "Kreis S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kreis" + }, + { + "ForeName": "Chantal", + "LastName": "Melchior", + "abbrevName": "Melchior C", + "email": null, + "isCollectiveName": false, + "name": "Chantal Melchior" + }, + { + "ForeName": "Johan", + "LastName": "Hoebeke", + "abbrevName": "Hoebeke J", + "email": null, + "isCollectiveName": false, + "name": "Johan Hoebeke" + }, + { + "ForeName": "Philippe", + "LastName": "Rondé", + "abbrevName": "Rondé P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Rondé" + }, + { + "ForeName": "Sébastien", + "LastName": "Plançon", + "abbrevName": "Plançon S", + "email": null, + "isCollectiveName": false, + "name": "Sébastien Plançon" + }, + { + "ForeName": "Kenneth", + "LastName": "Takeda", + "abbrevName": "Takeda K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Takeda" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M400947200", + "pmid": "15031296", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A fluorescence cell biology approach to map the second integrin-binding site of talin to a 130-amino acid sequence within the rod domain." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "21658602", + "pubmed": { + "ISODate": "2011-06-10T00:00:00.000Z", + "abstract": "Cdk specificity is determined by the intrinsic selectivity of the active site and by substrate docking sites on the cyclin subunit. There is a long-standing debate about the relative importance of these factors in the timing of Cdk1 substrate phosphorylation. We analyzed major budding yeast cyclins (the G1/S-cyclin Cln2, S-cyclin Clb5, G2/M-cyclin Clb3, and M-cyclin Clb2) and found that the activity of Cdk1 toward the consensus motif increased gradually in the sequence Cln2-Clb5-Clb3-Clb2, in parallel with cell cycle progression. Further, we identified a docking element that compensates for the weak intrinsic specificity of Cln2 toward G1-specific targets. In addition, Cln2-Cdk1 showed distinct consensus site specificity, suggesting that cyclins do not merely activate Cdk1 but also modulate its active-site specificity. Finally, we identified several Cln2-, Clb3-, and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1.", + "authors": { + "abbreviation": "Mardo Kõivomägi, Ervin Valk, Rainis Venta, ..., Mart Loog", + "authorList": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "abbrevName": "Kõivomägi M", + "email": "mart.loog@ut.ee", + "isCollectiveName": false, + "name": "Mardo Kõivomägi" + }, + { + "ForeName": "Ervin", + "LastName": "Valk", + "abbrevName": "Valk E", + "email": null, + "isCollectiveName": false, + "name": "Ervin Valk" + }, + { + "ForeName": "Rainis", + "LastName": "Venta", + "abbrevName": "Venta R", + "email": null, + "isCollectiveName": false, + "name": "Rainis Venta" + }, + { + "ForeName": "Anna", + "LastName": "Iofik", + "abbrevName": "Iofik A", + "email": null, + "isCollectiveName": false, + "name": "Anna Iofik" + }, + { + "ForeName": "Martin", + "LastName": "Lepiku", + "abbrevName": "Lepiku M", + "email": null, + "isCollectiveName": false, + "name": "Martin Lepiku" + }, + { + "ForeName": "David", + "LastName": "Morgan", + "abbrevName": "Morgan DO", + "email": null, + "isCollectiveName": false, + "name": "David O Morgan" + }, + { + "ForeName": "Mart", + "LastName": "Loog", + "abbrevName": "Loog M", + "email": null, + "isCollectiveName": false, + "name": "Mart Loog" + } + ], + "contacts": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "email": [ + "mart.loog@ut.ee" + ], + "name": "Mardo Kõivomägi" + } + ] + }, + "doi": "10.1016/j.molcel.2011.05.016", + "pmid": "21658602", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Dynamics of Cdk1 substrate specificity during the cell cycle." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "19948488", + "pubmed": { + "ISODate": "2009-11-30T00:00:00.000Z", + "abstract": "Integrin-dependent adhesion sites consist of clustered integrins that transmit mechanical forces and provide signaling required for cell survival and morphogenesis. Despite their importance, the regulation of integrin clustering by the cytoplasmic adapter protein talin (Tal) and phosphatidylinositol (PI)-4,5-biphosphate (PI(4,5)P(2)) lipids nor their dynamic coupling to the actin cytoskeleton is fully understood. By using a Tal-dependent integrin clustering assay in intact cells, we identified a PI(4,5)P(2)-binding basic ridge spanning across the F2 and F3 domains of the Tal head that regulates integrin clustering. Clustering requires a new PI(4,5)P(2)-binding site in F2 and is negatively regulated by autoinhibitory interactions between F3 and the Tal rod (Tal-R). The release of the Tal-R exposes a new beta3-integrin-binding site in F3, enabling interaction with a membrane proximal acidic motif, which involves the formation of salt bridges between K(316) and K(324) with E(726) and D(723), respectively. This interaction shields the beta-integrin tail from reassociation with its alpha subunit, thereby maintaining the integrin in a substrate-binding and clustering-competent form.", + "authors": { + "abbreviation": "Frédéric Saltel, Eva Mortier, Vesa P Hytönen, ..., Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Frédéric", + "LastName": "Saltel", + "abbrevName": "Saltel F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Saltel" + }, + { + "ForeName": "Eva", + "LastName": "Mortier", + "abbrevName": "Mortier E", + "email": null, + "isCollectiveName": false, + "name": "Eva Mortier" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Marie-Claude", + "LastName": "Jacquier", + "abbrevName": "Jacquier MC", + "email": null, + "isCollectiveName": false, + "name": "Marie-Claude Jacquier" + }, + { + "ForeName": "Pascale", + "LastName": "Zimmermann", + "abbrevName": "Zimmermann P", + "email": null, + "isCollectiveName": false, + "name": "Pascale Zimmermann" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": null, + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200908134", + "pmid": "19948488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 187 2009", + "title": "New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering." + } + }, + { + "pmid": "28701514", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and Drosophila to present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.", + "authors": { + "abbreviation": "Benjamin Klapholz, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": "nb117@cam.ac.uk", + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Brown", + "email": [ + "nb117@cam.ac.uk" + ], + "name": "Nicholas H Brown" + } + ] + }, + "doi": "10.1242/jcs.190991", + "pmid": "28701514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "Talin - the master of integrin adhesions." + } + }, + { + "pmid": "16135522", + "pubmed": { + "ISODate": "2005-11-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. Three vinculin binding sites (VBS1-3) have previously been identified in the talin rod using a yeast two-hybrid assay. To extend these studies, we spot-synthesized a series of peptides spanning all the alpha-helical regions predicted for the talin rod and identified eight additional VBSs, two of which overlap key functional regions of the rod, including the integrin binding site and C-terminal actin binding site. The talin VBS alpha-helices bind to a hydrophobic cleft in the N-terminal vinculin Vd1 domain. We have defined the specificity of this interaction by spot-synthesizing a series of 25-mer talin VBS1 peptides containing substitutions with all the commonly occurring amino acids. The consensus for recognition is LXXAAXXVAXX- VXXLIXXA with distinct classes of hydrophobic side chains at positions 1, 4, 5, 8, 9, 12, 15, and 16 required for vinculin binding. Positions 1, 8, 12, 15, and 16 require an aliphatic residue and will not tolerate alanine, whereas positions 4, 5, and 9 are less restrictive. These preferences are common to all 11 VBS sequences with a minor variation occurring in one case. A crystal structure of this variant VBS peptide in complex with the vinculin Vd1 domain reveals a subtly different mode of vinculin binding.", + "authors": { + "abbreviation": "Alexandre R Gingras, Wolfgang H Ziegler, Ronald Frank, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M508060200", + "pmid": "16135522", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod." + } + }, + { + "pmid": "16460027", + "pubmed": { + "ISODate": "2006-02-14T00:00:00.000Z", + "abstract": "Talin is a key protein involved in linking integrins to the actin cytoskeleton. The long flexible talin rod domain contains a number of binding sites for vinculin, a cytoskeletal protein important in stabilizing integrin-mediated cell-matrix junctions. Here we report the solution structure of a talin rod polypeptide (residues 1843-1973) which contains a single vinculin binding site (VBS; residues 1944-1969). Like other talin rod polypeptides, it consists of a helical bundle, in this case a four-helix bundle with a right-handed topology. The residues in the VBS important for vinculin binding were identified by studying the binding of a series of VBS-related peptides to the vinculin Vd1 domain. The key binding determinants are buried in the interior of the helical bundle, suggesting that a substantial structural change in the talin polypeptide is required for vinculin binding. Direct evidence for this was obtained by NMR and EPR spectroscopy. [1H,15N]-HSQC spectra of the talin fragment indicate that vinculin binding caused approximately two-thirds of the protein to adopt a flexible random coil. For EPR spectroscopy, nitroxide spin labels were attached to the talin polypeptide via appropriately located cysteine residues. Measurements of inter-nitroxide distances in doubly spin-labeled protein showed clearly that the helical bundle is disrupted and the mobility of the helices, except for the VBS helix, is markedly increased. Binding of vinculin to talin is thus a clear example of the unusual phenomenon of protein unfolding being required for protein/protein interaction.", + "authors": { + "abbreviation": "Alexandre R Gingras, Klaus-Peter Vogel, Heinz-Jürgen Steinhoff, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Klaus-Peter", + "LastName": "Vogel", + "abbrevName": "Vogel KP", + "email": null, + "isCollectiveName": false, + "name": "Klaus-Peter Vogel" + }, + { + "ForeName": "Heinz-Jürgen", + "LastName": "Steinhoff", + "abbrevName": "Steinhoff HJ", + "email": null, + "isCollectiveName": false, + "name": "Heinz-Jürgen Steinhoff" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi052136l", + "pmid": "16460027", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 45 2006", + "title": "Structural and dynamic characterization of a vinculin binding site in the talin rod." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "31539492", + "pubmed": { + "ISODate": "2019-09-19T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.", + "authors": { + "abbreviation": "Dirk Dedden, Stephanie Schumacher, Charlotte F Kelley, ..., Naoko Mizuno", + "authorList": [ + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Stephanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Schumacher" + }, + { + "ForeName": "Charlotte", + "LastName": "Kelley", + "abbrevName": "Kelley CF", + "email": null, + "isCollectiveName": false, + "name": "Charlotte F Kelley" + }, + { + "ForeName": "Martin", + "LastName": "Zacharias", + "abbrevName": "Zacharias M", + "email": null, + "isCollectiveName": false, + "name": "Martin Zacharias" + }, + { + "ForeName": "Christian", + "LastName": "Biertümpfel", + "abbrevName": "Biertümpfel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Biertümpfel" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": "mizuno@biochem.mpg.de", + "isCollectiveName": false, + "name": "Naoko Mizuno" + } + ], + "contacts": [ + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "email": [ + "mizuno@biochem.mpg.de" + ], + "name": "Naoko Mizuno" + } + ] + }, + "doi": "10.1016/j.cell.2019.08.034", + "pmid": "31539492", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell 179 2019", + "title": "The Architecture of Talin1 Reveals an Autoinhibition Mechanism." + } + }, + { + "pmid": "34708856", + "pubmed": { + "ISODate": "2021-10-15T00:00:00.000Z", + "abstract": "Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches - proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.", + "authors": { + "abbreviation": "Benjamin T Goult, Nicholas H Brown, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.258749", + "pmid": "34708856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 134 2021", + "title": "Talin in mechanotransduction and mechanomemory at a glance." + } + }, + { + "pmid": "30254158", + "pubmed": { + "ISODate": "2018-10-09T00:00:00.000Z", + "abstract": "Multicellular organisms have well-defined, tightly regulated mechanisms for cell adhesion. Heterodimeric αβ integrin receptors play central roles in this function and regulate processes for normal cell functions, including signaling, cell migration, and development, binding to the extracellular matrix, and senescence. They are involved in hemostasis and the immune response, participate in leukocyte function, and have biological implications in angiogenesis and cancer. Proper control of integrin activation for cellular communication with the external environment requires several physiological processes. Perturbation of these equilibria may lead to constitutive integrin activation that results in bleeding disorders. Furthermore, integrins play key roles in cancer progression and metastasis in which certain tumor types exhibit higher levels of various integrins. Thus, the integrin-associated signaling complex is important for cancer therapy development. During inside-out signaling, the cytoskeletal protein talin plays a key role in regulating integrin affinity whereby the talin head domain activates integrin by binding to the cytoplasmic tail of β-integrin and acidic membrane phospholipids. To understand the mechanism of integrin activation by talin, we determined the crystal structure of the talin head domain bound to the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), allowing us to design a lipid-binding-deficient talin mutant. Our confocal microscopy with talin knockout cells suggests that the talin-cell membrane interaction seems essential for focal adhesion formation and stabilization. Basal integrin activation in Chinese hamster ovary cells suggests that the lipid-binding-deficient talin mutant inhibits integrin activation. Thus, membrane attachment of talin seems necessary for integrin activation and focal adhesion formation.", + "authors": { + "abbreviation": "Krishna Chinthalapudi, Erumbi S Rangarajan, Tina Izard", + "authorList": [ + { + "ForeName": "Krishna", + "LastName": "Chinthalapudi", + "abbrevName": "Chinthalapudi K", + "email": null, + "isCollectiveName": false, + "name": "Krishna Chinthalapudi" + }, + { + "ForeName": "Erumbi", + "LastName": "Rangarajan", + "abbrevName": "Rangarajan ES", + "email": null, + "isCollectiveName": false, + "name": "Erumbi S Rangarajan" + }, + { + "ForeName": "Tina", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": "cmorrow@scripps.edu", + "isCollectiveName": false, + "name": "Tina Izard" + } + ], + "contacts": [ + { + "ForeName": "Tina", + "LastName": "Izard", + "email": [ + "cmorrow@scripps.edu" + ], + "name": "Tina Izard" + } + ] + }, + "doi": "10.1073/pnas.1806275115", + "pmid": "30254158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation." + } + }, + { + "pmid": "7622520", + "pubmed": { + "ISODate": "1995-07-14T00:00:00.000Z", + "abstract": "The interaction of cells with extracellular matrix proteins plays a critical role in a variety of biological processes. Recent studies suggest that cell-matrix interactions mediated by integrins can transduce biochemical signals to the cell interior that regulate cell proliferation and differentiation. These studies have placed the focal adhesion kinase (FAK), an intracellular protein tyrosine kinase, in a central position in integrin-initiated signal transduction pathways (Zachary, I., and Rozengurt, E. (1992) Cell 71, 891-894; Schaller, M., and Parsons, J. T. (1993) Trends Cell Biol. 3, 258-262). Here, we report data suggesting a possible association of FAK with the cytoskeletal protein talin in NIH 3T3 cells. We have identified a 48-amino acid sequence in the carboxyl-terminal domain of FAK necessary for talin binding in vitro. Furthermore, we have correlated the ability of integrin to induce FAK phosphorylation with its ability to bind talin using a mutant integrin lacking the carboxyl-terminal 13 amino acids. These studies suggest talin may be a mediator for FAK activation in signaling initiated by integrins and may provide an explanation for the dependence on the integrity of actin-cytoskeleton of multiple intracellular signaling pathways converging to FAK activation and autophosphorylation.", + "authors": { + "abbreviation": "H C Chen, P A Appeddu, J T Parsons, ..., J L Guan", + "authorList": [ + { + "ForeName": "H", + "LastName": "Chen", + "abbrevName": "Chen HC", + "email": null, + "isCollectiveName": false, + "name": "H C Chen" + }, + { + "ForeName": "P", + "LastName": "Appeddu", + "abbrevName": "Appeddu PA", + "email": null, + "isCollectiveName": false, + "name": "P A Appeddu" + }, + { + "ForeName": "J", + "LastName": "Parsons", + "abbrevName": "Parsons JT", + "email": null, + "isCollectiveName": false, + "name": "J T Parsons" + }, + { + "ForeName": "J", + "LastName": "Hildebrand", + "abbrevName": "Hildebrand JD", + "email": null, + "isCollectiveName": false, + "name": "J D Hildebrand" + }, + { + "ForeName": "M", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "M D Schaller" + }, + { + "ForeName": "J", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "J L Guan" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.270.28.16995", + "pmid": "7622520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 270 1995", + "title": "Interaction of focal adhesion kinase with cytoskeletal protein talin." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "22496808", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Talin is a large (∼2540 residues) dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs), where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell.", + "authors": { + "abbreviation": "Neil Bate, Alexandre R Gingras, Alexia Bachir, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir A", + "email": null, + "isCollectiveName": false, + "name": "Alexia Bachir" + }, + { + "ForeName": "Rick", + "LastName": "Horwitz", + "abbrevName": "Horwitz R", + "email": null, + "isCollectiveName": false, + "name": "Rick Horwitz" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0034461", + "pmid": "22496808", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics." + } + } + ], + "secret": "read-only", + "type": "phosphorylation" + }, + { + "_creationTimestamp": "2022-02-01T19:40:31.291Z", + "_newestOpId": "7e419005-b1d6-4e57-a543-474f1c438ae0", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "186745" + }, + { + "db": "HGNC", + "id": "HGNC:11845" + }, + { + "db": "Ensembl", + "id": "ENSG00000137076" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.344946, + "id": "7094", + "name": "TLN1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "ILWEQ", + "TLN", + "talin-1", + "talin 1" + ], + "synonyms": [ + "ILWEQ", + "TLN", + "talin-1", + "talin 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "e70f848c-4670-460b-932c-0cc788d0b5d5", + "liveId": "7b7407a5-be8c-4df7-98a7-849f031eddc0", + "lock": null, + "locked": false, + "name": "TLN1", + "position": { + "x": 47.38886719102975, + "y": -66.4984586231184 + }, + "relatedPapers": [ + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "10497223", + "pubmed": { + "ISODate": "1999-10-01T00:00:00.000Z", + "abstract": "Following platelet aggregation, integrin alpha(IIb)beta(3) becomes associated with the platelet cytoskeleton. The conserved NPLY sequence represents a potential beta-turn motif in the beta(3) cytoplasmic tail and has been suggested to mediate the interaction of beta(3) integrins with talin. In the present study, we performed a double mutation (N744Q/P745A) in the integrin beta(3) subunit to test the functional significance of this beta-turn motif. Chinese hamster ovary cells were co-transfected with cDNA constructs encoding mutant beta(3) and wild type alpha(IIb). Cells expressing either wild type (A5) or mutant (D4) alpha(IIb)beta(3) adhered to fibrinogen; however, as opposed to control A5 cells, adherent D4 cells failed to spread, form focal adhesions, or initiate protein tyrosine phosphorylation. To investigate the role of the NPLY motif in talin binding, we examined the ability of the mutant alpha(IIb)beta(3) to interact with talin in a solid phase binding assay. Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin. Additionally, purified talin failed to interact with peptides containing the AKWDTANNPLYK sequence indicating that the talin binding domain in the integrin beta(3) subunit does not reside in the NPLY motif. In contrast, specific binding of talin to peptides containing the membrane-proximal HDRKEFAKFEEERARAK sequence of the beta(3) cytoplasmic tail was observed, and this interaction was blocked by a recombinant protein fragment corresponding to the 47-kDa N-terminal head domain of talin (rTalin-N). In addition, RGD affinity purified platelet alpha(IIb)beta(3) bound dose-dependently to immobilized rTalin-N, indicating that an integrin-binding site is present in the talin N-terminal head domain. Collectively, these studies demonstrate that the NPLY beta-turn motif regulates post-ligand binding functions of alpha(IIb)beta(3) in a manner independent of talin interaction. Moreover, talin was shown to bind through its N-terminal head domain to the membrane-proximal sequence of the beta(3) cytoplasmic tail.", + "authors": { + "abbreviation": "S Patil, A Jedsadayanmata, J D Wencel-Drake, ..., S C Lam", + "authorList": [ + { + "ForeName": "S", + "LastName": "Patil", + "abbrevName": "Patil S", + "email": null, + "isCollectiveName": false, + "name": "S Patil" + }, + { + "ForeName": "A", + "LastName": "Jedsadayanmata", + "abbrevName": "Jedsadayanmata A", + "email": null, + "isCollectiveName": false, + "name": "A Jedsadayanmata" + }, + { + "ForeName": "J", + "LastName": "Wencel-Drake", + "abbrevName": "Wencel-Drake JD", + "email": null, + "isCollectiveName": false, + "name": "J D Wencel-Drake" + }, + { + "ForeName": "W", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "W Wang" + }, + { + "ForeName": "I", + "LastName": "Knezevic", + "abbrevName": "Knezevic I", + "email": null, + "isCollectiveName": false, + "name": "I Knezevic" + }, + { + "ForeName": "S", + "LastName": "Lam", + "abbrevName": "Lam SC", + "email": null, + "isCollectiveName": false, + "name": "S C Lam" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.274.40.28575", + "pmid": "10497223", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 274 1999", + "title": "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail." + } + }, + { + "pmid": "16135522", + "pubmed": { + "ISODate": "2005-11-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. Three vinculin binding sites (VBS1-3) have previously been identified in the talin rod using a yeast two-hybrid assay. To extend these studies, we spot-synthesized a series of peptides spanning all the alpha-helical regions predicted for the talin rod and identified eight additional VBSs, two of which overlap key functional regions of the rod, including the integrin binding site and C-terminal actin binding site. The talin VBS alpha-helices bind to a hydrophobic cleft in the N-terminal vinculin Vd1 domain. We have defined the specificity of this interaction by spot-synthesizing a series of 25-mer talin VBS1 peptides containing substitutions with all the commonly occurring amino acids. The consensus for recognition is LXXAAXXVAXX- VXXLIXXA with distinct classes of hydrophobic side chains at positions 1, 4, 5, 8, 9, 12, 15, and 16 required for vinculin binding. Positions 1, 8, 12, 15, and 16 require an aliphatic residue and will not tolerate alanine, whereas positions 4, 5, and 9 are less restrictive. These preferences are common to all 11 VBS sequences with a minor variation occurring in one case. A crystal structure of this variant VBS peptide in complex with the vinculin Vd1 domain reveals a subtly different mode of vinculin binding.", + "authors": { + "abbreviation": "Alexandre R Gingras, Wolfgang H Ziegler, Ronald Frank, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M508060200", + "pmid": "16135522", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod." + } + }, + { + "pmid": "7622520", + "pubmed": { + "ISODate": "1995-07-14T00:00:00.000Z", + "abstract": "The interaction of cells with extracellular matrix proteins plays a critical role in a variety of biological processes. Recent studies suggest that cell-matrix interactions mediated by integrins can transduce biochemical signals to the cell interior that regulate cell proliferation and differentiation. These studies have placed the focal adhesion kinase (FAK), an intracellular protein tyrosine kinase, in a central position in integrin-initiated signal transduction pathways (Zachary, I., and Rozengurt, E. (1992) Cell 71, 891-894; Schaller, M., and Parsons, J. T. (1993) Trends Cell Biol. 3, 258-262). Here, we report data suggesting a possible association of FAK with the cytoskeletal protein talin in NIH 3T3 cells. We have identified a 48-amino acid sequence in the carboxyl-terminal domain of FAK necessary for talin binding in vitro. Furthermore, we have correlated the ability of integrin to induce FAK phosphorylation with its ability to bind talin using a mutant integrin lacking the carboxyl-terminal 13 amino acids. These studies suggest talin may be a mediator for FAK activation in signaling initiated by integrins and may provide an explanation for the dependence on the integrity of actin-cytoskeleton of multiple intracellular signaling pathways converging to FAK activation and autophosphorylation.", + "authors": { + "abbreviation": "H C Chen, P A Appeddu, J T Parsons, ..., J L Guan", + "authorList": [ + { + "ForeName": "H", + "LastName": "Chen", + "abbrevName": "Chen HC", + "email": null, + "isCollectiveName": false, + "name": "H C Chen" + }, + { + "ForeName": "P", + "LastName": "Appeddu", + "abbrevName": "Appeddu PA", + "email": null, + "isCollectiveName": false, + "name": "P A Appeddu" + }, + { + "ForeName": "J", + "LastName": "Parsons", + "abbrevName": "Parsons JT", + "email": null, + "isCollectiveName": false, + "name": "J T Parsons" + }, + { + "ForeName": "J", + "LastName": "Hildebrand", + "abbrevName": "Hildebrand JD", + "email": null, + "isCollectiveName": false, + "name": "J D Hildebrand" + }, + { + "ForeName": "M", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "M D Schaller" + }, + { + "ForeName": "J", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "J L Guan" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.270.28.16995", + "pmid": "7622520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 270 1995", + "title": "Interaction of focal adhesion kinase with cytoskeletal protein talin." + } + }, + { + "pmid": "31393109", + "pubmed": { + "ISODate": "2019-11-26T00:00:00.000Z", + "abstract": "Mechanotransduction from the extracellular matrix into the cell is primarily supervised by a transmembrane receptor, integrin, and a cytosolic protein, talin. Integrin binds ligands on the extracellular side, whereas talin couples integrin receptors to the actin cytoskeleton and later acts as a \"force buffer\". Talin and integrin together form a mechanosensitive signaling hub that regulates crucial cellular processes and pathways, including cell signaling and formation of focal adhesion complexes, which help cells to sense their mechano-environment and transduce the signal accordingly. Although both proteins function in tandem, most literature focuses on them individually. Here, we provide a focused review of the talin-integrin mechano-interactome network in light of its role in the process of mechanotransduction and its connection to diseases. While working under force, these proteins drive numerous biomolecular interactions and form adhesion complexes, which in turn control many physiological processes such as cell migration; thus, they are invariably associated with several diseases from leukocyte adhesion deficiency to cancer. Gaining insights into their role in the occurrence of these pathological disorders might lead us to establish treatment methods and therapeutic techniques.", + "authors": { + "abbreviation": "Soham Chakraborty, Souradeep Banerjee, Manasven Raina, Shubhasis Haldar", + "authorList": [ + { + "ForeName": "Soham", + "LastName": "Chakraborty", + "abbrevName": "Chakraborty S", + "email": null, + "isCollectiveName": false, + "name": "Soham Chakraborty" + }, + { + "ForeName": "Souradeep", + "LastName": "Banerjee", + "abbrevName": "Banerjee S", + "email": null, + "isCollectiveName": false, + "name": "Souradeep Banerjee" + }, + { + "ForeName": "Manasven", + "LastName": "Raina", + "abbrevName": "Raina M", + "email": null, + "isCollectiveName": false, + "name": "Manasven Raina" + }, + { + "ForeName": "Shubhasis", + "LastName": "Haldar", + "abbrevName": "Haldar S", + "email": null, + "isCollectiveName": false, + "name": "Shubhasis Haldar" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.biochem.9b00442", + "pmid": "31393109", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochemistry 58 2019", + "title": "Force-Directed \"Mechanointeractome\" of Talin-Integrin." + } + }, + { + "pmid": "15031296", + "pubmed": { + "ISODate": "2004-05-21T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which provides a direct link between integrins and actin filaments, has been shown to contain two distinct binding sites for integrin beta subunits. Here, we report the precise delimitation and a first functional analysis of the talin rod domain integrin-binding site. Partially overlapping cDNAs covering the entire human talin gene were transiently expressed as DsRed fusion proteins in Chinese hamster ovary cells expressing alpha(IIb)beta(3), linked to green fluorescent protein (GFP). Two-color fluorescence analysis of the transfected cells, spread on fibrinogen, revealed distinct subcellular staining patterns including focal adhesion, actin filament, and granular labeling for different talin fragments. The rod domain fragment G (residues 1984-2344), devoid of any known actin- or vinculin-binding sites, colocalized with beta(3)-GFP in focal adhesions. Direct in vitro interaction of fragment G with native platelet integrin alpha(IIb)beta(3) or with the recombinant wild type, but not the Y747A mutant beta(3) cytoplasmic tail, linked to glutathione S-transferase, was demonstrated by surface plasmon resonance analysis and pull-down assays, respectively. Here, we demonstrate for the first time the in vivo relevance of this interaction by fluorescence resonance energy transfer between beta(3)-GFP and DsRed-talin fragment G. Further in vitro pull-down studies allowed us to map out the integrin-binding site within fragment G to a stretch of 130 residues (fragment J, residues 1984-2113) that also localized to focal adhesions. Finally, we show by a cell biology approach that this integrin-binding site within the talin rod domain is important for beta(3)-cytoskeletal interactions but does not participate in alpha(IIb)beta(3) activation.", + "authors": { + "abbreviation": "Laurent Tremuth, Stephanie Kreis, Chantal Melchior, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Stephanie", + "LastName": "Kreis", + "abbrevName": "Kreis S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kreis" + }, + { + "ForeName": "Chantal", + "LastName": "Melchior", + "abbrevName": "Melchior C", + "email": null, + "isCollectiveName": false, + "name": "Chantal Melchior" + }, + { + "ForeName": "Johan", + "LastName": "Hoebeke", + "abbrevName": "Hoebeke J", + "email": null, + "isCollectiveName": false, + "name": "Johan Hoebeke" + }, + { + "ForeName": "Philippe", + "LastName": "Rondé", + "abbrevName": "Rondé P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Rondé" + }, + { + "ForeName": "Sébastien", + "LastName": "Plançon", + "abbrevName": "Plançon S", + "email": null, + "isCollectiveName": false, + "name": "Sébastien Plançon" + }, + { + "ForeName": "Kenneth", + "LastName": "Takeda", + "abbrevName": "Takeda K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Takeda" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M400947200", + "pmid": "15031296", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A fluorescence cell biology approach to map the second integrin-binding site of talin to a 130-amino acid sequence within the rod domain." + } + }, + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "22496808", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Talin is a large (∼2540 residues) dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs), where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell.", + "authors": { + "abbreviation": "Neil Bate, Alexandre R Gingras, Alexia Bachir, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir A", + "email": null, + "isCollectiveName": false, + "name": "Alexia Bachir" + }, + { + "ForeName": "Rick", + "LastName": "Horwitz", + "abbrevName": "Horwitz R", + "email": null, + "isCollectiveName": false, + "name": "Rick Horwitz" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0034461", + "pmid": "22496808", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "34708856", + "pubmed": { + "ISODate": "2021-10-15T00:00:00.000Z", + "abstract": "Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches - proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.", + "authors": { + "abbreviation": "Benjamin T Goult, Nicholas H Brown, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.258749", + "pmid": "34708856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 134 2021", + "title": "Talin in mechanotransduction and mechanomemory at a glance." + } + }, + { + "pmid": "11591813", + "pubmed": { + "ISODate": "2001-09-01T00:00:00.000Z", + "abstract": "Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.", + "authors": { + "abbreviation": "C R Carlson, O Witczak, L Vossebein, ..., K Taskén", + "authorList": [ + { + "ForeName": "C", + "LastName": "Carlson", + "abbrevName": "Carlson CR", + "email": "cathrine.carlson@basalmed.uio.no", + "isCollectiveName": false, + "name": "C R Carlson" + }, + { + "ForeName": "O", + "LastName": "Witczak", + "abbrevName": "Witczak O", + "email": null, + "isCollectiveName": false, + "name": "O Witczak" + }, + { + "ForeName": "L", + "LastName": "Vossebein", + "abbrevName": "Vossebein L", + "email": null, + "isCollectiveName": false, + "name": "L Vossebein" + }, + { + "ForeName": "J", + "LastName": "Labbé", + "abbrevName": "Labbé JC", + "email": null, + "isCollectiveName": false, + "name": "J C Labbé" + }, + { + "ForeName": "B", + "LastName": "Skålhegg", + "abbrevName": "Skålhegg BS", + "email": null, + "isCollectiveName": false, + "name": "B S Skålhegg" + }, + { + "ForeName": "G", + "LastName": "Keryer", + "abbrevName": "Keryer G", + "email": null, + "isCollectiveName": false, + "name": "G Keryer" + }, + { + "ForeName": "F", + "LastName": "Herberg", + "abbrevName": "Herberg FW", + "email": null, + "isCollectiveName": false, + "name": "F W Herberg" + }, + { + "ForeName": "P", + "LastName": "Collas", + "abbrevName": "Collas P", + "email": null, + "isCollectiveName": false, + "name": "P Collas" + }, + { + "ForeName": "K", + "LastName": "Taskén", + "abbrevName": "Taskén K", + "email": null, + "isCollectiveName": false, + "name": "K Taskén" + } + ], + "contacts": [ + { + "ForeName": "C", + "LastName": "Carlson", + "email": [ + "cathrine.carlson@basalmed.uio.no" + ], + "name": "C R Carlson" + } + ] + }, + "doi": "10.1242/jcs.114.18.3243", + "pmid": "11591813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 114 2001", + "title": "CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis." + } + }, + { + "pmid": "28701514", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and Drosophila to present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.", + "authors": { + "abbreviation": "Benjamin Klapholz, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": "nb117@cam.ac.uk", + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Brown", + "email": [ + "nb117@cam.ac.uk" + ], + "name": "Nicholas H Brown" + } + ] + }, + "doi": "10.1242/jcs.190991", + "pmid": "28701514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "Talin - the master of integrin adhesions." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "29930204", + "pubmed": { + "ISODate": "2018-09-03T00:00:00.000Z", + "abstract": "In most tissues, anchorage-dependent growth and cell cycle progression are dependent on cells engaging extracellular matrices (ECMs) via integrin-receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings before division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell adhesion to the ECM. In this study, we demonstrate that cyclin-dependent kinase 1 (CDK1) mediates this link. CDK1, in complex with cyclin A2, promotes adhesion complex and actin cytoskeleton organization during interphase and mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area decreases in G2, and disassembly occurs several hours before mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1 is therefore the trigger that initiates remodeling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.", + "authors": { + "abbreviation": "Matthew C Jones, Janet A Askari, Jonathan D Humphries, Martin J Humphries", + "authorList": [ + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1083/jcb.201802088", + "pmid": "29930204", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Cell adhesion is regulated by CDK1 during the cell cycle." + } + }, + { + "pmid": "27603133", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The p17 protein of avian reovirus (ARV) causes cell cycle retardation in a variety of cell lines; however, the underlying mechanism(s) by which p17 regulates the cell cycle remains largely unknown. We demonstrate for the first time that p17 interacts with CDK1 and vimentin as revealed by reciprocal co-immunoprecipitation and GST pull-down assays. Both in vitro and in vivo studies indicated that direct interaction of p17 and CDK1/vimentin was mapped within the amino terminus (aa 1-60) of p17 and central region (aa 27-118) of CDK1/vimentin. Furthermore, p17 was found to occupy the Plk1-binding site within the vimentin, thereby blocking Plk1 recruitment to CDK1-induced vimentin phosphorylation at Ser 56. Interaction of p17 to CDK1 or vimentin interferes with CDK1-catalyzed phosphorylation of vimentin at Ser 56 and subsequently vimentin phosphorylation at Ser 82 by Plk1. Furthermore, we have identified upstream signaling pathways and cellular factor(s) targeted by p17 and found that p17 regulates inhibitory phosphorylation of CDK1 and blocks vimentin phosphorylation at Ser 56 and Ser 82. The p17-mediated inactivation of CDK1 is dependent on several mechanisms, which include direct interaction with CDK1, p17-mediated suppression of Plk1 by activating the Tpr/p53 and ATM/Chk1/PP2A pathways, and p17-mediated cdc25C degradation via an ubiquitin- proteasome pathway. Additionally, depletion of p53 with a shRNA as well as inhibition of ATM and vimentin by inhibitors diminished virus yield while Tpr and CDK1 knockdown increased virus yield. Taken together, results demonstrate that p17 suppresses both CDK1 and Plk1functions, disrupts vimentin phosphorylation, causes G2/M cell cycle arrest and thus benefits virus replication. ", + "authors": { + "abbreviation": "Hung-Chuan Chiu, Wei-Ru Huang, Tsai-Ling Liao, ..., Hung-Jen Liu", + "authorList": [ + { + "ForeName": "Hung-Chuan", + "LastName": "Chiu", + "abbrevName": "Chiu HC", + "email": null, + "isCollectiveName": false, + "name": "Hung-Chuan Chiu" + }, + { + "ForeName": "Wei-Ru", + "LastName": "Huang", + "abbrevName": "Huang WR", + "email": null, + "isCollectiveName": false, + "name": "Wei-Ru Huang" + }, + { + "ForeName": "Tsai-Ling", + "LastName": "Liao", + "abbrevName": "Liao TL", + "email": null, + "isCollectiveName": false, + "name": "Tsai-Ling Liao" + }, + { + "ForeName": "Hung-Yi", + "LastName": "Wu", + "abbrevName": "Wu HY", + "email": null, + "isCollectiveName": false, + "name": "Hung-Yi Wu" + }, + { + "ForeName": "Muhammad", + "LastName": "Munir", + "abbrevName": "Munir M", + "email": null, + "isCollectiveName": false, + "name": "Muhammad Munir" + }, + { + "ForeName": "Wing-Ling", + "LastName": "Shih", + "abbrevName": "Shih WL", + "email": null, + "isCollectiveName": false, + "name": "Wing-Ling Shih" + }, + { + "ForeName": "Hung-Jen", + "LastName": "Liu", + "abbrevName": "Liu HJ", + "email": null, + "isCollectiveName": false, + "name": "Hung-Jen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0162356", + "pmid": "27603133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 11 2016", + "title": "Suppression of Vimentin Phosphorylation by the Avian Reovirus p17 through Inhibition of CDK1 and Plk1 Impacting the G2/M Phase of the Cell Cycle." + } + }, + { + "pmid": "20150896", + "pubmed": { + "ISODate": "2010-03-17T00:00:00.000Z", + "abstract": "Talin is a 270-kDa protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM domain comprised of F1, F2 and F3 domains, but it is atypical in that F1 contains a large insert and is preceded by an extra domain F0. Although F3 contains the binding site for beta-integrin tails, F0 and F1 are also required for activation of beta1-integrins. Here, we report the solution structures of F0, F1 and of the F0F1 double domain. Both F0 and F1 have ubiquitin-like folds joined in a novel fixed orientation by an extensive charged interface. The F1 insert forms a loop with helical propensity, and basic residues predicted to reside on one surface of the helix are required for binding to acidic phospholipids and for talin-mediated activation of beta1-integrins. This and the fact that basic residues on F2 and F3 are also essential for integrin activation suggest that extensive interactions between the talin FERM domain and acidic membrane phospholipids are required to orientate the FERM domain such that it can activate integrins.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, Paul R Elliott, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1038/emboj.2010.4", + "pmid": "20150896", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 29 2010", + "title": "Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation." + } + }, + { + "pmid": "30254158", + "pubmed": { + "ISODate": "2018-10-09T00:00:00.000Z", + "abstract": "Multicellular organisms have well-defined, tightly regulated mechanisms for cell adhesion. Heterodimeric αβ integrin receptors play central roles in this function and regulate processes for normal cell functions, including signaling, cell migration, and development, binding to the extracellular matrix, and senescence. They are involved in hemostasis and the immune response, participate in leukocyte function, and have biological implications in angiogenesis and cancer. Proper control of integrin activation for cellular communication with the external environment requires several physiological processes. Perturbation of these equilibria may lead to constitutive integrin activation that results in bleeding disorders. Furthermore, integrins play key roles in cancer progression and metastasis in which certain tumor types exhibit higher levels of various integrins. Thus, the integrin-associated signaling complex is important for cancer therapy development. During inside-out signaling, the cytoskeletal protein talin plays a key role in regulating integrin affinity whereby the talin head domain activates integrin by binding to the cytoplasmic tail of β-integrin and acidic membrane phospholipids. To understand the mechanism of integrin activation by talin, we determined the crystal structure of the talin head domain bound to the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), allowing us to design a lipid-binding-deficient talin mutant. Our confocal microscopy with talin knockout cells suggests that the talin-cell membrane interaction seems essential for focal adhesion formation and stabilization. Basal integrin activation in Chinese hamster ovary cells suggests that the lipid-binding-deficient talin mutant inhibits integrin activation. Thus, membrane attachment of talin seems necessary for integrin activation and focal adhesion formation.", + "authors": { + "abbreviation": "Krishna Chinthalapudi, Erumbi S Rangarajan, Tina Izard", + "authorList": [ + { + "ForeName": "Krishna", + "LastName": "Chinthalapudi", + "abbrevName": "Chinthalapudi K", + "email": null, + "isCollectiveName": false, + "name": "Krishna Chinthalapudi" + }, + { + "ForeName": "Erumbi", + "LastName": "Rangarajan", + "abbrevName": "Rangarajan ES", + "email": null, + "isCollectiveName": false, + "name": "Erumbi S Rangarajan" + }, + { + "ForeName": "Tina", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": "cmorrow@scripps.edu", + "isCollectiveName": false, + "name": "Tina Izard" + } + ], + "contacts": [ + { + "ForeName": "Tina", + "LastName": "Izard", + "email": [ + "cmorrow@scripps.edu" + ], + "name": "Tina Izard" + } + ] + }, + "doi": "10.1073/pnas.1806275115", + "pmid": "30254158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "18550856", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Leukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (K(d), 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (K(d), 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated beta2 integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion.", + "authors": { + "abbreviation": "Heikki Takala, Elisa Nurminen, Susanna M Nurmi, ..., Susanna C Fagerholm", + "authorList": [ + { + "ForeName": "Heikki", + "LastName": "Takala", + "abbrevName": "Takala H", + "email": null, + "isCollectiveName": false, + "name": "Heikki Takala" + }, + { + "ForeName": "Elisa", + "LastName": "Nurminen", + "abbrevName": "Nurminen E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Nurminen" + }, + { + "ForeName": "Susanna", + "LastName": "Nurmi", + "abbrevName": "Nurmi SM", + "email": null, + "isCollectiveName": false, + "name": "Susanna M Nurmi" + }, + { + "ForeName": "Maria", + "LastName": "Aatonen", + "abbrevName": "Aatonen M", + "email": null, + "isCollectiveName": false, + "name": "Maria Aatonen" + }, + { + "ForeName": "Tomas", + "LastName": "Strandin", + "abbrevName": "Strandin T", + "email": null, + "isCollectiveName": false, + "name": "Tomas Strandin" + }, + { + "ForeName": "Maarit", + "LastName": "Takatalo", + "abbrevName": "Takatalo M", + "email": null, + "isCollectiveName": false, + "name": "Maarit Takatalo" + }, + { + "ForeName": "Tiila", + "LastName": "Kiema", + "abbrevName": "Kiema T", + "email": null, + "isCollectiveName": false, + "name": "Tiila Kiema" + }, + { + "ForeName": "Carl", + "LastName": "Gahmberg", + "abbrevName": "Gahmberg CG", + "email": null, + "isCollectiveName": false, + "name": "Carl G Gahmberg" + }, + { + "ForeName": "Jari", + "LastName": "Ylänne", + "abbrevName": "Ylänne J", + "email": null, + "isCollectiveName": false, + "name": "Jari Ylänne" + }, + { + "ForeName": "Susanna", + "LastName": "Fagerholm", + "abbrevName": "Fagerholm SC", + "email": null, + "isCollectiveName": false, + "name": "Susanna C Fagerholm" + } + ], + "contacts": [] + }, + "doi": "10.1182/blood-2007-12-127795", + "pmid": "18550856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Blood 112 2008", + "title": "Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding." + } + }, + { + "pmid": "19948488", + "pubmed": { + "ISODate": "2009-11-30T00:00:00.000Z", + "abstract": "Integrin-dependent adhesion sites consist of clustered integrins that transmit mechanical forces and provide signaling required for cell survival and morphogenesis. Despite their importance, the regulation of integrin clustering by the cytoplasmic adapter protein talin (Tal) and phosphatidylinositol (PI)-4,5-biphosphate (PI(4,5)P(2)) lipids nor their dynamic coupling to the actin cytoskeleton is fully understood. By using a Tal-dependent integrin clustering assay in intact cells, we identified a PI(4,5)P(2)-binding basic ridge spanning across the F2 and F3 domains of the Tal head that regulates integrin clustering. Clustering requires a new PI(4,5)P(2)-binding site in F2 and is negatively regulated by autoinhibitory interactions between F3 and the Tal rod (Tal-R). The release of the Tal-R exposes a new beta3-integrin-binding site in F3, enabling interaction with a membrane proximal acidic motif, which involves the formation of salt bridges between K(316) and K(324) with E(726) and D(723), respectively. This interaction shields the beta-integrin tail from reassociation with its alpha subunit, thereby maintaining the integrin in a substrate-binding and clustering-competent form.", + "authors": { + "abbreviation": "Frédéric Saltel, Eva Mortier, Vesa P Hytönen, ..., Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Frédéric", + "LastName": "Saltel", + "abbrevName": "Saltel F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Saltel" + }, + { + "ForeName": "Eva", + "LastName": "Mortier", + "abbrevName": "Mortier E", + "email": null, + "isCollectiveName": false, + "name": "Eva Mortier" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Marie-Claude", + "LastName": "Jacquier", + "abbrevName": "Jacquier MC", + "email": null, + "isCollectiveName": false, + "name": "Marie-Claude Jacquier" + }, + { + "ForeName": "Pascale", + "LastName": "Zimmermann", + "abbrevName": "Zimmermann P", + "email": null, + "isCollectiveName": false, + "name": "Pascale Zimmermann" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": null, + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200908134", + "pmid": "19948488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 187 2009", + "title": "New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "17430904", + "pubmed": { + "ISODate": "2007-06-08T00:00:00.000Z", + "abstract": "Talin1 is a large cytoskeletal protein that links integrins to actin filaments through two distinct integrin binding sites, one present in the talin head domain (IBS1) necessary for integrin activation and a second (IBS2) that we have previously mapped to talin residues 1984-2113 (fragment J) of the talin rod domain (1 Tremuth, L., Kreis, S., Melchior, C., Hoebeke, J., Ronde, P., Plancon, S., Takeda, K., and Kieffer, N. (2004) J. Biol. Chem. 279, 22258-22266), but whose functional role is still elusive. Using a bioinformatics and cell biology approach, we have determined the minimal structure of IBS2 and show that this integrin binding site corresponds to 23 residues located in alpha helix 50 of the talin rod domain (residues 2077-2099). Alanine mutation of 2 highly conserved residues (L2094A/I2095A) within this alpha helix, which disrupted the alpha-helical structure of IBS2 as demonstrated by infrared spectroscopy and limited trypsin proteolysis, was sufficient to prevent in vivo talin fragment J targeting to alphaIIbbeta3 integrin in focal adhesions and to inhibit in vitro this association as shown by an alphaIIbbeta3 pulldown assay. Moreover, expression of a full-length mouse green fluorescent protein-talin LI/AA mutant in mouse talin1(-/-) cells was unable to rescue the inability of these cells to assemble focal adhesions (in contrast to green fluorescent protein-talin wild type) despite the presence of IBS1. Our data provide the first direct evidence that IBS2 in the talin rod is essential to link integrins to the cytoskeleton.", + "authors": { + "abbreviation": "Michèle Moes, Sophie Rodius, Stacey J Coleman, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Michèle", + "LastName": "Moes", + "abbrevName": "Moes M", + "email": null, + "isCollectiveName": false, + "name": "Michèle Moes" + }, + { + "ForeName": "Sophie", + "LastName": "Rodius", + "abbrevName": "Rodius S", + "email": null, + "isCollectiveName": false, + "name": "Sophie Rodius" + }, + { + "ForeName": "Stacey", + "LastName": "Coleman", + "abbrevName": "Coleman SJ", + "email": null, + "isCollectiveName": false, + "name": "Stacey J Coleman" + }, + { + "ForeName": "Susan", + "LastName": "Monkley", + "abbrevName": "Monkley SJ", + "email": null, + "isCollectiveName": false, + "name": "Susan J Monkley" + }, + { + "ForeName": "Erik", + "LastName": "Goormaghtigh", + "abbrevName": "Goormaghtigh E", + "email": null, + "isCollectiveName": false, + "name": "Erik Goormaghtigh" + }, + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Corinne", + "LastName": "Kox", + "abbrevName": "Kox C", + "email": null, + "isCollectiveName": false, + "name": "Corinne Kox" + }, + { + "ForeName": "Patrick", + "LastName": "van der Holst", + "abbrevName": "van der Holst PP", + "email": null, + "isCollectiveName": false, + "name": "Patrick P G van der Holst" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M611846200", + "pmid": "17430904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 282 2007", + "title": "The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin beta subunits to the cytoskeleton." + } + }, + { + "pmid": "21658602", + "pubmed": { + "ISODate": "2011-06-10T00:00:00.000Z", + "abstract": "Cdk specificity is determined by the intrinsic selectivity of the active site and by substrate docking sites on the cyclin subunit. There is a long-standing debate about the relative importance of these factors in the timing of Cdk1 substrate phosphorylation. We analyzed major budding yeast cyclins (the G1/S-cyclin Cln2, S-cyclin Clb5, G2/M-cyclin Clb3, and M-cyclin Clb2) and found that the activity of Cdk1 toward the consensus motif increased gradually in the sequence Cln2-Clb5-Clb3-Clb2, in parallel with cell cycle progression. Further, we identified a docking element that compensates for the weak intrinsic specificity of Cln2 toward G1-specific targets. In addition, Cln2-Cdk1 showed distinct consensus site specificity, suggesting that cyclins do not merely activate Cdk1 but also modulate its active-site specificity. Finally, we identified several Cln2-, Clb3-, and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1.", + "authors": { + "abbreviation": "Mardo Kõivomägi, Ervin Valk, Rainis Venta, ..., Mart Loog", + "authorList": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "abbrevName": "Kõivomägi M", + "email": "mart.loog@ut.ee", + "isCollectiveName": false, + "name": "Mardo Kõivomägi" + }, + { + "ForeName": "Ervin", + "LastName": "Valk", + "abbrevName": "Valk E", + "email": null, + "isCollectiveName": false, + "name": "Ervin Valk" + }, + { + "ForeName": "Rainis", + "LastName": "Venta", + "abbrevName": "Venta R", + "email": null, + "isCollectiveName": false, + "name": "Rainis Venta" + }, + { + "ForeName": "Anna", + "LastName": "Iofik", + "abbrevName": "Iofik A", + "email": null, + "isCollectiveName": false, + "name": "Anna Iofik" + }, + { + "ForeName": "Martin", + "LastName": "Lepiku", + "abbrevName": "Lepiku M", + "email": null, + "isCollectiveName": false, + "name": "Martin Lepiku" + }, + { + "ForeName": "David", + "LastName": "Morgan", + "abbrevName": "Morgan DO", + "email": null, + "isCollectiveName": false, + "name": "David O Morgan" + }, + { + "ForeName": "Mart", + "LastName": "Loog", + "abbrevName": "Loog M", + "email": null, + "isCollectiveName": false, + "name": "Mart Loog" + } + ], + "contacts": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "email": [ + "mart.loog@ut.ee" + ], + "name": "Mardo Kõivomägi" + } + ] + }, + "doi": "10.1016/j.molcel.2011.05.016", + "pmid": "21658602", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Dynamics of Cdk1 substrate specificity during the cell cycle." + } + }, + { + "pmid": "16648844", + "pubmed": { + "ISODate": "2006-06-01T00:00:00.000Z", + "abstract": "Transmembrane adhesion receptors, such as integrins, mediate cell adhesion by interacting with intracellular proteins that connect to the cytoskeleton. Talin, one such linker protein, is thought to have two roles: mediating inside-out activation of integrins, and connecting extracellular matrix (ECM)-bound integrins to the cytoskeleton. Talin's amino-terminal head, which consists of a FERM domain, binds an NPxY motif within the cytoplasmic tail of most integrin beta subunits. This is consistent with the role of FERM domains in recruiting other proteins to the plasma membrane. We tested the role of the talin-head-NPxY interaction in integrin function in Drosophila. We found that introduction of a mutation that perturbs this binding in vitro into the isolated talin head disrupts its recruitment by integrins in vivo. Surprisingly, when engineered into the full-length talin, this mutation did not disrupt talin recruitment by integrins nor its ability to connect integrins to the cytoskeleton. However, it reduced the ability of talin to strengthen integrin adhesion to the ECM, indicating that the function of the talin-head-NPxY interaction is solely to regulate integrin adhesion.", + "authors": { + "abbreviation": "Guy Tanentzapf, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": null, + "isCollectiveName": false, + "name": "Guy Tanentzapf" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1411", + "pmid": "16648844", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 8 2006", + "title": "An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton." + } + }, + { + "pmid": "27252130", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellular matrix (ECM) via its connection with the actin cytoskeleton and membrane integrins. It is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the field of mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as well as its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival. New data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states.-Haining, A. W. M., Lieberthal, T. J., del Río Hernández, A. Talin: a mechanosensitive molecule in health and disease.", + "authors": { + "abbreviation": "Alexander W M Haining, Tyler J Lieberthal, Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AW", + "email": null, + "isCollectiveName": false, + "name": "Alexander W M Haining" + }, + { + "ForeName": "Tyler", + "LastName": "Lieberthal", + "abbrevName": "Lieberthal TJ", + "email": null, + "isCollectiveName": false, + "name": "Tyler J Lieberthal" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": "a.del-rio-hernandez@imperial.ac.uk", + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [ + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "email": [ + "a.del-rio-hernandez@imperial.ac.uk" + ], + "name": "Armando Del Río Hernández" + } + ] + }, + "doi": "10.1096/fj.201500080R", + "pmid": "27252130", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FASEB J 30 2016", + "title": "Talin: a mechanosensitive molecule in health and disease." + } + }, + { + "pmid": "31539492", + "pubmed": { + "ISODate": "2019-09-19T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.", + "authors": { + "abbreviation": "Dirk Dedden, Stephanie Schumacher, Charlotte F Kelley, ..., Naoko Mizuno", + "authorList": [ + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Stephanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Schumacher" + }, + { + "ForeName": "Charlotte", + "LastName": "Kelley", + "abbrevName": "Kelley CF", + "email": null, + "isCollectiveName": false, + "name": "Charlotte F Kelley" + }, + { + "ForeName": "Martin", + "LastName": "Zacharias", + "abbrevName": "Zacharias M", + "email": null, + "isCollectiveName": false, + "name": "Martin Zacharias" + }, + { + "ForeName": "Christian", + "LastName": "Biertümpfel", + "abbrevName": "Biertümpfel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Biertümpfel" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": "mizuno@biochem.mpg.de", + "isCollectiveName": false, + "name": "Naoko Mizuno" + } + ], + "contacts": [ + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "email": [ + "mizuno@biochem.mpg.de" + ], + "name": "Naoko Mizuno" + } + ] + }, + "doi": "10.1016/j.cell.2019.08.034", + "pmid": "31539492", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell 179 2019", + "title": "The Architecture of Talin1 Reveals an Autoinhibition Mechanism." + } + }, + { + "pmid": "16081423", + "pubmed": { + "ISODate": "2005-09-23T00:00:00.000Z", + "abstract": "Previous experiments with peptide fusion proteins suggested that cyclin A/Cdk1 and Cdk2 might exhibit similar yet distinct phosphorylation specificities. Using a physiological substrate, CDP/Cux, our study confirms this notion. Proteolytic processing of CDP/Cux by cathepsin L generates the CDP/Cux p110 isoform at the beginning of S phase. CDP/Cux p110 makes stable interactions with DNA during S phase but is inhibited in G2 following the phosphorylation of serine 1237 by cyclin A/Cdk1. In this study, we propose that differential phosphorylation by cyclin A/Cdk1 and cyclin A/Cdk2 enables CDP/Cux p110 to exert its function as a transcriptional regulator specifically during S phase. We found that like cyclin A/Cdk1, cyclin A/Cdk2 interacted efficiently with recombinant CDP/Cux proteins that contain the Cut homeodomain and an adjacent cyclin-binding motif (Cy). In contrast to cyclin A/Cdk1, however, cyclin A/Cdk2 did not efficiently phosphorylate CDP/Cux p110 on serine 1237 and did not inhibit its DNA binding activity in vitro. Accordingly, co-expression with cyclin A/Cdk2 in cells did not inhibit the DNA binding and transcriptional activities of CDP/Cux p110. To confirm that the sequence surrounding serine 1237 was responsible for the differential regulation by Cdk1 and Cdk2, we replaced 4 amino acids flanking the phosphorylation site to mimic a known Cdk2 phosphorylation site present in the Cdc6 protein. Both cyclin A/Cdk2 and Cdk1 efficiently phosphorylated the CDP/Cux(Cdc6) mutant and inhibited its DNA binding activity. Altogether our results help explain why the DNA binding activity of CDP/Cux p110 is maximal during S phase and decreases in G2 phase.", + "authors": { + "abbreviation": "Marianne Santaguida, Alain Nepveu", + "authorList": [ + { + "ForeName": "Marianne", + "LastName": "Santaguida", + "abbrevName": "Santaguida M", + "email": null, + "isCollectiveName": false, + "name": "Marianne Santaguida" + }, + { + "ForeName": "Alain", + "LastName": "Nepveu", + "abbrevName": "Nepveu A", + "email": null, + "isCollectiveName": false, + "name": "Alain Nepveu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M505417200", + "pmid": "16081423", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Differential regulation of CDP/Cux p110 by cyclin A/Cdk2 and cyclin A/Cdk1." + } + }, + { + "pmid": "16460027", + "pubmed": { + "ISODate": "2006-02-14T00:00:00.000Z", + "abstract": "Talin is a key protein involved in linking integrins to the actin cytoskeleton. The long flexible talin rod domain contains a number of binding sites for vinculin, a cytoskeletal protein important in stabilizing integrin-mediated cell-matrix junctions. Here we report the solution structure of a talin rod polypeptide (residues 1843-1973) which contains a single vinculin binding site (VBS; residues 1944-1969). Like other talin rod polypeptides, it consists of a helical bundle, in this case a four-helix bundle with a right-handed topology. The residues in the VBS important for vinculin binding were identified by studying the binding of a series of VBS-related peptides to the vinculin Vd1 domain. The key binding determinants are buried in the interior of the helical bundle, suggesting that a substantial structural change in the talin polypeptide is required for vinculin binding. Direct evidence for this was obtained by NMR and EPR spectroscopy. [1H,15N]-HSQC spectra of the talin fragment indicate that vinculin binding caused approximately two-thirds of the protein to adopt a flexible random coil. For EPR spectroscopy, nitroxide spin labels were attached to the talin polypeptide via appropriately located cysteine residues. Measurements of inter-nitroxide distances in doubly spin-labeled protein showed clearly that the helical bundle is disrupted and the mobility of the helices, except for the VBS helix, is markedly increased. Binding of vinculin to talin is thus a clear example of the unusual phenomenon of protein unfolding being required for protein/protein interaction.", + "authors": { + "abbreviation": "Alexandre R Gingras, Klaus-Peter Vogel, Heinz-Jürgen Steinhoff, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Klaus-Peter", + "LastName": "Vogel", + "abbrevName": "Vogel KP", + "email": null, + "isCollectiveName": false, + "name": "Klaus-Peter Vogel" + }, + { + "ForeName": "Heinz-Jürgen", + "LastName": "Steinhoff", + "abbrevName": "Steinhoff HJ", + "email": null, + "isCollectiveName": false, + "name": "Heinz-Jürgen Steinhoff" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi052136l", + "pmid": "16460027", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 45 2006", + "title": "Structural and dynamic characterization of a vinculin binding site in the talin rod." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T15:57:52.915Z", + "_newestOpId": "0b4c7a0a-5af8-4be7-be3b-55a4aed37527", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "65414935-0004-44be-9c0a-3e8945acde43" + }, + { + "group": "unsigned", + "id": "e70f848c-4670-460b-932c-0cc788d0b5d5" + } + ], + "id": "e39d0a06-5b02-44e3-9c36-27cc1f9ac08c", + "liveId": "11cc4b53-e253-43d5-a088-dec912255a6e", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": -106.3660337552743, + "y": -95.81223628691984 + }, + "relatedPapers": [ + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "15031296", + "pubmed": { + "ISODate": "2004-05-21T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which provides a direct link between integrins and actin filaments, has been shown to contain two distinct binding sites for integrin beta subunits. Here, we report the precise delimitation and a first functional analysis of the talin rod domain integrin-binding site. Partially overlapping cDNAs covering the entire human talin gene were transiently expressed as DsRed fusion proteins in Chinese hamster ovary cells expressing alpha(IIb)beta(3), linked to green fluorescent protein (GFP). Two-color fluorescence analysis of the transfected cells, spread on fibrinogen, revealed distinct subcellular staining patterns including focal adhesion, actin filament, and granular labeling for different talin fragments. The rod domain fragment G (residues 1984-2344), devoid of any known actin- or vinculin-binding sites, colocalized with beta(3)-GFP in focal adhesions. Direct in vitro interaction of fragment G with native platelet integrin alpha(IIb)beta(3) or with the recombinant wild type, but not the Y747A mutant beta(3) cytoplasmic tail, linked to glutathione S-transferase, was demonstrated by surface plasmon resonance analysis and pull-down assays, respectively. Here, we demonstrate for the first time the in vivo relevance of this interaction by fluorescence resonance energy transfer between beta(3)-GFP and DsRed-talin fragment G. Further in vitro pull-down studies allowed us to map out the integrin-binding site within fragment G to a stretch of 130 residues (fragment J, residues 1984-2113) that also localized to focal adhesions. Finally, we show by a cell biology approach that this integrin-binding site within the talin rod domain is important for beta(3)-cytoskeletal interactions but does not participate in alpha(IIb)beta(3) activation.", + "authors": { + "abbreviation": "Laurent Tremuth, Stephanie Kreis, Chantal Melchior, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Stephanie", + "LastName": "Kreis", + "abbrevName": "Kreis S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kreis" + }, + { + "ForeName": "Chantal", + "LastName": "Melchior", + "abbrevName": "Melchior C", + "email": null, + "isCollectiveName": false, + "name": "Chantal Melchior" + }, + { + "ForeName": "Johan", + "LastName": "Hoebeke", + "abbrevName": "Hoebeke J", + "email": null, + "isCollectiveName": false, + "name": "Johan Hoebeke" + }, + { + "ForeName": "Philippe", + "LastName": "Rondé", + "abbrevName": "Rondé P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Rondé" + }, + { + "ForeName": "Sébastien", + "LastName": "Plançon", + "abbrevName": "Plançon S", + "email": null, + "isCollectiveName": false, + "name": "Sébastien Plançon" + }, + { + "ForeName": "Kenneth", + "LastName": "Takeda", + "abbrevName": "Takeda K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Takeda" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M400947200", + "pmid": "15031296", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A fluorescence cell biology approach to map the second integrin-binding site of talin to a 130-amino acid sequence within the rod domain." + } + }, + { + "pmid": "10497223", + "pubmed": { + "ISODate": "1999-10-01T00:00:00.000Z", + "abstract": "Following platelet aggregation, integrin alpha(IIb)beta(3) becomes associated with the platelet cytoskeleton. The conserved NPLY sequence represents a potential beta-turn motif in the beta(3) cytoplasmic tail and has been suggested to mediate the interaction of beta(3) integrins with talin. In the present study, we performed a double mutation (N744Q/P745A) in the integrin beta(3) subunit to test the functional significance of this beta-turn motif. Chinese hamster ovary cells were co-transfected with cDNA constructs encoding mutant beta(3) and wild type alpha(IIb). Cells expressing either wild type (A5) or mutant (D4) alpha(IIb)beta(3) adhered to fibrinogen; however, as opposed to control A5 cells, adherent D4 cells failed to spread, form focal adhesions, or initiate protein tyrosine phosphorylation. To investigate the role of the NPLY motif in talin binding, we examined the ability of the mutant alpha(IIb)beta(3) to interact with talin in a solid phase binding assay. Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin. Additionally, purified talin failed to interact with peptides containing the AKWDTANNPLYK sequence indicating that the talin binding domain in the integrin beta(3) subunit does not reside in the NPLY motif. In contrast, specific binding of talin to peptides containing the membrane-proximal HDRKEFAKFEEERARAK sequence of the beta(3) cytoplasmic tail was observed, and this interaction was blocked by a recombinant protein fragment corresponding to the 47-kDa N-terminal head domain of talin (rTalin-N). In addition, RGD affinity purified platelet alpha(IIb)beta(3) bound dose-dependently to immobilized rTalin-N, indicating that an integrin-binding site is present in the talin N-terminal head domain. Collectively, these studies demonstrate that the NPLY beta-turn motif regulates post-ligand binding functions of alpha(IIb)beta(3) in a manner independent of talin interaction. Moreover, talin was shown to bind through its N-terminal head domain to the membrane-proximal sequence of the beta(3) cytoplasmic tail.", + "authors": { + "abbreviation": "S Patil, A Jedsadayanmata, J D Wencel-Drake, ..., S C Lam", + "authorList": [ + { + "ForeName": "S", + "LastName": "Patil", + "abbrevName": "Patil S", + "email": null, + "isCollectiveName": false, + "name": "S Patil" + }, + { + "ForeName": "A", + "LastName": "Jedsadayanmata", + "abbrevName": "Jedsadayanmata A", + "email": null, + "isCollectiveName": false, + "name": "A Jedsadayanmata" + }, + { + "ForeName": "J", + "LastName": "Wencel-Drake", + "abbrevName": "Wencel-Drake JD", + "email": null, + "isCollectiveName": false, + "name": "J D Wencel-Drake" + }, + { + "ForeName": "W", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "W Wang" + }, + { + "ForeName": "I", + "LastName": "Knezevic", + "abbrevName": "Knezevic I", + "email": null, + "isCollectiveName": false, + "name": "I Knezevic" + }, + { + "ForeName": "S", + "LastName": "Lam", + "abbrevName": "Lam SC", + "email": null, + "isCollectiveName": false, + "name": "S C Lam" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.274.40.28575", + "pmid": "10497223", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 274 1999", + "title": "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "31393109", + "pubmed": { + "ISODate": "2019-11-26T00:00:00.000Z", + "abstract": "Mechanotransduction from the extracellular matrix into the cell is primarily supervised by a transmembrane receptor, integrin, and a cytosolic protein, talin. Integrin binds ligands on the extracellular side, whereas talin couples integrin receptors to the actin cytoskeleton and later acts as a \"force buffer\". Talin and integrin together form a mechanosensitive signaling hub that regulates crucial cellular processes and pathways, including cell signaling and formation of focal adhesion complexes, which help cells to sense their mechano-environment and transduce the signal accordingly. Although both proteins function in tandem, most literature focuses on them individually. Here, we provide a focused review of the talin-integrin mechano-interactome network in light of its role in the process of mechanotransduction and its connection to diseases. While working under force, these proteins drive numerous biomolecular interactions and form adhesion complexes, which in turn control many physiological processes such as cell migration; thus, they are invariably associated with several diseases from leukocyte adhesion deficiency to cancer. Gaining insights into their role in the occurrence of these pathological disorders might lead us to establish treatment methods and therapeutic techniques.", + "authors": { + "abbreviation": "Soham Chakraborty, Souradeep Banerjee, Manasven Raina, Shubhasis Haldar", + "authorList": [ + { + "ForeName": "Soham", + "LastName": "Chakraborty", + "abbrevName": "Chakraborty S", + "email": null, + "isCollectiveName": false, + "name": "Soham Chakraborty" + }, + { + "ForeName": "Souradeep", + "LastName": "Banerjee", + "abbrevName": "Banerjee S", + "email": null, + "isCollectiveName": false, + "name": "Souradeep Banerjee" + }, + { + "ForeName": "Manasven", + "LastName": "Raina", + "abbrevName": "Raina M", + "email": null, + "isCollectiveName": false, + "name": "Manasven Raina" + }, + { + "ForeName": "Shubhasis", + "LastName": "Haldar", + "abbrevName": "Haldar S", + "email": null, + "isCollectiveName": false, + "name": "Shubhasis Haldar" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.biochem.9b00442", + "pmid": "31393109", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochemistry 58 2019", + "title": "Force-Directed \"Mechanointeractome\" of Talin-Integrin." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "34708856", + "pubmed": { + "ISODate": "2021-10-15T00:00:00.000Z", + "abstract": "Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches - proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.", + "authors": { + "abbreviation": "Benjamin T Goult, Nicholas H Brown, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.258749", + "pmid": "34708856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 134 2021", + "title": "Talin in mechanotransduction and mechanomemory at a glance." + } + }, + { + "pmid": "18550856", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Leukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (K(d), 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (K(d), 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated beta2 integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion.", + "authors": { + "abbreviation": "Heikki Takala, Elisa Nurminen, Susanna M Nurmi, ..., Susanna C Fagerholm", + "authorList": [ + { + "ForeName": "Heikki", + "LastName": "Takala", + "abbrevName": "Takala H", + "email": null, + "isCollectiveName": false, + "name": "Heikki Takala" + }, + { + "ForeName": "Elisa", + "LastName": "Nurminen", + "abbrevName": "Nurminen E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Nurminen" + }, + { + "ForeName": "Susanna", + "LastName": "Nurmi", + "abbrevName": "Nurmi SM", + "email": null, + "isCollectiveName": false, + "name": "Susanna M Nurmi" + }, + { + "ForeName": "Maria", + "LastName": "Aatonen", + "abbrevName": "Aatonen M", + "email": null, + "isCollectiveName": false, + "name": "Maria Aatonen" + }, + { + "ForeName": "Tomas", + "LastName": "Strandin", + "abbrevName": "Strandin T", + "email": null, + "isCollectiveName": false, + "name": "Tomas Strandin" + }, + { + "ForeName": "Maarit", + "LastName": "Takatalo", + "abbrevName": "Takatalo M", + "email": null, + "isCollectiveName": false, + "name": "Maarit Takatalo" + }, + { + "ForeName": "Tiila", + "LastName": "Kiema", + "abbrevName": "Kiema T", + "email": null, + "isCollectiveName": false, + "name": "Tiila Kiema" + }, + { + "ForeName": "Carl", + "LastName": "Gahmberg", + "abbrevName": "Gahmberg CG", + "email": null, + "isCollectiveName": false, + "name": "Carl G Gahmberg" + }, + { + "ForeName": "Jari", + "LastName": "Ylänne", + "abbrevName": "Ylänne J", + "email": null, + "isCollectiveName": false, + "name": "Jari Ylänne" + }, + { + "ForeName": "Susanna", + "LastName": "Fagerholm", + "abbrevName": "Fagerholm SC", + "email": null, + "isCollectiveName": false, + "name": "Susanna C Fagerholm" + } + ], + "contacts": [] + }, + "doi": "10.1182/blood-2007-12-127795", + "pmid": "18550856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Blood 112 2008", + "title": "Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding." + } + }, + { + "pmid": "7622520", + "pubmed": { + "ISODate": "1995-07-14T00:00:00.000Z", + "abstract": "The interaction of cells with extracellular matrix proteins plays a critical role in a variety of biological processes. Recent studies suggest that cell-matrix interactions mediated by integrins can transduce biochemical signals to the cell interior that regulate cell proliferation and differentiation. These studies have placed the focal adhesion kinase (FAK), an intracellular protein tyrosine kinase, in a central position in integrin-initiated signal transduction pathways (Zachary, I., and Rozengurt, E. (1992) Cell 71, 891-894; Schaller, M., and Parsons, J. T. (1993) Trends Cell Biol. 3, 258-262). Here, we report data suggesting a possible association of FAK with the cytoskeletal protein talin in NIH 3T3 cells. We have identified a 48-amino acid sequence in the carboxyl-terminal domain of FAK necessary for talin binding in vitro. Furthermore, we have correlated the ability of integrin to induce FAK phosphorylation with its ability to bind talin using a mutant integrin lacking the carboxyl-terminal 13 amino acids. These studies suggest talin may be a mediator for FAK activation in signaling initiated by integrins and may provide an explanation for the dependence on the integrity of actin-cytoskeleton of multiple intracellular signaling pathways converging to FAK activation and autophosphorylation.", + "authors": { + "abbreviation": "H C Chen, P A Appeddu, J T Parsons, ..., J L Guan", + "authorList": [ + { + "ForeName": "H", + "LastName": "Chen", + "abbrevName": "Chen HC", + "email": null, + "isCollectiveName": false, + "name": "H C Chen" + }, + { + "ForeName": "P", + "LastName": "Appeddu", + "abbrevName": "Appeddu PA", + "email": null, + "isCollectiveName": false, + "name": "P A Appeddu" + }, + { + "ForeName": "J", + "LastName": "Parsons", + "abbrevName": "Parsons JT", + "email": null, + "isCollectiveName": false, + "name": "J T Parsons" + }, + { + "ForeName": "J", + "LastName": "Hildebrand", + "abbrevName": "Hildebrand JD", + "email": null, + "isCollectiveName": false, + "name": "J D Hildebrand" + }, + { + "ForeName": "M", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "M D Schaller" + }, + { + "ForeName": "J", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "J L Guan" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.270.28.16995", + "pmid": "7622520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 270 1995", + "title": "Interaction of focal adhesion kinase with cytoskeletal protein talin." + } + }, + { + "pmid": "21658602", + "pubmed": { + "ISODate": "2011-06-10T00:00:00.000Z", + "abstract": "Cdk specificity is determined by the intrinsic selectivity of the active site and by substrate docking sites on the cyclin subunit. There is a long-standing debate about the relative importance of these factors in the timing of Cdk1 substrate phosphorylation. We analyzed major budding yeast cyclins (the G1/S-cyclin Cln2, S-cyclin Clb5, G2/M-cyclin Clb3, and M-cyclin Clb2) and found that the activity of Cdk1 toward the consensus motif increased gradually in the sequence Cln2-Clb5-Clb3-Clb2, in parallel with cell cycle progression. Further, we identified a docking element that compensates for the weak intrinsic specificity of Cln2 toward G1-specific targets. In addition, Cln2-Cdk1 showed distinct consensus site specificity, suggesting that cyclins do not merely activate Cdk1 but also modulate its active-site specificity. Finally, we identified several Cln2-, Clb3-, and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1.", + "authors": { + "abbreviation": "Mardo Kõivomägi, Ervin Valk, Rainis Venta, ..., Mart Loog", + "authorList": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "abbrevName": "Kõivomägi M", + "email": "mart.loog@ut.ee", + "isCollectiveName": false, + "name": "Mardo Kõivomägi" + }, + { + "ForeName": "Ervin", + "LastName": "Valk", + "abbrevName": "Valk E", + "email": null, + "isCollectiveName": false, + "name": "Ervin Valk" + }, + { + "ForeName": "Rainis", + "LastName": "Venta", + "abbrevName": "Venta R", + "email": null, + "isCollectiveName": false, + "name": "Rainis Venta" + }, + { + "ForeName": "Anna", + "LastName": "Iofik", + "abbrevName": "Iofik A", + "email": null, + "isCollectiveName": false, + "name": "Anna Iofik" + }, + { + "ForeName": "Martin", + "LastName": "Lepiku", + "abbrevName": "Lepiku M", + "email": null, + "isCollectiveName": false, + "name": "Martin Lepiku" + }, + { + "ForeName": "David", + "LastName": "Morgan", + "abbrevName": "Morgan DO", + "email": null, + "isCollectiveName": false, + "name": "David O Morgan" + }, + { + "ForeName": "Mart", + "LastName": "Loog", + "abbrevName": "Loog M", + "email": null, + "isCollectiveName": false, + "name": "Mart Loog" + } + ], + "contacts": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "email": [ + "mart.loog@ut.ee" + ], + "name": "Mardo Kõivomägi" + } + ] + }, + "doi": "10.1016/j.molcel.2011.05.016", + "pmid": "21658602", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Dynamics of Cdk1 substrate specificity during the cell cycle." + } + }, + { + "pmid": "16648844", + "pubmed": { + "ISODate": "2006-06-01T00:00:00.000Z", + "abstract": "Transmembrane adhesion receptors, such as integrins, mediate cell adhesion by interacting with intracellular proteins that connect to the cytoskeleton. Talin, one such linker protein, is thought to have two roles: mediating inside-out activation of integrins, and connecting extracellular matrix (ECM)-bound integrins to the cytoskeleton. Talin's amino-terminal head, which consists of a FERM domain, binds an NPxY motif within the cytoplasmic tail of most integrin beta subunits. This is consistent with the role of FERM domains in recruiting other proteins to the plasma membrane. We tested the role of the talin-head-NPxY interaction in integrin function in Drosophila. We found that introduction of a mutation that perturbs this binding in vitro into the isolated talin head disrupts its recruitment by integrins in vivo. Surprisingly, when engineered into the full-length talin, this mutation did not disrupt talin recruitment by integrins nor its ability to connect integrins to the cytoskeleton. However, it reduced the ability of talin to strengthen integrin adhesion to the ECM, indicating that the function of the talin-head-NPxY interaction is solely to regulate integrin adhesion.", + "authors": { + "abbreviation": "Guy Tanentzapf, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": null, + "isCollectiveName": false, + "name": "Guy Tanentzapf" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1411", + "pmid": "16648844", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 8 2006", + "title": "An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton." + } + }, + { + "pmid": "11591813", + "pubmed": { + "ISODate": "2001-09-01T00:00:00.000Z", + "abstract": "Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.", + "authors": { + "abbreviation": "C R Carlson, O Witczak, L Vossebein, ..., K Taskén", + "authorList": [ + { + "ForeName": "C", + "LastName": "Carlson", + "abbrevName": "Carlson CR", + "email": "cathrine.carlson@basalmed.uio.no", + "isCollectiveName": false, + "name": "C R Carlson" + }, + { + "ForeName": "O", + "LastName": "Witczak", + "abbrevName": "Witczak O", + "email": null, + "isCollectiveName": false, + "name": "O Witczak" + }, + { + "ForeName": "L", + "LastName": "Vossebein", + "abbrevName": "Vossebein L", + "email": null, + "isCollectiveName": false, + "name": "L Vossebein" + }, + { + "ForeName": "J", + "LastName": "Labbé", + "abbrevName": "Labbé JC", + "email": null, + "isCollectiveName": false, + "name": "J C Labbé" + }, + { + "ForeName": "B", + "LastName": "Skålhegg", + "abbrevName": "Skålhegg BS", + "email": null, + "isCollectiveName": false, + "name": "B S Skålhegg" + }, + { + "ForeName": "G", + "LastName": "Keryer", + "abbrevName": "Keryer G", + "email": null, + "isCollectiveName": false, + "name": "G Keryer" + }, + { + "ForeName": "F", + "LastName": "Herberg", + "abbrevName": "Herberg FW", + "email": null, + "isCollectiveName": false, + "name": "F W Herberg" + }, + { + "ForeName": "P", + "LastName": "Collas", + "abbrevName": "Collas P", + "email": null, + "isCollectiveName": false, + "name": "P Collas" + }, + { + "ForeName": "K", + "LastName": "Taskén", + "abbrevName": "Taskén K", + "email": null, + "isCollectiveName": false, + "name": "K Taskén" + } + ], + "contacts": [ + { + "ForeName": "C", + "LastName": "Carlson", + "email": [ + "cathrine.carlson@basalmed.uio.no" + ], + "name": "C R Carlson" + } + ] + }, + "doi": "10.1242/jcs.114.18.3243", + "pmid": "11591813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 114 2001", + "title": "CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis." + } + }, + { + "pmid": "27603133", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The p17 protein of avian reovirus (ARV) causes cell cycle retardation in a variety of cell lines; however, the underlying mechanism(s) by which p17 regulates the cell cycle remains largely unknown. We demonstrate for the first time that p17 interacts with CDK1 and vimentin as revealed by reciprocal co-immunoprecipitation and GST pull-down assays. Both in vitro and in vivo studies indicated that direct interaction of p17 and CDK1/vimentin was mapped within the amino terminus (aa 1-60) of p17 and central region (aa 27-118) of CDK1/vimentin. Furthermore, p17 was found to occupy the Plk1-binding site within the vimentin, thereby blocking Plk1 recruitment to CDK1-induced vimentin phosphorylation at Ser 56. Interaction of p17 to CDK1 or vimentin interferes with CDK1-catalyzed phosphorylation of vimentin at Ser 56 and subsequently vimentin phosphorylation at Ser 82 by Plk1. Furthermore, we have identified upstream signaling pathways and cellular factor(s) targeted by p17 and found that p17 regulates inhibitory phosphorylation of CDK1 and blocks vimentin phosphorylation at Ser 56 and Ser 82. The p17-mediated inactivation of CDK1 is dependent on several mechanisms, which include direct interaction with CDK1, p17-mediated suppression of Plk1 by activating the Tpr/p53 and ATM/Chk1/PP2A pathways, and p17-mediated cdc25C degradation via an ubiquitin- proteasome pathway. Additionally, depletion of p53 with a shRNA as well as inhibition of ATM and vimentin by inhibitors diminished virus yield while Tpr and CDK1 knockdown increased virus yield. Taken together, results demonstrate that p17 suppresses both CDK1 and Plk1functions, disrupts vimentin phosphorylation, causes G2/M cell cycle arrest and thus benefits virus replication. ", + "authors": { + "abbreviation": "Hung-Chuan Chiu, Wei-Ru Huang, Tsai-Ling Liao, ..., Hung-Jen Liu", + "authorList": [ + { + "ForeName": "Hung-Chuan", + "LastName": "Chiu", + "abbrevName": "Chiu HC", + "email": null, + "isCollectiveName": false, + "name": "Hung-Chuan Chiu" + }, + { + "ForeName": "Wei-Ru", + "LastName": "Huang", + "abbrevName": "Huang WR", + "email": null, + "isCollectiveName": false, + "name": "Wei-Ru Huang" + }, + { + "ForeName": "Tsai-Ling", + "LastName": "Liao", + "abbrevName": "Liao TL", + "email": null, + "isCollectiveName": false, + "name": "Tsai-Ling Liao" + }, + { + "ForeName": "Hung-Yi", + "LastName": "Wu", + "abbrevName": "Wu HY", + "email": null, + "isCollectiveName": false, + "name": "Hung-Yi Wu" + }, + { + "ForeName": "Muhammad", + "LastName": "Munir", + "abbrevName": "Munir M", + "email": null, + "isCollectiveName": false, + "name": "Muhammad Munir" + }, + { + "ForeName": "Wing-Ling", + "LastName": "Shih", + "abbrevName": "Shih WL", + "email": null, + "isCollectiveName": false, + "name": "Wing-Ling Shih" + }, + { + "ForeName": "Hung-Jen", + "LastName": "Liu", + "abbrevName": "Liu HJ", + "email": null, + "isCollectiveName": false, + "name": "Hung-Jen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0162356", + "pmid": "27603133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 11 2016", + "title": "Suppression of Vimentin Phosphorylation by the Avian Reovirus p17 through Inhibition of CDK1 and Plk1 Impacting the G2/M Phase of the Cell Cycle." + } + }, + { + "pmid": "19948488", + "pubmed": { + "ISODate": "2009-11-30T00:00:00.000Z", + "abstract": "Integrin-dependent adhesion sites consist of clustered integrins that transmit mechanical forces and provide signaling required for cell survival and morphogenesis. Despite their importance, the regulation of integrin clustering by the cytoplasmic adapter protein talin (Tal) and phosphatidylinositol (PI)-4,5-biphosphate (PI(4,5)P(2)) lipids nor their dynamic coupling to the actin cytoskeleton is fully understood. By using a Tal-dependent integrin clustering assay in intact cells, we identified a PI(4,5)P(2)-binding basic ridge spanning across the F2 and F3 domains of the Tal head that regulates integrin clustering. Clustering requires a new PI(4,5)P(2)-binding site in F2 and is negatively regulated by autoinhibitory interactions between F3 and the Tal rod (Tal-R). The release of the Tal-R exposes a new beta3-integrin-binding site in F3, enabling interaction with a membrane proximal acidic motif, which involves the formation of salt bridges between K(316) and K(324) with E(726) and D(723), respectively. This interaction shields the beta-integrin tail from reassociation with its alpha subunit, thereby maintaining the integrin in a substrate-binding and clustering-competent form.", + "authors": { + "abbreviation": "Frédéric Saltel, Eva Mortier, Vesa P Hytönen, ..., Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Frédéric", + "LastName": "Saltel", + "abbrevName": "Saltel F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Saltel" + }, + { + "ForeName": "Eva", + "LastName": "Mortier", + "abbrevName": "Mortier E", + "email": null, + "isCollectiveName": false, + "name": "Eva Mortier" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Marie-Claude", + "LastName": "Jacquier", + "abbrevName": "Jacquier MC", + "email": null, + "isCollectiveName": false, + "name": "Marie-Claude Jacquier" + }, + { + "ForeName": "Pascale", + "LastName": "Zimmermann", + "abbrevName": "Zimmermann P", + "email": null, + "isCollectiveName": false, + "name": "Pascale Zimmermann" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": null, + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200908134", + "pmid": "19948488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 187 2009", + "title": "New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering." + } + }, + { + "pmid": "17430904", + "pubmed": { + "ISODate": "2007-06-08T00:00:00.000Z", + "abstract": "Talin1 is a large cytoskeletal protein that links integrins to actin filaments through two distinct integrin binding sites, one present in the talin head domain (IBS1) necessary for integrin activation and a second (IBS2) that we have previously mapped to talin residues 1984-2113 (fragment J) of the talin rod domain (1 Tremuth, L., Kreis, S., Melchior, C., Hoebeke, J., Ronde, P., Plancon, S., Takeda, K., and Kieffer, N. (2004) J. Biol. Chem. 279, 22258-22266), but whose functional role is still elusive. Using a bioinformatics and cell biology approach, we have determined the minimal structure of IBS2 and show that this integrin binding site corresponds to 23 residues located in alpha helix 50 of the talin rod domain (residues 2077-2099). Alanine mutation of 2 highly conserved residues (L2094A/I2095A) within this alpha helix, which disrupted the alpha-helical structure of IBS2 as demonstrated by infrared spectroscopy and limited trypsin proteolysis, was sufficient to prevent in vivo talin fragment J targeting to alphaIIbbeta3 integrin in focal adhesions and to inhibit in vitro this association as shown by an alphaIIbbeta3 pulldown assay. Moreover, expression of a full-length mouse green fluorescent protein-talin LI/AA mutant in mouse talin1(-/-) cells was unable to rescue the inability of these cells to assemble focal adhesions (in contrast to green fluorescent protein-talin wild type) despite the presence of IBS1. Our data provide the first direct evidence that IBS2 in the talin rod is essential to link integrins to the cytoskeleton.", + "authors": { + "abbreviation": "Michèle Moes, Sophie Rodius, Stacey J Coleman, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Michèle", + "LastName": "Moes", + "abbrevName": "Moes M", + "email": null, + "isCollectiveName": false, + "name": "Michèle Moes" + }, + { + "ForeName": "Sophie", + "LastName": "Rodius", + "abbrevName": "Rodius S", + "email": null, + "isCollectiveName": false, + "name": "Sophie Rodius" + }, + { + "ForeName": "Stacey", + "LastName": "Coleman", + "abbrevName": "Coleman SJ", + "email": null, + "isCollectiveName": false, + "name": "Stacey J Coleman" + }, + { + "ForeName": "Susan", + "LastName": "Monkley", + "abbrevName": "Monkley SJ", + "email": null, + "isCollectiveName": false, + "name": "Susan J Monkley" + }, + { + "ForeName": "Erik", + "LastName": "Goormaghtigh", + "abbrevName": "Goormaghtigh E", + "email": null, + "isCollectiveName": false, + "name": "Erik Goormaghtigh" + }, + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Corinne", + "LastName": "Kox", + "abbrevName": "Kox C", + "email": null, + "isCollectiveName": false, + "name": "Corinne Kox" + }, + { + "ForeName": "Patrick", + "LastName": "van der Holst", + "abbrevName": "van der Holst PP", + "email": null, + "isCollectiveName": false, + "name": "Patrick P G van der Holst" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M611846200", + "pmid": "17430904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 282 2007", + "title": "The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin beta subunits to the cytoskeleton." + } + }, + { + "pmid": "30254158", + "pubmed": { + "ISODate": "2018-10-09T00:00:00.000Z", + "abstract": "Multicellular organisms have well-defined, tightly regulated mechanisms for cell adhesion. Heterodimeric αβ integrin receptors play central roles in this function and regulate processes for normal cell functions, including signaling, cell migration, and development, binding to the extracellular matrix, and senescence. They are involved in hemostasis and the immune response, participate in leukocyte function, and have biological implications in angiogenesis and cancer. Proper control of integrin activation for cellular communication with the external environment requires several physiological processes. Perturbation of these equilibria may lead to constitutive integrin activation that results in bleeding disorders. Furthermore, integrins play key roles in cancer progression and metastasis in which certain tumor types exhibit higher levels of various integrins. Thus, the integrin-associated signaling complex is important for cancer therapy development. During inside-out signaling, the cytoskeletal protein talin plays a key role in regulating integrin affinity whereby the talin head domain activates integrin by binding to the cytoplasmic tail of β-integrin and acidic membrane phospholipids. To understand the mechanism of integrin activation by talin, we determined the crystal structure of the talin head domain bound to the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), allowing us to design a lipid-binding-deficient talin mutant. Our confocal microscopy with talin knockout cells suggests that the talin-cell membrane interaction seems essential for focal adhesion formation and stabilization. Basal integrin activation in Chinese hamster ovary cells suggests that the lipid-binding-deficient talin mutant inhibits integrin activation. Thus, membrane attachment of talin seems necessary for integrin activation and focal adhesion formation.", + "authors": { + "abbreviation": "Krishna Chinthalapudi, Erumbi S Rangarajan, Tina Izard", + "authorList": [ + { + "ForeName": "Krishna", + "LastName": "Chinthalapudi", + "abbrevName": "Chinthalapudi K", + "email": null, + "isCollectiveName": false, + "name": "Krishna Chinthalapudi" + }, + { + "ForeName": "Erumbi", + "LastName": "Rangarajan", + "abbrevName": "Rangarajan ES", + "email": null, + "isCollectiveName": false, + "name": "Erumbi S Rangarajan" + }, + { + "ForeName": "Tina", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": "cmorrow@scripps.edu", + "isCollectiveName": false, + "name": "Tina Izard" + } + ], + "contacts": [ + { + "ForeName": "Tina", + "LastName": "Izard", + "email": [ + "cmorrow@scripps.edu" + ], + "name": "Tina Izard" + } + ] + }, + "doi": "10.1073/pnas.1806275115", + "pmid": "30254158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation." + } + }, + { + "pmid": "29930204", + "pubmed": { + "ISODate": "2018-09-03T00:00:00.000Z", + "abstract": "In most tissues, anchorage-dependent growth and cell cycle progression are dependent on cells engaging extracellular matrices (ECMs) via integrin-receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings before division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell adhesion to the ECM. In this study, we demonstrate that cyclin-dependent kinase 1 (CDK1) mediates this link. CDK1, in complex with cyclin A2, promotes adhesion complex and actin cytoskeleton organization during interphase and mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area decreases in G2, and disassembly occurs several hours before mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1 is therefore the trigger that initiates remodeling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.", + "authors": { + "abbreviation": "Matthew C Jones, Janet A Askari, Jonathan D Humphries, Martin J Humphries", + "authorList": [ + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1083/jcb.201802088", + "pmid": "29930204", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Cell adhesion is regulated by CDK1 during the cell cycle." + } + }, + { + "pmid": "20150896", + "pubmed": { + "ISODate": "2010-03-17T00:00:00.000Z", + "abstract": "Talin is a 270-kDa protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM domain comprised of F1, F2 and F3 domains, but it is atypical in that F1 contains a large insert and is preceded by an extra domain F0. Although F3 contains the binding site for beta-integrin tails, F0 and F1 are also required for activation of beta1-integrins. Here, we report the solution structures of F0, F1 and of the F0F1 double domain. Both F0 and F1 have ubiquitin-like folds joined in a novel fixed orientation by an extensive charged interface. The F1 insert forms a loop with helical propensity, and basic residues predicted to reside on one surface of the helix are required for binding to acidic phospholipids and for talin-mediated activation of beta1-integrins. This and the fact that basic residues on F2 and F3 are also essential for integrin activation suggest that extensive interactions between the talin FERM domain and acidic membrane phospholipids are required to orientate the FERM domain such that it can activate integrins.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, Paul R Elliott, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1038/emboj.2010.4", + "pmid": "20150896", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 29 2010", + "title": "Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "22496808", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Talin is a large (∼2540 residues) dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs), where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell.", + "authors": { + "abbreviation": "Neil Bate, Alexandre R Gingras, Alexia Bachir, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir A", + "email": null, + "isCollectiveName": false, + "name": "Alexia Bachir" + }, + { + "ForeName": "Rick", + "LastName": "Horwitz", + "abbrevName": "Horwitz R", + "email": null, + "isCollectiveName": false, + "name": "Rick Horwitz" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0034461", + "pmid": "22496808", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics." + } + }, + { + "pmid": "27252130", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellular matrix (ECM) via its connection with the actin cytoskeleton and membrane integrins. It is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the field of mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as well as its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival. New data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states.-Haining, A. W. M., Lieberthal, T. J., del Río Hernández, A. Talin: a mechanosensitive molecule in health and disease.", + "authors": { + "abbreviation": "Alexander W M Haining, Tyler J Lieberthal, Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AW", + "email": null, + "isCollectiveName": false, + "name": "Alexander W M Haining" + }, + { + "ForeName": "Tyler", + "LastName": "Lieberthal", + "abbrevName": "Lieberthal TJ", + "email": null, + "isCollectiveName": false, + "name": "Tyler J Lieberthal" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": "a.del-rio-hernandez@imperial.ac.uk", + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [ + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "email": [ + "a.del-rio-hernandez@imperial.ac.uk" + ], + "name": "Armando Del Río Hernández" + } + ] + }, + "doi": "10.1096/fj.201500080R", + "pmid": "27252130", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FASEB J 30 2016", + "title": "Talin: a mechanosensitive molecule in health and disease." + } + }, + { + "pmid": "16081423", + "pubmed": { + "ISODate": "2005-09-23T00:00:00.000Z", + "abstract": "Previous experiments with peptide fusion proteins suggested that cyclin A/Cdk1 and Cdk2 might exhibit similar yet distinct phosphorylation specificities. Using a physiological substrate, CDP/Cux, our study confirms this notion. Proteolytic processing of CDP/Cux by cathepsin L generates the CDP/Cux p110 isoform at the beginning of S phase. CDP/Cux p110 makes stable interactions with DNA during S phase but is inhibited in G2 following the phosphorylation of serine 1237 by cyclin A/Cdk1. In this study, we propose that differential phosphorylation by cyclin A/Cdk1 and cyclin A/Cdk2 enables CDP/Cux p110 to exert its function as a transcriptional regulator specifically during S phase. We found that like cyclin A/Cdk1, cyclin A/Cdk2 interacted efficiently with recombinant CDP/Cux proteins that contain the Cut homeodomain and an adjacent cyclin-binding motif (Cy). In contrast to cyclin A/Cdk1, however, cyclin A/Cdk2 did not efficiently phosphorylate CDP/Cux p110 on serine 1237 and did not inhibit its DNA binding activity in vitro. Accordingly, co-expression with cyclin A/Cdk2 in cells did not inhibit the DNA binding and transcriptional activities of CDP/Cux p110. To confirm that the sequence surrounding serine 1237 was responsible for the differential regulation by Cdk1 and Cdk2, we replaced 4 amino acids flanking the phosphorylation site to mimic a known Cdk2 phosphorylation site present in the Cdc6 protein. Both cyclin A/Cdk2 and Cdk1 efficiently phosphorylated the CDP/Cux(Cdc6) mutant and inhibited its DNA binding activity. Altogether our results help explain why the DNA binding activity of CDP/Cux p110 is maximal during S phase and decreases in G2 phase.", + "authors": { + "abbreviation": "Marianne Santaguida, Alain Nepveu", + "authorList": [ + { + "ForeName": "Marianne", + "LastName": "Santaguida", + "abbrevName": "Santaguida M", + "email": null, + "isCollectiveName": false, + "name": "Marianne Santaguida" + }, + { + "ForeName": "Alain", + "LastName": "Nepveu", + "abbrevName": "Nepveu A", + "email": null, + "isCollectiveName": false, + "name": "Alain Nepveu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M505417200", + "pmid": "16081423", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Differential regulation of CDP/Cux p110 by cyclin A/Cdk2 and cyclin A/Cdk1." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "28701514", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and Drosophila to present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.", + "authors": { + "abbreviation": "Benjamin Klapholz, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": "nb117@cam.ac.uk", + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Brown", + "email": [ + "nb117@cam.ac.uk" + ], + "name": "Nicholas H Brown" + } + ] + }, + "doi": "10.1242/jcs.190991", + "pmid": "28701514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "Talin - the master of integrin adhesions." + } + }, + { + "pmid": "16460027", + "pubmed": { + "ISODate": "2006-02-14T00:00:00.000Z", + "abstract": "Talin is a key protein involved in linking integrins to the actin cytoskeleton. The long flexible talin rod domain contains a number of binding sites for vinculin, a cytoskeletal protein important in stabilizing integrin-mediated cell-matrix junctions. Here we report the solution structure of a talin rod polypeptide (residues 1843-1973) which contains a single vinculin binding site (VBS; residues 1944-1969). Like other talin rod polypeptides, it consists of a helical bundle, in this case a four-helix bundle with a right-handed topology. The residues in the VBS important for vinculin binding were identified by studying the binding of a series of VBS-related peptides to the vinculin Vd1 domain. The key binding determinants are buried in the interior of the helical bundle, suggesting that a substantial structural change in the talin polypeptide is required for vinculin binding. Direct evidence for this was obtained by NMR and EPR spectroscopy. [1H,15N]-HSQC spectra of the talin fragment indicate that vinculin binding caused approximately two-thirds of the protein to adopt a flexible random coil. For EPR spectroscopy, nitroxide spin labels were attached to the talin polypeptide via appropriately located cysteine residues. Measurements of inter-nitroxide distances in doubly spin-labeled protein showed clearly that the helical bundle is disrupted and the mobility of the helices, except for the VBS helix, is markedly increased. Binding of vinculin to talin is thus a clear example of the unusual phenomenon of protein unfolding being required for protein/protein interaction.", + "authors": { + "abbreviation": "Alexandre R Gingras, Klaus-Peter Vogel, Heinz-Jürgen Steinhoff, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Klaus-Peter", + "LastName": "Vogel", + "abbrevName": "Vogel KP", + "email": null, + "isCollectiveName": false, + "name": "Klaus-Peter Vogel" + }, + { + "ForeName": "Heinz-Jürgen", + "LastName": "Steinhoff", + "abbrevName": "Steinhoff HJ", + "email": null, + "isCollectiveName": false, + "name": "Heinz-Jürgen Steinhoff" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi052136l", + "pmid": "16460027", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 45 2006", + "title": "Structural and dynamic characterization of a vinculin binding site in the talin rod." + } + }, + { + "pmid": "31539492", + "pubmed": { + "ISODate": "2019-09-19T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.", + "authors": { + "abbreviation": "Dirk Dedden, Stephanie Schumacher, Charlotte F Kelley, ..., Naoko Mizuno", + "authorList": [ + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Stephanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Schumacher" + }, + { + "ForeName": "Charlotte", + "LastName": "Kelley", + "abbrevName": "Kelley CF", + "email": null, + "isCollectiveName": false, + "name": "Charlotte F Kelley" + }, + { + "ForeName": "Martin", + "LastName": "Zacharias", + "abbrevName": "Zacharias M", + "email": null, + "isCollectiveName": false, + "name": "Martin Zacharias" + }, + { + "ForeName": "Christian", + "LastName": "Biertümpfel", + "abbrevName": "Biertümpfel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Biertümpfel" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": "mizuno@biochem.mpg.de", + "isCollectiveName": false, + "name": "Naoko Mizuno" + } + ], + "contacts": [ + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "email": [ + "mizuno@biochem.mpg.de" + ], + "name": "Naoko Mizuno" + } + ] + }, + "doi": "10.1016/j.cell.2019.08.034", + "pmid": "31539492", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell 179 2019", + "title": "The Architecture of Talin1 Reveals an Autoinhibition Mechanism." + } + }, + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "16135522", + "pubmed": { + "ISODate": "2005-11-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. Three vinculin binding sites (VBS1-3) have previously been identified in the talin rod using a yeast two-hybrid assay. To extend these studies, we spot-synthesized a series of peptides spanning all the alpha-helical regions predicted for the talin rod and identified eight additional VBSs, two of which overlap key functional regions of the rod, including the integrin binding site and C-terminal actin binding site. The talin VBS alpha-helices bind to a hydrophobic cleft in the N-terminal vinculin Vd1 domain. We have defined the specificity of this interaction by spot-synthesizing a series of 25-mer talin VBS1 peptides containing substitutions with all the commonly occurring amino acids. The consensus for recognition is LXXAAXXVAXX- VXXLIXXA with distinct classes of hydrophobic side chains at positions 1, 4, 5, 8, 9, 12, 15, and 16 required for vinculin binding. Positions 1, 8, 12, 15, and 16 require an aliphatic residue and will not tolerate alanine, whereas positions 4, 5, and 9 are less restrictive. These preferences are common to all 11 VBS sequences with a minor variation occurring in one case. A crystal structure of this variant VBS peptide in complex with the vinculin Vd1 domain reveals a subtly different mode of vinculin binding.", + "authors": { + "abbreviation": "Alexandre R Gingras, Wolfgang H Ziegler, Ronald Frank, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M508060200", + "pmid": "16135522", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-01T19:41:03.005Z", + "_newestOpId": "10c25618-5691-4737-ab99-13d59e0574c6", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "116940" + }, + { + "db": "HGNC", + "id": "HGNC:1722" + }, + { + "db": "Ensembl", + "id": "ENSG00000170312" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 10.753665, + "id": "983", + "name": "CDK1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "CDC2", + "CDC28A", + "P34CDC2", + "cyclin-dependent kinase 1", + "cell cycle controller CDC2", + "cell division control protein 2 homolog", + "cell division cycle 2, G1 to S and G2 to M", + "cell division protein kinase 1", + "p34 protein kinase", + "cyclin dependent kinase 1" + ], + "synonyms": [ + "CDC2", + "CDC28A", + "P34CDC2", + "cyclin-dependent kinase 1", + "cell cycle controller CDC2", + "cell division control protein 2 homolog", + "cell division cycle 2, G1 to S and G2 to M", + "cell division protein kinase 1", + "p34 protein kinase", + "cyclin dependent kinase 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "65414935-0004-44be-9c0a-3e8945acde43", + "liveId": "9d203cd6-ea31-4053-aa45-bddb169b6546", + "lock": null, + "locked": false, + "name": "CDK1", + "position": { + "x": 152.22842622665317, + "y": -66.51373871496378 + }, + "relatedPapers": [ + { + "pmid": "34708856", + "pubmed": { + "ISODate": "2021-10-15T00:00:00.000Z", + "abstract": "Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches - proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.", + "authors": { + "abbreviation": "Benjamin T Goult, Nicholas H Brown, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.258749", + "pmid": "34708856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 134 2021", + "title": "Talin in mechanotransduction and mechanomemory at a glance." + } + }, + { + "pmid": "10497223", + "pubmed": { + "ISODate": "1999-10-01T00:00:00.000Z", + "abstract": "Following platelet aggregation, integrin alpha(IIb)beta(3) becomes associated with the platelet cytoskeleton. The conserved NPLY sequence represents a potential beta-turn motif in the beta(3) cytoplasmic tail and has been suggested to mediate the interaction of beta(3) integrins with talin. In the present study, we performed a double mutation (N744Q/P745A) in the integrin beta(3) subunit to test the functional significance of this beta-turn motif. Chinese hamster ovary cells were co-transfected with cDNA constructs encoding mutant beta(3) and wild type alpha(IIb). Cells expressing either wild type (A5) or mutant (D4) alpha(IIb)beta(3) adhered to fibrinogen; however, as opposed to control A5 cells, adherent D4 cells failed to spread, form focal adhesions, or initiate protein tyrosine phosphorylation. To investigate the role of the NPLY motif in talin binding, we examined the ability of the mutant alpha(IIb)beta(3) to interact with talin in a solid phase binding assay. Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin. Additionally, purified talin failed to interact with peptides containing the AKWDTANNPLYK sequence indicating that the talin binding domain in the integrin beta(3) subunit does not reside in the NPLY motif. In contrast, specific binding of talin to peptides containing the membrane-proximal HDRKEFAKFEEERARAK sequence of the beta(3) cytoplasmic tail was observed, and this interaction was blocked by a recombinant protein fragment corresponding to the 47-kDa N-terminal head domain of talin (rTalin-N). In addition, RGD affinity purified platelet alpha(IIb)beta(3) bound dose-dependently to immobilized rTalin-N, indicating that an integrin-binding site is present in the talin N-terminal head domain. Collectively, these studies demonstrate that the NPLY beta-turn motif regulates post-ligand binding functions of alpha(IIb)beta(3) in a manner independent of talin interaction. Moreover, talin was shown to bind through its N-terminal head domain to the membrane-proximal sequence of the beta(3) cytoplasmic tail.", + "authors": { + "abbreviation": "S Patil, A Jedsadayanmata, J D Wencel-Drake, ..., S C Lam", + "authorList": [ + { + "ForeName": "S", + "LastName": "Patil", + "abbrevName": "Patil S", + "email": null, + "isCollectiveName": false, + "name": "S Patil" + }, + { + "ForeName": "A", + "LastName": "Jedsadayanmata", + "abbrevName": "Jedsadayanmata A", + "email": null, + "isCollectiveName": false, + "name": "A Jedsadayanmata" + }, + { + "ForeName": "J", + "LastName": "Wencel-Drake", + "abbrevName": "Wencel-Drake JD", + "email": null, + "isCollectiveName": false, + "name": "J D Wencel-Drake" + }, + { + "ForeName": "W", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "W Wang" + }, + { + "ForeName": "I", + "LastName": "Knezevic", + "abbrevName": "Knezevic I", + "email": null, + "isCollectiveName": false, + "name": "I Knezevic" + }, + { + "ForeName": "S", + "LastName": "Lam", + "abbrevName": "Lam SC", + "email": null, + "isCollectiveName": false, + "name": "S C Lam" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.274.40.28575", + "pmid": "10497223", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 274 1999", + "title": "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "15031296", + "pubmed": { + "ISODate": "2004-05-21T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which provides a direct link between integrins and actin filaments, has been shown to contain two distinct binding sites for integrin beta subunits. Here, we report the precise delimitation and a first functional analysis of the talin rod domain integrin-binding site. Partially overlapping cDNAs covering the entire human talin gene were transiently expressed as DsRed fusion proteins in Chinese hamster ovary cells expressing alpha(IIb)beta(3), linked to green fluorescent protein (GFP). Two-color fluorescence analysis of the transfected cells, spread on fibrinogen, revealed distinct subcellular staining patterns including focal adhesion, actin filament, and granular labeling for different talin fragments. The rod domain fragment G (residues 1984-2344), devoid of any known actin- or vinculin-binding sites, colocalized with beta(3)-GFP in focal adhesions. Direct in vitro interaction of fragment G with native platelet integrin alpha(IIb)beta(3) or with the recombinant wild type, but not the Y747A mutant beta(3) cytoplasmic tail, linked to glutathione S-transferase, was demonstrated by surface plasmon resonance analysis and pull-down assays, respectively. Here, we demonstrate for the first time the in vivo relevance of this interaction by fluorescence resonance energy transfer between beta(3)-GFP and DsRed-talin fragment G. Further in vitro pull-down studies allowed us to map out the integrin-binding site within fragment G to a stretch of 130 residues (fragment J, residues 1984-2113) that also localized to focal adhesions. Finally, we show by a cell biology approach that this integrin-binding site within the talin rod domain is important for beta(3)-cytoskeletal interactions but does not participate in alpha(IIb)beta(3) activation.", + "authors": { + "abbreviation": "Laurent Tremuth, Stephanie Kreis, Chantal Melchior, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Stephanie", + "LastName": "Kreis", + "abbrevName": "Kreis S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Kreis" + }, + { + "ForeName": "Chantal", + "LastName": "Melchior", + "abbrevName": "Melchior C", + "email": null, + "isCollectiveName": false, + "name": "Chantal Melchior" + }, + { + "ForeName": "Johan", + "LastName": "Hoebeke", + "abbrevName": "Hoebeke J", + "email": null, + "isCollectiveName": false, + "name": "Johan Hoebeke" + }, + { + "ForeName": "Philippe", + "LastName": "Rondé", + "abbrevName": "Rondé P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Rondé" + }, + { + "ForeName": "Sébastien", + "LastName": "Plançon", + "abbrevName": "Plançon S", + "email": null, + "isCollectiveName": false, + "name": "Sébastien Plançon" + }, + { + "ForeName": "Kenneth", + "LastName": "Takeda", + "abbrevName": "Takeda K", + "email": null, + "isCollectiveName": false, + "name": "Kenneth Takeda" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M400947200", + "pmid": "15031296", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A fluorescence cell biology approach to map the second integrin-binding site of talin to a 130-amino acid sequence within the rod domain." + } + }, + { + "pmid": "28701514", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and Drosophila to present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.", + "authors": { + "abbreviation": "Benjamin Klapholz, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": "nb117@cam.ac.uk", + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Brown", + "email": [ + "nb117@cam.ac.uk" + ], + "name": "Nicholas H Brown" + } + ] + }, + "doi": "10.1242/jcs.190991", + "pmid": "28701514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 130 2017", + "title": "Talin - the master of integrin adhesions." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "29930204", + "pubmed": { + "ISODate": "2018-09-03T00:00:00.000Z", + "abstract": "In most tissues, anchorage-dependent growth and cell cycle progression are dependent on cells engaging extracellular matrices (ECMs) via integrin-receptor adhesion complexes. In a highly conserved manner, cells disassemble adhesion complexes, round up, and retract from their surroundings before division, suggestive of a primordial link between the cell cycle machinery and the regulation of cell adhesion to the ECM. In this study, we demonstrate that cyclin-dependent kinase 1 (CDK1) mediates this link. CDK1, in complex with cyclin A2, promotes adhesion complex and actin cytoskeleton organization during interphase and mediates a large increase in adhesion complex area as cells transition from G1 into S. Adhesion complex area decreases in G2, and disassembly occurs several hours before mitosis. This loss requires elevated cyclin B1 levels and is caused by inhibitory phosphorylation of CDK1-cyclin complexes. The inactivation of CDK1 is therefore the trigger that initiates remodeling of adhesion complexes and the actin cytoskeleton in preparation for rapid entry into mitosis.", + "authors": { + "abbreviation": "Matthew C Jones, Janet A Askari, Jonathan D Humphries, Martin J Humphries", + "authorList": [ + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + } + ] + }, + "doi": "10.1083/jcb.201802088", + "pmid": "29930204", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Cell adhesion is regulated by CDK1 during the cell cycle." + } + }, + { + "pmid": "20150896", + "pubmed": { + "ISODate": "2010-03-17T00:00:00.000Z", + "abstract": "Talin is a 270-kDa protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM domain comprised of F1, F2 and F3 domains, but it is atypical in that F1 contains a large insert and is preceded by an extra domain F0. Although F3 contains the binding site for beta-integrin tails, F0 and F1 are also required for activation of beta1-integrins. Here, we report the solution structures of F0, F1 and of the F0F1 double domain. Both F0 and F1 have ubiquitin-like folds joined in a novel fixed orientation by an extensive charged interface. The F1 insert forms a loop with helical propensity, and basic residues predicted to reside on one surface of the helix are required for binding to acidic phospholipids and for talin-mediated activation of beta1-integrins. This and the fact that basic residues on F2 and F3 are also essential for integrin activation suggest that extensive interactions between the talin FERM domain and acidic membrane phospholipids are required to orientate the FERM domain such that it can activate integrins.", + "authors": { + "abbreviation": "Benjamin T Goult, Mohamed Bouaouina, Paul R Elliott, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Mohamed", + "LastName": "Bouaouina", + "abbrevName": "Bouaouina M", + "email": null, + "isCollectiveName": false, + "name": "Mohamed Bouaouina" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1038/emboj.2010.4", + "pmid": "20150896", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 29 2010", + "title": "Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation." + } + }, + { + "pmid": "7622520", + "pubmed": { + "ISODate": "1995-07-14T00:00:00.000Z", + "abstract": "The interaction of cells with extracellular matrix proteins plays a critical role in a variety of biological processes. Recent studies suggest that cell-matrix interactions mediated by integrins can transduce biochemical signals to the cell interior that regulate cell proliferation and differentiation. These studies have placed the focal adhesion kinase (FAK), an intracellular protein tyrosine kinase, in a central position in integrin-initiated signal transduction pathways (Zachary, I., and Rozengurt, E. (1992) Cell 71, 891-894; Schaller, M., and Parsons, J. T. (1993) Trends Cell Biol. 3, 258-262). Here, we report data suggesting a possible association of FAK with the cytoskeletal protein talin in NIH 3T3 cells. We have identified a 48-amino acid sequence in the carboxyl-terminal domain of FAK necessary for talin binding in vitro. Furthermore, we have correlated the ability of integrin to induce FAK phosphorylation with its ability to bind talin using a mutant integrin lacking the carboxyl-terminal 13 amino acids. These studies suggest talin may be a mediator for FAK activation in signaling initiated by integrins and may provide an explanation for the dependence on the integrity of actin-cytoskeleton of multiple intracellular signaling pathways converging to FAK activation and autophosphorylation.", + "authors": { + "abbreviation": "H C Chen, P A Appeddu, J T Parsons, ..., J L Guan", + "authorList": [ + { + "ForeName": "H", + "LastName": "Chen", + "abbrevName": "Chen HC", + "email": null, + "isCollectiveName": false, + "name": "H C Chen" + }, + { + "ForeName": "P", + "LastName": "Appeddu", + "abbrevName": "Appeddu PA", + "email": null, + "isCollectiveName": false, + "name": "P A Appeddu" + }, + { + "ForeName": "J", + "LastName": "Parsons", + "abbrevName": "Parsons JT", + "email": null, + "isCollectiveName": false, + "name": "J T Parsons" + }, + { + "ForeName": "J", + "LastName": "Hildebrand", + "abbrevName": "Hildebrand JD", + "email": null, + "isCollectiveName": false, + "name": "J D Hildebrand" + }, + { + "ForeName": "M", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "M D Schaller" + }, + { + "ForeName": "J", + "LastName": "Guan", + "abbrevName": "Guan JL", + "email": null, + "isCollectiveName": false, + "name": "J L Guan" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.270.28.16995", + "pmid": "7622520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biol Chem 270 1995", + "title": "Interaction of focal adhesion kinase with cytoskeletal protein talin." + } + }, + { + "pmid": "27603133", + "pubmed": { + "ISODate": "2016-01-01T00:00:00.000Z", + "abstract": "The p17 protein of avian reovirus (ARV) causes cell cycle retardation in a variety of cell lines; however, the underlying mechanism(s) by which p17 regulates the cell cycle remains largely unknown. We demonstrate for the first time that p17 interacts with CDK1 and vimentin as revealed by reciprocal co-immunoprecipitation and GST pull-down assays. Both in vitro and in vivo studies indicated that direct interaction of p17 and CDK1/vimentin was mapped within the amino terminus (aa 1-60) of p17 and central region (aa 27-118) of CDK1/vimentin. Furthermore, p17 was found to occupy the Plk1-binding site within the vimentin, thereby blocking Plk1 recruitment to CDK1-induced vimentin phosphorylation at Ser 56. Interaction of p17 to CDK1 or vimentin interferes with CDK1-catalyzed phosphorylation of vimentin at Ser 56 and subsequently vimentin phosphorylation at Ser 82 by Plk1. Furthermore, we have identified upstream signaling pathways and cellular factor(s) targeted by p17 and found that p17 regulates inhibitory phosphorylation of CDK1 and blocks vimentin phosphorylation at Ser 56 and Ser 82. The p17-mediated inactivation of CDK1 is dependent on several mechanisms, which include direct interaction with CDK1, p17-mediated suppression of Plk1 by activating the Tpr/p53 and ATM/Chk1/PP2A pathways, and p17-mediated cdc25C degradation via an ubiquitin- proteasome pathway. Additionally, depletion of p53 with a shRNA as well as inhibition of ATM and vimentin by inhibitors diminished virus yield while Tpr and CDK1 knockdown increased virus yield. Taken together, results demonstrate that p17 suppresses both CDK1 and Plk1functions, disrupts vimentin phosphorylation, causes G2/M cell cycle arrest and thus benefits virus replication. ", + "authors": { + "abbreviation": "Hung-Chuan Chiu, Wei-Ru Huang, Tsai-Ling Liao, ..., Hung-Jen Liu", + "authorList": [ + { + "ForeName": "Hung-Chuan", + "LastName": "Chiu", + "abbrevName": "Chiu HC", + "email": null, + "isCollectiveName": false, + "name": "Hung-Chuan Chiu" + }, + { + "ForeName": "Wei-Ru", + "LastName": "Huang", + "abbrevName": "Huang WR", + "email": null, + "isCollectiveName": false, + "name": "Wei-Ru Huang" + }, + { + "ForeName": "Tsai-Ling", + "LastName": "Liao", + "abbrevName": "Liao TL", + "email": null, + "isCollectiveName": false, + "name": "Tsai-Ling Liao" + }, + { + "ForeName": "Hung-Yi", + "LastName": "Wu", + "abbrevName": "Wu HY", + "email": null, + "isCollectiveName": false, + "name": "Hung-Yi Wu" + }, + { + "ForeName": "Muhammad", + "LastName": "Munir", + "abbrevName": "Munir M", + "email": null, + "isCollectiveName": false, + "name": "Muhammad Munir" + }, + { + "ForeName": "Wing-Ling", + "LastName": "Shih", + "abbrevName": "Shih WL", + "email": null, + "isCollectiveName": false, + "name": "Wing-Ling Shih" + }, + { + "ForeName": "Hung-Jen", + "LastName": "Liu", + "abbrevName": "Liu HJ", + "email": null, + "isCollectiveName": false, + "name": "Hung-Jen Liu" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0162356", + "pmid": "27603133", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 11 2016", + "title": "Suppression of Vimentin Phosphorylation by the Avian Reovirus p17 through Inhibition of CDK1 and Plk1 Impacting the G2/M Phase of the Cell Cycle." + } + }, + { + "pmid": "16648844", + "pubmed": { + "ISODate": "2006-06-01T00:00:00.000Z", + "abstract": "Transmembrane adhesion receptors, such as integrins, mediate cell adhesion by interacting with intracellular proteins that connect to the cytoskeleton. Talin, one such linker protein, is thought to have two roles: mediating inside-out activation of integrins, and connecting extracellular matrix (ECM)-bound integrins to the cytoskeleton. Talin's amino-terminal head, which consists of a FERM domain, binds an NPxY motif within the cytoplasmic tail of most integrin beta subunits. This is consistent with the role of FERM domains in recruiting other proteins to the plasma membrane. We tested the role of the talin-head-NPxY interaction in integrin function in Drosophila. We found that introduction of a mutation that perturbs this binding in vitro into the isolated talin head disrupts its recruitment by integrins in vivo. Surprisingly, when engineered into the full-length talin, this mutation did not disrupt talin recruitment by integrins nor its ability to connect integrins to the cytoskeleton. However, it reduced the ability of talin to strengthen integrin adhesion to the ECM, indicating that the function of the talin-head-NPxY interaction is solely to regulate integrin adhesion.", + "authors": { + "abbreviation": "Guy Tanentzapf, Nicholas H Brown", + "authorList": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": null, + "isCollectiveName": false, + "name": "Guy Tanentzapf" + }, + { + "ForeName": "Nicholas", + "LastName": "Brown", + "abbrevName": "Brown NH", + "email": null, + "isCollectiveName": false, + "name": "Nicholas H Brown" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1411", + "pmid": "16648844", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 8 2006", + "title": "An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton." + } + }, + { + "pmid": "11591813", + "pubmed": { + "ISODate": "2001-09-01T00:00:00.000Z", + "abstract": "Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.", + "authors": { + "abbreviation": "C R Carlson, O Witczak, L Vossebein, ..., K Taskén", + "authorList": [ + { + "ForeName": "C", + "LastName": "Carlson", + "abbrevName": "Carlson CR", + "email": "cathrine.carlson@basalmed.uio.no", + "isCollectiveName": false, + "name": "C R Carlson" + }, + { + "ForeName": "O", + "LastName": "Witczak", + "abbrevName": "Witczak O", + "email": null, + "isCollectiveName": false, + "name": "O Witczak" + }, + { + "ForeName": "L", + "LastName": "Vossebein", + "abbrevName": "Vossebein L", + "email": null, + "isCollectiveName": false, + "name": "L Vossebein" + }, + { + "ForeName": "J", + "LastName": "Labbé", + "abbrevName": "Labbé JC", + "email": null, + "isCollectiveName": false, + "name": "J C Labbé" + }, + { + "ForeName": "B", + "LastName": "Skålhegg", + "abbrevName": "Skålhegg BS", + "email": null, + "isCollectiveName": false, + "name": "B S Skålhegg" + }, + { + "ForeName": "G", + "LastName": "Keryer", + "abbrevName": "Keryer G", + "email": null, + "isCollectiveName": false, + "name": "G Keryer" + }, + { + "ForeName": "F", + "LastName": "Herberg", + "abbrevName": "Herberg FW", + "email": null, + "isCollectiveName": false, + "name": "F W Herberg" + }, + { + "ForeName": "P", + "LastName": "Collas", + "abbrevName": "Collas P", + "email": null, + "isCollectiveName": false, + "name": "P Collas" + }, + { + "ForeName": "K", + "LastName": "Taskén", + "abbrevName": "Taskén K", + "email": null, + "isCollectiveName": false, + "name": "K Taskén" + } + ], + "contacts": [ + { + "ForeName": "C", + "LastName": "Carlson", + "email": [ + "cathrine.carlson@basalmed.uio.no" + ], + "name": "C R Carlson" + } + ] + }, + "doi": "10.1242/jcs.114.18.3243", + "pmid": "11591813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 114 2001", + "title": "CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis." + } + }, + { + "pmid": "27252130", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellular matrix (ECM) via its connection with the actin cytoskeleton and membrane integrins. It is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the field of mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as well as its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival. New data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states.-Haining, A. W. M., Lieberthal, T. J., del Río Hernández, A. Talin: a mechanosensitive molecule in health and disease.", + "authors": { + "abbreviation": "Alexander W M Haining, Tyler J Lieberthal, Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AW", + "email": null, + "isCollectiveName": false, + "name": "Alexander W M Haining" + }, + { + "ForeName": "Tyler", + "LastName": "Lieberthal", + "abbrevName": "Lieberthal TJ", + "email": null, + "isCollectiveName": false, + "name": "Tyler J Lieberthal" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": "a.del-rio-hernandez@imperial.ac.uk", + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [ + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "email": [ + "a.del-rio-hernandez@imperial.ac.uk" + ], + "name": "Armando Del Río Hernández" + } + ] + }, + "doi": "10.1096/fj.201500080R", + "pmid": "27252130", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FASEB J 30 2016", + "title": "Talin: a mechanosensitive molecule in health and disease." + } + }, + { + "pmid": "31393109", + "pubmed": { + "ISODate": "2019-11-26T00:00:00.000Z", + "abstract": "Mechanotransduction from the extracellular matrix into the cell is primarily supervised by a transmembrane receptor, integrin, and a cytosolic protein, talin. Integrin binds ligands on the extracellular side, whereas talin couples integrin receptors to the actin cytoskeleton and later acts as a \"force buffer\". Talin and integrin together form a mechanosensitive signaling hub that regulates crucial cellular processes and pathways, including cell signaling and formation of focal adhesion complexes, which help cells to sense their mechano-environment and transduce the signal accordingly. Although both proteins function in tandem, most literature focuses on them individually. Here, we provide a focused review of the talin-integrin mechano-interactome network in light of its role in the process of mechanotransduction and its connection to diseases. While working under force, these proteins drive numerous biomolecular interactions and form adhesion complexes, which in turn control many physiological processes such as cell migration; thus, they are invariably associated with several diseases from leukocyte adhesion deficiency to cancer. Gaining insights into their role in the occurrence of these pathological disorders might lead us to establish treatment methods and therapeutic techniques.", + "authors": { + "abbreviation": "Soham Chakraborty, Souradeep Banerjee, Manasven Raina, Shubhasis Haldar", + "authorList": [ + { + "ForeName": "Soham", + "LastName": "Chakraborty", + "abbrevName": "Chakraborty S", + "email": null, + "isCollectiveName": false, + "name": "Soham Chakraborty" + }, + { + "ForeName": "Souradeep", + "LastName": "Banerjee", + "abbrevName": "Banerjee S", + "email": null, + "isCollectiveName": false, + "name": "Souradeep Banerjee" + }, + { + "ForeName": "Manasven", + "LastName": "Raina", + "abbrevName": "Raina M", + "email": null, + "isCollectiveName": false, + "name": "Manasven Raina" + }, + { + "ForeName": "Shubhasis", + "LastName": "Haldar", + "abbrevName": "Haldar S", + "email": null, + "isCollectiveName": false, + "name": "Shubhasis Haldar" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.biochem.9b00442", + "pmid": "31393109", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochemistry 58 2019", + "title": "Force-Directed \"Mechanointeractome\" of Talin-Integrin." + } + }, + { + "pmid": "30254158", + "pubmed": { + "ISODate": "2018-10-09T00:00:00.000Z", + "abstract": "Multicellular organisms have well-defined, tightly regulated mechanisms for cell adhesion. Heterodimeric αβ integrin receptors play central roles in this function and regulate processes for normal cell functions, including signaling, cell migration, and development, binding to the extracellular matrix, and senescence. They are involved in hemostasis and the immune response, participate in leukocyte function, and have biological implications in angiogenesis and cancer. Proper control of integrin activation for cellular communication with the external environment requires several physiological processes. Perturbation of these equilibria may lead to constitutive integrin activation that results in bleeding disorders. Furthermore, integrins play key roles in cancer progression and metastasis in which certain tumor types exhibit higher levels of various integrins. Thus, the integrin-associated signaling complex is important for cancer therapy development. During inside-out signaling, the cytoskeletal protein talin plays a key role in regulating integrin affinity whereby the talin head domain activates integrin by binding to the cytoplasmic tail of β-integrin and acidic membrane phospholipids. To understand the mechanism of integrin activation by talin, we determined the crystal structure of the talin head domain bound to the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), allowing us to design a lipid-binding-deficient talin mutant. Our confocal microscopy with talin knockout cells suggests that the talin-cell membrane interaction seems essential for focal adhesion formation and stabilization. Basal integrin activation in Chinese hamster ovary cells suggests that the lipid-binding-deficient talin mutant inhibits integrin activation. Thus, membrane attachment of talin seems necessary for integrin activation and focal adhesion formation.", + "authors": { + "abbreviation": "Krishna Chinthalapudi, Erumbi S Rangarajan, Tina Izard", + "authorList": [ + { + "ForeName": "Krishna", + "LastName": "Chinthalapudi", + "abbrevName": "Chinthalapudi K", + "email": null, + "isCollectiveName": false, + "name": "Krishna Chinthalapudi" + }, + { + "ForeName": "Erumbi", + "LastName": "Rangarajan", + "abbrevName": "Rangarajan ES", + "email": null, + "isCollectiveName": false, + "name": "Erumbi S Rangarajan" + }, + { + "ForeName": "Tina", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": "cmorrow@scripps.edu", + "isCollectiveName": false, + "name": "Tina Izard" + } + ], + "contacts": [ + { + "ForeName": "Tina", + "LastName": "Izard", + "email": [ + "cmorrow@scripps.edu" + ], + "name": "Tina Izard" + } + ] + }, + "doi": "10.1073/pnas.1806275115", + "pmid": "30254158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Proc Natl Acad Sci U S A 115 2018", + "title": "The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation." + } + }, + { + "pmid": "30028837", + "pubmed": { + "ISODate": "2018-07-01T00:00:00.000Z", + "abstract": "The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.", + "authors": { + "abbreviation": "Alexander William M Haining, Rolle Rahikainen, Ernesto Cortes, ..., Armando Del Río Hernández", + "authorList": [ + { + "ForeName": "Alexander", + "LastName": "Haining", + "abbrevName": "Haining AWM", + "email": null, + "isCollectiveName": false, + "name": "Alexander William M Haining" + }, + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Ernesto", + "LastName": "Cortes", + "abbrevName": "Cortes E", + "email": null, + "isCollectiveName": false, + "name": "Ernesto Cortes" + }, + { + "ForeName": "Dariusz", + "LastName": "Lachowski", + "abbrevName": "Lachowski D", + "email": null, + "isCollectiveName": false, + "name": "Dariusz Lachowski" + }, + { + "ForeName": "Alistair", + "LastName": "Rice", + "abbrevName": "Rice A", + "email": null, + "isCollectiveName": false, + "name": "Alistair Rice" + }, + { + "ForeName": "Magdalena", + "LastName": "von Essen", + "abbrevName": "von Essen M", + "email": null, + "isCollectiveName": false, + "name": "Magdalena von Essen" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Armando", + "LastName": "Del Río Hernández", + "abbrevName": "Del Río Hernández A", + "email": null, + "isCollectiveName": false, + "name": "Armando Del Río Hernández" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.2005599", + "pmid": "30028837", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 16 2018", + "title": "Mechanotransduction in talin through the interaction of the R8 domain with DLC1." + } + }, + { + "pmid": "18550856", + "pubmed": { + "ISODate": "2008-09-01T00:00:00.000Z", + "abstract": "Leukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (K(d), 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (K(d), 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated beta2 integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion.", + "authors": { + "abbreviation": "Heikki Takala, Elisa Nurminen, Susanna M Nurmi, ..., Susanna C Fagerholm", + "authorList": [ + { + "ForeName": "Heikki", + "LastName": "Takala", + "abbrevName": "Takala H", + "email": null, + "isCollectiveName": false, + "name": "Heikki Takala" + }, + { + "ForeName": "Elisa", + "LastName": "Nurminen", + "abbrevName": "Nurminen E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Nurminen" + }, + { + "ForeName": "Susanna", + "LastName": "Nurmi", + "abbrevName": "Nurmi SM", + "email": null, + "isCollectiveName": false, + "name": "Susanna M Nurmi" + }, + { + "ForeName": "Maria", + "LastName": "Aatonen", + "abbrevName": "Aatonen M", + "email": null, + "isCollectiveName": false, + "name": "Maria Aatonen" + }, + { + "ForeName": "Tomas", + "LastName": "Strandin", + "abbrevName": "Strandin T", + "email": null, + "isCollectiveName": false, + "name": "Tomas Strandin" + }, + { + "ForeName": "Maarit", + "LastName": "Takatalo", + "abbrevName": "Takatalo M", + "email": null, + "isCollectiveName": false, + "name": "Maarit Takatalo" + }, + { + "ForeName": "Tiila", + "LastName": "Kiema", + "abbrevName": "Kiema T", + "email": null, + "isCollectiveName": false, + "name": "Tiila Kiema" + }, + { + "ForeName": "Carl", + "LastName": "Gahmberg", + "abbrevName": "Gahmberg CG", + "email": null, + "isCollectiveName": false, + "name": "Carl G Gahmberg" + }, + { + "ForeName": "Jari", + "LastName": "Ylänne", + "abbrevName": "Ylänne J", + "email": null, + "isCollectiveName": false, + "name": "Jari Ylänne" + }, + { + "ForeName": "Susanna", + "LastName": "Fagerholm", + "abbrevName": "Fagerholm SC", + "email": null, + "isCollectiveName": false, + "name": "Susanna C Fagerholm" + } + ], + "contacts": [] + }, + "doi": "10.1182/blood-2007-12-127795", + "pmid": "18550856", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Blood 112 2008", + "title": "Beta2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding." + } + }, + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "31539492", + "pubmed": { + "ISODate": "2019-09-19T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.", + "authors": { + "abbreviation": "Dirk Dedden, Stephanie Schumacher, Charlotte F Kelley, ..., Naoko Mizuno", + "authorList": [ + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Stephanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Schumacher" + }, + { + "ForeName": "Charlotte", + "LastName": "Kelley", + "abbrevName": "Kelley CF", + "email": null, + "isCollectiveName": false, + "name": "Charlotte F Kelley" + }, + { + "ForeName": "Martin", + "LastName": "Zacharias", + "abbrevName": "Zacharias M", + "email": null, + "isCollectiveName": false, + "name": "Martin Zacharias" + }, + { + "ForeName": "Christian", + "LastName": "Biertümpfel", + "abbrevName": "Biertümpfel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Biertümpfel" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": "mizuno@biochem.mpg.de", + "isCollectiveName": false, + "name": "Naoko Mizuno" + } + ], + "contacts": [ + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "email": [ + "mizuno@biochem.mpg.de" + ], + "name": "Naoko Mizuno" + } + ] + }, + "doi": "10.1016/j.cell.2019.08.034", + "pmid": "31539492", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell 179 2019", + "title": "The Architecture of Talin1 Reveals an Autoinhibition Mechanism." + } + }, + { + "pmid": "17430904", + "pubmed": { + "ISODate": "2007-06-08T00:00:00.000Z", + "abstract": "Talin1 is a large cytoskeletal protein that links integrins to actin filaments through two distinct integrin binding sites, one present in the talin head domain (IBS1) necessary for integrin activation and a second (IBS2) that we have previously mapped to talin residues 1984-2113 (fragment J) of the talin rod domain (1 Tremuth, L., Kreis, S., Melchior, C., Hoebeke, J., Ronde, P., Plancon, S., Takeda, K., and Kieffer, N. (2004) J. Biol. Chem. 279, 22258-22266), but whose functional role is still elusive. Using a bioinformatics and cell biology approach, we have determined the minimal structure of IBS2 and show that this integrin binding site corresponds to 23 residues located in alpha helix 50 of the talin rod domain (residues 2077-2099). Alanine mutation of 2 highly conserved residues (L2094A/I2095A) within this alpha helix, which disrupted the alpha-helical structure of IBS2 as demonstrated by infrared spectroscopy and limited trypsin proteolysis, was sufficient to prevent in vivo talin fragment J targeting to alphaIIbbeta3 integrin in focal adhesions and to inhibit in vitro this association as shown by an alphaIIbbeta3 pulldown assay. Moreover, expression of a full-length mouse green fluorescent protein-talin LI/AA mutant in mouse talin1(-/-) cells was unable to rescue the inability of these cells to assemble focal adhesions (in contrast to green fluorescent protein-talin wild type) despite the presence of IBS1. Our data provide the first direct evidence that IBS2 in the talin rod is essential to link integrins to the cytoskeleton.", + "authors": { + "abbreviation": "Michèle Moes, Sophie Rodius, Stacey J Coleman, ..., Nelly Kieffer", + "authorList": [ + { + "ForeName": "Michèle", + "LastName": "Moes", + "abbrevName": "Moes M", + "email": null, + "isCollectiveName": false, + "name": "Michèle Moes" + }, + { + "ForeName": "Sophie", + "LastName": "Rodius", + "abbrevName": "Rodius S", + "email": null, + "isCollectiveName": false, + "name": "Sophie Rodius" + }, + { + "ForeName": "Stacey", + "LastName": "Coleman", + "abbrevName": "Coleman SJ", + "email": null, + "isCollectiveName": false, + "name": "Stacey J Coleman" + }, + { + "ForeName": "Susan", + "LastName": "Monkley", + "abbrevName": "Monkley SJ", + "email": null, + "isCollectiveName": false, + "name": "Susan J Monkley" + }, + { + "ForeName": "Erik", + "LastName": "Goormaghtigh", + "abbrevName": "Goormaghtigh E", + "email": null, + "isCollectiveName": false, + "name": "Erik Goormaghtigh" + }, + { + "ForeName": "Laurent", + "LastName": "Tremuth", + "abbrevName": "Tremuth L", + "email": null, + "isCollectiveName": false, + "name": "Laurent Tremuth" + }, + { + "ForeName": "Corinne", + "LastName": "Kox", + "abbrevName": "Kox C", + "email": null, + "isCollectiveName": false, + "name": "Corinne Kox" + }, + { + "ForeName": "Patrick", + "LastName": "van der Holst", + "abbrevName": "van der Holst PP", + "email": null, + "isCollectiveName": false, + "name": "Patrick P G van der Holst" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Nelly", + "LastName": "Kieffer", + "abbrevName": "Kieffer N", + "email": null, + "isCollectiveName": false, + "name": "Nelly Kieffer" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M611846200", + "pmid": "17430904", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 282 2007", + "title": "The integrin binding site 2 (IBS2) in the talin rod domain is essential for linking integrin beta subunits to the cytoskeleton." + } + }, + { + "pmid": "16135522", + "pubmed": { + "ISODate": "2005-11-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. Three vinculin binding sites (VBS1-3) have previously been identified in the talin rod using a yeast two-hybrid assay. To extend these studies, we spot-synthesized a series of peptides spanning all the alpha-helical regions predicted for the talin rod and identified eight additional VBSs, two of which overlap key functional regions of the rod, including the integrin binding site and C-terminal actin binding site. The talin VBS alpha-helices bind to a hydrophobic cleft in the N-terminal vinculin Vd1 domain. We have defined the specificity of this interaction by spot-synthesizing a series of 25-mer talin VBS1 peptides containing substitutions with all the commonly occurring amino acids. The consensus for recognition is LXXAAXXVAXX- VXXLIXXA with distinct classes of hydrophobic side chains at positions 1, 4, 5, 8, 9, 12, 15, and 16 required for vinculin binding. Positions 1, 8, 12, 15, and 16 require an aliphatic residue and will not tolerate alanine, whereas positions 4, 5, and 9 are less restrictive. These preferences are common to all 11 VBS sequences with a minor variation occurring in one case. A crystal structure of this variant VBS peptide in complex with the vinculin Vd1 domain reveals a subtly different mode of vinculin binding.", + "authors": { + "abbreviation": "Alexandre R Gingras, Wolfgang H Ziegler, Ronald Frank, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M508060200", + "pmid": "16135522", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod." + } + }, + { + "pmid": "19948488", + "pubmed": { + "ISODate": "2009-11-30T00:00:00.000Z", + "abstract": "Integrin-dependent adhesion sites consist of clustered integrins that transmit mechanical forces and provide signaling required for cell survival and morphogenesis. Despite their importance, the regulation of integrin clustering by the cytoplasmic adapter protein talin (Tal) and phosphatidylinositol (PI)-4,5-biphosphate (PI(4,5)P(2)) lipids nor their dynamic coupling to the actin cytoskeleton is fully understood. By using a Tal-dependent integrin clustering assay in intact cells, we identified a PI(4,5)P(2)-binding basic ridge spanning across the F2 and F3 domains of the Tal head that regulates integrin clustering. Clustering requires a new PI(4,5)P(2)-binding site in F2 and is negatively regulated by autoinhibitory interactions between F3 and the Tal rod (Tal-R). The release of the Tal-R exposes a new beta3-integrin-binding site in F3, enabling interaction with a membrane proximal acidic motif, which involves the formation of salt bridges between K(316) and K(324) with E(726) and D(723), respectively. This interaction shields the beta-integrin tail from reassociation with its alpha subunit, thereby maintaining the integrin in a substrate-binding and clustering-competent form.", + "authors": { + "abbreviation": "Frédéric Saltel, Eva Mortier, Vesa P Hytönen, ..., Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Frédéric", + "LastName": "Saltel", + "abbrevName": "Saltel F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Saltel" + }, + { + "ForeName": "Eva", + "LastName": "Mortier", + "abbrevName": "Mortier E", + "email": null, + "isCollectiveName": false, + "name": "Eva Mortier" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": null, + "isCollectiveName": false, + "name": "Vesa P Hytönen" + }, + { + "ForeName": "Marie-Claude", + "LastName": "Jacquier", + "abbrevName": "Jacquier MC", + "email": null, + "isCollectiveName": false, + "name": "Marie-Claude Jacquier" + }, + { + "ForeName": "Pascale", + "LastName": "Zimmermann", + "abbrevName": "Zimmermann P", + "email": null, + "isCollectiveName": false, + "name": "Pascale Zimmermann" + }, + { + "ForeName": "Viola", + "LastName": "Vogel", + "abbrevName": "Vogel V", + "email": null, + "isCollectiveName": false, + "name": "Viola Vogel" + }, + { + "ForeName": "Wei", + "LastName": "Liu", + "abbrevName": "Liu W", + "email": null, + "isCollectiveName": false, + "name": "Wei Liu" + }, + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": null, + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200908134", + "pmid": "19948488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 187 2009", + "title": "New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering." + } + }, + { + "pmid": "16081423", + "pubmed": { + "ISODate": "2005-09-23T00:00:00.000Z", + "abstract": "Previous experiments with peptide fusion proteins suggested that cyclin A/Cdk1 and Cdk2 might exhibit similar yet distinct phosphorylation specificities. Using a physiological substrate, CDP/Cux, our study confirms this notion. Proteolytic processing of CDP/Cux by cathepsin L generates the CDP/Cux p110 isoform at the beginning of S phase. CDP/Cux p110 makes stable interactions with DNA during S phase but is inhibited in G2 following the phosphorylation of serine 1237 by cyclin A/Cdk1. In this study, we propose that differential phosphorylation by cyclin A/Cdk1 and cyclin A/Cdk2 enables CDP/Cux p110 to exert its function as a transcriptional regulator specifically during S phase. We found that like cyclin A/Cdk1, cyclin A/Cdk2 interacted efficiently with recombinant CDP/Cux proteins that contain the Cut homeodomain and an adjacent cyclin-binding motif (Cy). In contrast to cyclin A/Cdk1, however, cyclin A/Cdk2 did not efficiently phosphorylate CDP/Cux p110 on serine 1237 and did not inhibit its DNA binding activity in vitro. Accordingly, co-expression with cyclin A/Cdk2 in cells did not inhibit the DNA binding and transcriptional activities of CDP/Cux p110. To confirm that the sequence surrounding serine 1237 was responsible for the differential regulation by Cdk1 and Cdk2, we replaced 4 amino acids flanking the phosphorylation site to mimic a known Cdk2 phosphorylation site present in the Cdc6 protein. Both cyclin A/Cdk2 and Cdk1 efficiently phosphorylated the CDP/Cux(Cdc6) mutant and inhibited its DNA binding activity. Altogether our results help explain why the DNA binding activity of CDP/Cux p110 is maximal during S phase and decreases in G2 phase.", + "authors": { + "abbreviation": "Marianne Santaguida, Alain Nepveu", + "authorList": [ + { + "ForeName": "Marianne", + "LastName": "Santaguida", + "abbrevName": "Santaguida M", + "email": null, + "isCollectiveName": false, + "name": "Marianne Santaguida" + }, + { + "ForeName": "Alain", + "LastName": "Nepveu", + "abbrevName": "Nepveu A", + "email": null, + "isCollectiveName": false, + "name": "Alain Nepveu" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M505417200", + "pmid": "16081423", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 280 2005", + "title": "Differential regulation of CDP/Cux p110 by cyclin A/Cdk2 and cyclin A/Cdk1." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "22496808", + "pubmed": { + "ISODate": "2012-01-01T00:00:00.000Z", + "abstract": "Talin is a large (∼2540 residues) dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs), where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell.", + "authors": { + "abbreviation": "Neil Bate, Alexandre R Gingras, Alexia Bachir, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir A", + "email": null, + "isCollectiveName": false, + "name": "Alexia Bachir" + }, + { + "ForeName": "Rick", + "LastName": "Horwitz", + "abbrevName": "Horwitz R", + "email": null, + "isCollectiveName": false, + "name": "Rick Horwitz" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0034461", + "pmid": "22496808", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics." + } + }, + { + "pmid": "16460027", + "pubmed": { + "ISODate": "2006-02-14T00:00:00.000Z", + "abstract": "Talin is a key protein involved in linking integrins to the actin cytoskeleton. The long flexible talin rod domain contains a number of binding sites for vinculin, a cytoskeletal protein important in stabilizing integrin-mediated cell-matrix junctions. Here we report the solution structure of a talin rod polypeptide (residues 1843-1973) which contains a single vinculin binding site (VBS; residues 1944-1969). Like other talin rod polypeptides, it consists of a helical bundle, in this case a four-helix bundle with a right-handed topology. The residues in the VBS important for vinculin binding were identified by studying the binding of a series of VBS-related peptides to the vinculin Vd1 domain. The key binding determinants are buried in the interior of the helical bundle, suggesting that a substantial structural change in the talin polypeptide is required for vinculin binding. Direct evidence for this was obtained by NMR and EPR spectroscopy. [1H,15N]-HSQC spectra of the talin fragment indicate that vinculin binding caused approximately two-thirds of the protein to adopt a flexible random coil. For EPR spectroscopy, nitroxide spin labels were attached to the talin polypeptide via appropriately located cysteine residues. Measurements of inter-nitroxide distances in doubly spin-labeled protein showed clearly that the helical bundle is disrupted and the mobility of the helices, except for the VBS helix, is markedly increased. Binding of vinculin to talin is thus a clear example of the unusual phenomenon of protein unfolding being required for protein/protein interaction.", + "authors": { + "abbreviation": "Alexandre R Gingras, Klaus-Peter Vogel, Heinz-Jürgen Steinhoff, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Klaus-Peter", + "LastName": "Vogel", + "abbrevName": "Vogel KP", + "email": null, + "isCollectiveName": false, + "name": "Klaus-Peter Vogel" + }, + { + "ForeName": "Heinz-Jürgen", + "LastName": "Steinhoff", + "abbrevName": "Steinhoff HJ", + "email": null, + "isCollectiveName": false, + "name": "Heinz-Jürgen Steinhoff" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi052136l", + "pmid": "16460027", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 45 2006", + "title": "Structural and dynamic characterization of a vinculin binding site in the talin rod." + } + }, + { + "pmid": "15272303", + "pubmed": { + "ISODate": "2004-08-04T00:00:00.000Z", + "abstract": "The interaction between the cytoskeletal proteins talin and vinculin plays a key role in integrin-mediated cell adhesion and migration. We have determined the crystal structures of two domains from the talin rod spanning residues 482-789. Talin 482-655, which contains a vinculin-binding site (VBS), folds into a five-helix bundle whereas talin 656-789 is a four-helix bundle. We show that the VBS is composed of a hydrophobic surface spanning five turns of helix 4. All the key side chains from the VBS are buried and contribute to the hydrophobic core of the talin 482-655 fold. We demonstrate that the talin 482-655 five-helix bundle represents an inactive conformation, and mutations that disrupt the hydrophobic core or deletion of helix 5 are required to induce an active conformation in which the VBS is exposed. We also report the crystal structure of the N-terminal vinculin head domain in complex with an activated form of talin. Activation of the VBS in talin and the recruitment of vinculin may support the maturation of small integrin/talin complexes into more stable adhesions.", + "authors": { + "abbreviation": "Evangelos Papagrigoriou, Alexandre R Gingras, Igor L Barsukov, ..., Jonas Emsley", + "authorList": [ + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Ronald", + "LastName": "Frank", + "abbrevName": "Frank R", + "email": null, + "isCollectiveName": false, + "name": "Ronald Frank" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": null, + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600285", + "pmid": "15272303", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle." + } + }, + { + "pmid": "21658602", + "pubmed": { + "ISODate": "2011-06-10T00:00:00.000Z", + "abstract": "Cdk specificity is determined by the intrinsic selectivity of the active site and by substrate docking sites on the cyclin subunit. There is a long-standing debate about the relative importance of these factors in the timing of Cdk1 substrate phosphorylation. We analyzed major budding yeast cyclins (the G1/S-cyclin Cln2, S-cyclin Clb5, G2/M-cyclin Clb3, and M-cyclin Clb2) and found that the activity of Cdk1 toward the consensus motif increased gradually in the sequence Cln2-Clb5-Clb3-Clb2, in parallel with cell cycle progression. Further, we identified a docking element that compensates for the weak intrinsic specificity of Cln2 toward G1-specific targets. In addition, Cln2-Cdk1 showed distinct consensus site specificity, suggesting that cyclins do not merely activate Cdk1 but also modulate its active-site specificity. Finally, we identified several Cln2-, Clb3-, and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1.", + "authors": { + "abbreviation": "Mardo Kõivomägi, Ervin Valk, Rainis Venta, ..., Mart Loog", + "authorList": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "abbrevName": "Kõivomägi M", + "email": "mart.loog@ut.ee", + "isCollectiveName": false, + "name": "Mardo Kõivomägi" + }, + { + "ForeName": "Ervin", + "LastName": "Valk", + "abbrevName": "Valk E", + "email": null, + "isCollectiveName": false, + "name": "Ervin Valk" + }, + { + "ForeName": "Rainis", + "LastName": "Venta", + "abbrevName": "Venta R", + "email": null, + "isCollectiveName": false, + "name": "Rainis Venta" + }, + { + "ForeName": "Anna", + "LastName": "Iofik", + "abbrevName": "Iofik A", + "email": null, + "isCollectiveName": false, + "name": "Anna Iofik" + }, + { + "ForeName": "Martin", + "LastName": "Lepiku", + "abbrevName": "Lepiku M", + "email": null, + "isCollectiveName": false, + "name": "Martin Lepiku" + }, + { + "ForeName": "David", + "LastName": "Morgan", + "abbrevName": "Morgan DO", + "email": null, + "isCollectiveName": false, + "name": "David O Morgan" + }, + { + "ForeName": "Mart", + "LastName": "Loog", + "abbrevName": "Loog M", + "email": null, + "isCollectiveName": false, + "name": "Mart Loog" + } + ], + "contacts": [ + { + "ForeName": "Mardo", + "LastName": "Kõivomägi", + "email": [ + "mart.loog@ut.ee" + ], + "name": "Mardo Kõivomägi" + } + ] + }, + "doi": "10.1016/j.molcel.2011.05.016", + "pmid": "21658602", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell 42 2011", + "title": "Dynamics of Cdk1 substrate specificity during the cell cycle." + } + } + ], + "secret": "read-only", + "type": "protein" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/doct_tests_4.json b/neo4j-test/document/doct_tests_4.json new file mode 100644 index 000000000..3be787b51 --- /dev/null +++ b/neo4j-test/document/doct_tests_4.json @@ -0,0 +1,30234 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-02-02T21:53:33.891Z", + "_newestOpId": "448689c2-1e25-4689-bbbc-9c9d7cc1f519", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "ArticleTitle": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Benjamin P", + "Identifier": [], + "Initials": "BP", + "LastName": "Bouchet" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, United Kingdom.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rosemarie E", + "Identifier": [], + "Initials": "RE", + "LastName": "Gough" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "York-Christoph", + "Identifier": [], + "Initials": "YC", + "LastName": "Ammon" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Dieudonnée", + "Identifier": [], + "Initials": "D", + "LastName": "van de Willige" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, The Netherlands.", + "email": null + }, + { + "Affiliation": "Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.", + "email": null + }, + { + "Affiliation": "Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.", + "email": null + }, + { + "Affiliation": "The Netherlands Proteomics Centre, Utrecht 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null + } + ], + "CollectiveName": null, + "ForeName": "Af Maarten", + "Identifier": [], + "Initials": "AM", + "LastName": "Altelaar" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, The Netherlands.", + "email": null + }, + { + "Affiliation": "Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.", + "email": null + }, + { + "Affiliation": "Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.", + "email": null + }, + { + "Affiliation": "The Netherlands Proteomics Centre, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Albert Jr", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-2405-4404" + } + ], + "Initials": "AJ", + "LastName": "Heck" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, United Kingdom.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Benjamin T", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-3438-2807" + } + ], + "Initials": "BT", + "LastName": "Goult" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Anna", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-9048-8614" + } + ], + "Initials": "A", + "LastName": "Akhmanova" + } + ], + "Journal": { + "ISOAbbreviation": "Elife", + "ISSN": { + "IssnType": "Electronic", + "value": "2050-084X" + }, + "JournalIssue": { + "Issue": null, + "PubDate": { + "Day": "13", + "Month": "Jul", + "Year": "2016" + }, + "Volume": "5" + }, + "Title": "eLife" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ] + }, + "ChemicalList": [ + { + "NameOfSubstance": { + "UI": 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The Journal of Cell Biology. 2012;198:481–489. doi: 10.1083/jcb.201206050." + }, + { + "ArticleIdList": [ + { + "IdType": "doi", + "id": "10.1038/ncb2975" + }, + { + "IdType": "pmc", + "id": "PMC4108447" + }, + { + "IdType": "pubmed", + "id": "24859005" + } + ], + "Citation": "Stehbens SJ, Paszek M, Pemble H, Ettinger A, Gierke S, Wittmann T. CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover. Nature Cell Biology. 2014;16:561–573. doi: 10.1038/ncb2975." + }, + { + "ArticleIdList": [ + { + "IdType": "doi", + "id": "10.1016/j.devcel.2012.11.005" + }, + { + "IdType": "pubmed", + "id": "23237952" + } + ], + "Citation": "Theisen U, Straube E, Straube A. Directional persistence of migrating cells requires Kif1C-mediated stabilization of trailing adhesions. 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The HADDOCK2.2 web server: user-friendly integrative modeling of biomolecular complexes. Journal of Molecular Biology. 2016;428:720–725. doi: 10.1016/j.jmb.2015.09.014." + }, + { + "ArticleIdList": [ + { + "IdType": "doi", + "id": "10.1016/j.ceb.2012.06.010" + }, + { + "IdType": "pubmed", + "id": "22819514" + } + ], + "Citation": "Wehrle-Haller B. Assembly and disassembly of cell matrix adhesions. Current Opinion in Cell Biology. 2012;24:569–581. doi: 10.1016/j.ceb.2012.06.010." + }, + { + "ArticleIdList": [ + { + "IdType": "doi", + "id": "10.1007/BF00211777" + }, + { + "IdType": "pubmed", + "id": "8589602" + } + ], + "Citation": "Wishart DS, Bigam CG, Yao J, Abildgaard F, Dyson HJ, Oldfield E, Markley JL, Sykes BD. 1H, 13C and 15N chemical shift referencing in biomolecular NMR. 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Developmental Cell. 2014;31:572–585. doi: 10.1016/j.devcel.2014.10.025." + }, + { + "ArticleIdList": [ + { + "IdType": "doi", + "id": "10.1016/j.str.2016.04.016" + }, + { + "IdType": "pmc", + "id": "PMC4938799" + }, + { + "IdType": "pubmed", + "id": "27265849" + } + ], + "Citation": "Zacharchenko T, Qian X, Goult BT, Jethwa D, Almeida TB, Ballestrem C, Critchley DR, Lowy DR, Barsukov IL. LD motif recognition by talin: structure of the talin-DLC1 complex. Structure. 2016;24:1130–1141. doi: 10.1016/j.str.2016.04.016." + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet", + "orcid": null + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough", + "orcid": "0000-0002-5587-4683" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon", + "orcid": null + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige", + "orcid": "0000-0003-3556-9347" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post", + "orcid": null + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet", + "orcid": "0000-0002-9286-920X" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar", + "orcid": "0000-0001-5093-5945" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck", + "orcid": "0000-0002-2405-4404" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult", + "orcid": "0000-0002-3438-2807" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova", + "orcid": "0000-0002-9048-8614" + } + ], + "caption": "Cell migration, cell adhesion", + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1643838813, + "entries": [ + { + "id": "3687b1d5-e08d-45e2-b63f-f0de188511a5" + }, + { + "id": "ff1f0206-ea65-408c-9b1c-16ddb3dfa365" + }, + { + "id": "b6d9c0fb-154b-4810-84c1-b14772f00228" + }, + { + "id": "6bf463a2-7eb9-4c8e-8507-ca5182b04c8a" + }, + { + "id": "e56263d8-d5b6-4812-bc2f-8d905a66f0f9" + }, + { + "id": "013b7e2a-7240-4668-b628-2653c60f47e9" + }, + { + "id": "5a374667-a51d-4aa3-bf93-526fe203b04e" + }, + { + "id": "651326eb-3d90-40be-a8d7-2ece04e82226" + } + ], + "id": "a48ccff1-e647-462d-89fd-fb323f3410f3", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1643838967, + "liveId": "4bbc46e3-93fe-4d38-a684-71cfd7c11e45", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "26410586", + "pubmed": { + "ISODate": "2016-02-22T00:00:00.000Z", + "abstract": "The prediction of the quaternary structure of biomolecular macromolecules is of paramount importance for fundamental understanding of cellular processes and drug design. In the era of integrative structural biology, one way of increasing the accuracy of modeling methods used to predict the structure of biomolecular complexes is to include as much experimental or predictive information as possible in the process. This has been at the core of our information-driven docking approach HADDOCK. We present here the updated version 2.2 of the HADDOCK portal, which offers new features such as support for mixed molecule types, additional experimental restraints and improved protocols, all of this in a user-friendly interface. With well over 6000 registered users and 108,000 jobs served, an increasing fraction of which on grid resources, we hope that this timely upgrade will help the community to solve important biological questions and further advance the field. The HADDOCK2.2 Web server is freely accessible to non-profit users at http://haddock.science.uu.nl/services/HADDOCK2.2. ", + "authors": { + "abbreviation": "G C P van Zundert, J P G L M Rodrigues, M Trellet, ..., A M J J Bonvin", + "authorList": [ + { + "ForeName": "G", + "LastName": "van Zundert", + "abbrevName": "van Zundert GCP", + "email": null, + "isCollectiveName": false, + "name": "G C P van Zundert" + }, + { + "ForeName": "J", + "LastName": "Rodrigues", + "abbrevName": "Rodrigues JPGLM", + "email": null, + "isCollectiveName": false, + "name": "J P G L M Rodrigues" + }, + { + "ForeName": "M", + "LastName": "Trellet", + "abbrevName": "Trellet M", + "email": null, + "isCollectiveName": false, + "name": "M Trellet" + }, + { + "ForeName": "C", + "LastName": "Schmitz", + "abbrevName": "Schmitz C", + "email": null, + "isCollectiveName": false, + "name": "C Schmitz" + }, + { + "ForeName": "P", + "LastName": "Kastritis", + "abbrevName": "Kastritis PL", + "email": null, + "isCollectiveName": false, + "name": "P L Kastritis" + }, + { + "ForeName": "E", + "LastName": "Karaca", + "abbrevName": "Karaca E", + "email": null, + "isCollectiveName": false, + "name": "E Karaca" + }, + { + "ForeName": "A", + "LastName": "Melquiond", + "abbrevName": "Melquiond ASJ", + "email": null, + "isCollectiveName": false, + "name": "A S J Melquiond" + }, + { + "ForeName": "M", + "LastName": "van Dijk", + "abbrevName": "van Dijk M", + "email": null, + "isCollectiveName": false, + "name": "M van Dijk" + }, + { + "ForeName": "S", + "LastName": "de Vries", + "abbrevName": "de Vries SJ", + "email": null, + "isCollectiveName": false, + "name": "S J de Vries" + }, + { + "ForeName": "A", + "LastName": "Bonvin", + "abbrevName": "Bonvin AMJJ", + "email": null, + "isCollectiveName": false, + "name": "A M J J Bonvin" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2015.09.014", + "pmid": "26410586", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 428 2016", + "title": "The HADDOCK2.2 Web Server: User-Friendly Integrative Modeling of Biomolecular Complexes." + } + }, + { + "pmid": "26097520", + "pubmed": { + "ISODate": null, + "abstract": "A fundamental question in mechanobiology is how mechanical stimuli are sensed by mechanosensing proteins and converted into signals that direct cells to adapt to the external environment. A key function of cell adhesion to the extracellular matrix (ECM) is to transduce mechanical forces between cells and their extracellular environment. Talin, a cytoplasmic adapter essential for integrin-mediated adhesion to the ECM, links the actin cytoskeleton to integrin at the plasma membrane. Here, we review recent progress in the understanding of talin-dependent mechanosensing revealed by stretching single talin molecules. Rapid progress in single-molecule force manipulation technologies has made it possible to directly study the impact of mechanical force on talin's conformations and its interactions with other signaling proteins. We also provide our views on how findings from such studies may bring new insights into understanding the principles of mechanobiology on a broader scale, and how such fundamental knowledge may be harnessed for mechanopharmacology.", + "authors": { + "abbreviation": "Jie Yan, Mingxi Yao, Benjamin T Goult, Michael P Sheetz", + "authorList": [ + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + } + ], + "contacts": [] + }, + "doi": "10.1007/s12195-014-0364-5", + "pmid": "26097520", + "pubTypes": [ + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell Mol Bioeng 8", + "title": "Talin Dependent Mechanosensitivity of Cell Focal Adhesions." + } + }, + { + "pmid": "25961457", + "pubmed": { + "ISODate": "2015-06-01T00:00:00.000Z", + "abstract": "Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling. ", + "authors": { + "abbreviation": "Heon Yung Gee, Fujian Zhang, Shazia Ashraf, ..., Friedhelm Hildebrandt", + "authorList": [ + { + "ForeName": "Heon", + "LastName": "Gee", + "abbrevName": "Gee HY", + "email": null, + "isCollectiveName": false, + "name": "Heon Yung Gee" + }, + { + "ForeName": "Fujian", + "LastName": "Zhang", + "abbrevName": "Zhang F", + "email": null, + "isCollectiveName": false, + "name": "Fujian Zhang" + }, + { + "ForeName": "Shazia", + "LastName": "Ashraf", + "abbrevName": "Ashraf S", + "email": null, + "isCollectiveName": false, + "name": "Shazia Ashraf" + }, + { + "ForeName": "Stefan", + "LastName": "Kohl", + "abbrevName": "Kohl S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Kohl" + }, + { + "ForeName": "Carolin", + "LastName": "Sadowski", + "abbrevName": "Sadowski CE", + "email": null, + "isCollectiveName": false, + "name": "Carolin E Sadowski" + }, + { + "ForeName": "Virginia", + "LastName": "Vega-Warner", + "abbrevName": "Vega-Warner V", + "email": null, + "isCollectiveName": false, + "name": "Virginia Vega-Warner" + }, + { + "ForeName": "Weibin", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Weibin Zhou" + }, + { + "ForeName": "Svjetlana", + "LastName": "Lovric", + "abbrevName": "Lovric S", + "email": null, + "isCollectiveName": false, + "name": "Svjetlana Lovric" + }, + { + "ForeName": "Humphrey", + "LastName": "Fang", + "abbrevName": "Fang H", + "email": null, + "isCollectiveName": false, + "name": "Humphrey Fang" + }, + { + "ForeName": "Margaret", + "LastName": "Nettleton", + "abbrevName": "Nettleton M", + "email": null, + "isCollectiveName": false, + "name": "Margaret Nettleton" + }, + { + "ForeName": "Jun-yi", + "LastName": "Zhu", + "abbrevName": "Zhu JY", + "email": null, + "isCollectiveName": false, + "name": "Jun-yi Zhu" + }, + { + "ForeName": "Julia", + "LastName": "Hoefele", + "abbrevName": "Hoefele J", + "email": null, + "isCollectiveName": false, + "name": "Julia Hoefele" + }, + { + "ForeName": "Lutz", + "LastName": "Weber", + "abbrevName": "Weber LT", + "email": null, + "isCollectiveName": false, + "name": "Lutz T Weber" + }, + { + "ForeName": "Ludmila", + "LastName": "Podracka", + "abbrevName": "Podracka L", + "email": null, + "isCollectiveName": false, + "name": "Ludmila Podracka" + }, + { + "ForeName": "Andrej", + "LastName": "Boor", + "abbrevName": "Boor A", + "email": null, + "isCollectiveName": false, + "name": "Andrej Boor" + }, + { + "ForeName": "Henry", + "LastName": "Fehrenbach", + "abbrevName": "Fehrenbach H", + "email": null, + "isCollectiveName": false, + "name": "Henry Fehrenbach" + }, + { + "ForeName": "Jeffrey", + "LastName": "Innis", + "abbrevName": "Innis JW", + "email": null, + "isCollectiveName": false, + "name": "Jeffrey W Innis" + }, + { + "ForeName": "Joseph", + "LastName": "Washburn", + "abbrevName": "Washburn J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Washburn" + }, + { + "ForeName": "Shawn", + "LastName": "Levy", + "abbrevName": "Levy S", + "email": null, + "isCollectiveName": false, + "name": "Shawn Levy" + }, + { + "ForeName": "Richard", + "LastName": "Lifton", + "abbrevName": "Lifton RP", + "email": null, + "isCollectiveName": false, + "name": "Richard P Lifton" + }, + { + "ForeName": "Edgar", + "LastName": "Otto", + "abbrevName": "Otto EA", + "email": null, + "isCollectiveName": false, + "name": "Edgar A Otto" + }, + { + "ForeName": "Zhe", + "LastName": "Han", + "abbrevName": "Han Z", + "email": null, + "isCollectiveName": false, + "name": "Zhe Han" + }, + { + "ForeName": "Friedhelm", + "LastName": "Hildebrandt", + "abbrevName": "Hildebrandt F", + "email": null, + "isCollectiveName": false, + "name": "Friedhelm Hildebrandt" + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI79504", + "pmid": "25961457", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 125 2015", + "title": "KANK deficiency leads to podocyte dysfunction and nephrotic syndrome." + } + }, + { + "pmid": "25759479", + "pubmed": { + "ISODate": "2015-03-10T00:00:00.000Z", + "abstract": "Specialized regions of the plasma membrane dedicated to diverse cellular processes, such as vesicle exocytosis, extracellular matrix remodeling, and cell migration, share a few cytosolic scaffold proteins that associate to form large plasma membrane-associated platforms (PMAPs). PMAPs organize signaling events and trafficking of membranes and molecules at specific membrane domains. On the basis of the intrinsic disorder of the proteins constituting the core of these PMAPs and of the dynamics of these structures at the periphery of motile cells, we propose a working model for the assembly and turnover of these platforms. ", + "authors": { + "abbreviation": "Veronica Astro, Ivan de Curtis", + "authorList": [ + { + "ForeName": "Veronica", + "LastName": "Astro", + "abbrevName": "Astro V", + "email": null, + "isCollectiveName": false, + "name": "Veronica Astro" + }, + { + "ForeName": "Ivan", + "LastName": "de Curtis", + "abbrevName": "de Curtis I", + "email": "decurtis.ivan@hsr.it", + "isCollectiveName": false, + "name": "Ivan de Curtis" + } + ], + "contacts": [ + { + "ForeName": "Ivan", + "LastName": "de Curtis", + "email": [ + "decurtis.ivan@hsr.it" + ], + "name": "Ivan de Curtis" + } + ] + }, + "doi": "10.1126/scisignal.aaa3312", + "pmid": "25759479", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Sci Signal 8 2015", + "title": "Plasma membrane-associated platforms: dynamic scaffolds that organize membrane-associated events." + } + }, + { + "pmid": "25615869", + "pubmed": { + "ISODate": "2015-01-01T00:00:00.000Z", + "abstract": "CcpNmr Analysis provides a streamlined pipeline for both NMR chemical shift assignment and structure determination of biological macromolecules. In addition, it encompasses tools to analyse the many additional experiments that make NMR such a pivotal technique for research into complex biological questions. This report describes how CcpNmr Analysis can seamlessly link together all of the tasks in the NMR structure-determination process. It details each of the stages from generating NMR restraints [distance, dihedral, hydrogen bonds and residual dipolar couplings (RDCs)], exporting these to and subsequently re-importing them from structure-calculation software (such as the programs CYANA or ARIA) and analysing and validating the results obtained from the structure calculation to, ultimately, the streamlined deposition of the completed assignments and the refined ensemble of structures into the PDBe repository. Until recently, such solution-structure determination by NMR has been quite a laborious task, requiring multiple stages and programs. However, with the new enhancements to CcpNmr Analysis described here, this process is now much more intuitive and efficient and less error-prone. ", + "authors": { + "abbreviation": "Simon P Skinner, Benjamin T Goult, Rasmus H Fogh, ..., Geerten W Vuister", + "authorList": [ + { + "ForeName": "Simon", + "LastName": "Skinner", + "abbrevName": "Skinner SP", + "email": null, + "isCollectiveName": false, + "name": "Simon P Skinner" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Rasmus", + "LastName": "Fogh", + "abbrevName": "Fogh RH", + "email": null, + "isCollectiveName": false, + "name": "Rasmus H Fogh" + }, + { + "ForeName": "Wayne", + "LastName": "Boucher", + "abbrevName": "Boucher W", + "email": null, + "isCollectiveName": false, + "name": "Wayne Boucher" + }, + { + "ForeName": "Tim", + "LastName": "Stevens", + "abbrevName": "Stevens TJ", + "email": null, + "isCollectiveName": false, + "name": "Tim J Stevens" + }, + { + "ForeName": "Ernest", + "LastName": "Laue", + "abbrevName": "Laue ED", + "email": null, + "isCollectiveName": false, + "name": "Ernest D Laue" + }, + { + "ForeName": "Geerten", + "LastName": "Vuister", + "abbrevName": "Vuister GW", + "email": null, + "isCollectiveName": false, + "name": "Geerten W Vuister" + } + ], + "contacts": [] + }, + "doi": "10.1107/S1399004714026662", + "pmid": "25615869", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D023361", + "value": "Validation Study" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 71 2015", + "title": "Structure calculation, refinement and validation using CcpNmr Analysis." + } + }, + { + "pmid": "25609142", + "pubmed": { + "ISODate": "2015-01-22T00:00:00.000Z", + "abstract": "Integrin activation, which is regulated by allosteric changes in receptor conformation, enables cellular responses to the chemical, mechanical and topological features of the extracellular microenvironment. A global view of how activation state converts the molecular composition of the region proximal to integrins into functional readouts is, however, lacking. Here, using conformation-specific monoclonal antibodies, we report the isolation of integrin activation state-dependent complexes and their characterization by mass spectrometry. Quantitative comparisons, integrating network, clustering, pathway and image analyses, define multiple functional protein modules enriched in a conformation-specific manner. Notably, active integrin complexes are specifically enriched for proteins associated with microtubule-based functions. Visualization of microtubules on micropatterned surfaces and live cell imaging demonstrate that active integrins establish an environment that stabilizes microtubules at the cell periphery. These data provide a resource for the interrogation of the global molecular connections that link integrin activation to adhesion signalling. ", + "authors": { + "abbreviation": "Adam Byron, Janet A Askari, Jonathan D Humphries, ..., Martin J Humphries", + "authorList": [ + { + "ForeName": "Adam", + "LastName": "Byron", + "abbrevName": "Byron A", + "email": null, + "isCollectiveName": false, + "name": "Adam Byron" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ewa", + "LastName": "Koper", + "abbrevName": "Koper EJ", + "email": null, + "isCollectiveName": false, + "name": "Ewa J Koper" + }, + { + "ForeName": "Stacey", + "LastName": "Warwood", + "abbrevName": "Warwood S", + "email": null, + "isCollectiveName": false, + "name": "Stacey Warwood" + }, + { + "ForeName": "Colin", + "LastName": "Choi", + "abbrevName": "Choi CK", + "email": null, + "isCollectiveName": false, + "name": "Colin K Choi" + }, + { + "ForeName": "Matthew", + "LastName": "Stroud", + "abbrevName": "Stroud MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J Stroud" + }, + { + "ForeName": "Christopher", + "LastName": "Chen", + "abbrevName": "Chen CS", + "email": null, + "isCollectiveName": false, + "name": "Christopher S Chen" + }, + { + "ForeName": "David", + "LastName": "Knight", + "abbrevName": "Knight D", + "email": null, + "isCollectiveName": false, + "name": "David Knight" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms7135", + "pmid": "25609142", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting." + } + }, + { + "pmid": "25589673", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "A hallmark of the neuromuscular junction (NMJ) is the high density of acetylcholine receptors (AChRs) in the postsynaptic muscle membrane. The postsynaptic apparatus of the NMJ is organized by agrin secreted from motor neurons. The mechanisms that underlie the focal delivery of AChRs to the adult NMJ are not yet understood in detail. We previously showed that microtubule (MT) capture by the plus end-tracking protein CLASP2 regulates AChR density at agrin-induced AChR clusters in cultured myotubes via PI3 kinase acting through GSK3β. Here we show that knockdown of the CLASP2-interaction partner LL5β by RNAi and forced expression of a CLASP2 fragment blocking the CLASP2/LL5β interaction inhibit microtubule capture. The same treatments impair focal vesicle delivery to the clusters. Consistent with these findings, knockdown of LL5β at the NMJ in vivo reduces the density and insertion of AChRs into the postsynaptic membrane. MT capture and focal vesicle delivery to agrin-induced AChR clusters are also inhibited by microtubule- and actin-depolymerizing drugs, invoking both cytoskeletal systems in MT capture and in the fusion of AChR vesicles with the cluster membrane. Combined our data identify a transport system, organized by agrin through PI3 kinase, GSK3β, CLASP2, and LL5β, for precise delivery of AChR vesicles from the subsynaptic nuclei to the overlying synaptic membrane. ", + "authors": { + "abbreviation": "Sreya Basu, Stefan Sladecek, Isabel Martinez de la Peña y Valenzuela, ..., Hans Rudolf Brenner", + "authorList": [ + { + "ForeName": "Sreya", + "LastName": "Basu", + "abbrevName": "Basu S", + "email": null, + "isCollectiveName": false, + "name": "Sreya Basu" + }, + { + "ForeName": "Stefan", + "LastName": "Sladecek", + "abbrevName": "Sladecek S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Sladecek" + }, + { + "ForeName": "Isabel", + "LastName": "Martinez de la Peña y Valenzuela", + "abbrevName": "Martinez de la Peña y Valenzuela I", + "email": null, + "isCollectiveName": false, + "name": "Isabel Martinez de la Peña y Valenzuela" + }, + { + "ForeName": "Mohammed", + "LastName": "Akaaboune", + "abbrevName": "Akaaboune M", + "email": null, + "isCollectiveName": false, + "name": "Mohammed Akaaboune" + }, + { + "ForeName": "Ihor", + "LastName": "Smal", + "abbrevName": "Smal I", + "email": null, + "isCollectiveName": false, + "name": "Ihor Smal" + }, + { + "ForeName": "Katrin", + "LastName": "Martin", + "abbrevName": "Martin K", + "email": null, + "isCollectiveName": false, + "name": "Katrin Martin" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Hans", + "LastName": "Brenner", + "abbrevName": "Brenner HR", + "email": "Hans-Rudolf.Brenner@unibas.ch", + "isCollectiveName": false, + "name": "Hans Rudolf Brenner" + } + ], + "contacts": [ + { + "ForeName": "Hans", + "LastName": "Brenner", + "email": [ + "Hans-Rudolf.Brenner@unibas.ch", + "n.galjart@erasmusmc.nl" + ], + "name": "Hans Rudolf Brenner" + } + ] + }, + "doi": "10.1091/mbc.E14-06-1158", + "pmid": "25589673", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Biol Cell 26 2015", + "title": "CLASP2-dependent microtubule capture at the neuromuscular junction membrane requires LL5β and actin for focal delivery of acetylcholine receptor vesicles." + } + }, + { + "pmid": "25490267", + "pubmed": { + "ISODate": "2014-12-08T00:00:00.000Z", + "abstract": "Disassembly of focal adhesions (FAs) allows cell retraction and integrin detachment from the extracellular matrix, processes critical for cell movement. Growth of microtubules (MTs) can promote FA turnover by serving as tracks to deliver proteins essential for FA disassembly. The molecular nature of this FA \"disassembly factor,\" however, remains elusive. By quantitative proteomics, we identified mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) as an FA regulator that associates with MTs. Knockout of MAP4K4 stabilizes FAs and impairs cell migration. By exploring underlying mechanisms, we further show that MAP4K4 associates with ending binding 2 (EB2) and IQ motif and SEC7 domain-containing protein 1 (IQSEC1), a guanine nucleotide exchange factor specific for Arf6, whose activation promotes integrin internalization. Together, our findings provide critical insight into FA disassembly, suggesting that MTs can deliver MAP4K4 toward FAs through EB2, where MAP4K4 can, in turn, activate Arf6 via IQSEC1 and enhance FA dissolution.", + "authors": { + "abbreviation": "Jiping Yue, Min Xie, Xuewen Gou, ..., Xiaoyang Wu", + "authorList": [ + { + "ForeName": "Jiping", + "LastName": "Yue", + "abbrevName": "Yue J", + "email": null, + "isCollectiveName": false, + "name": "Jiping Yue" + }, + { + "ForeName": "Min", + "LastName": "Xie", + "abbrevName": "Xie M", + "email": null, + "isCollectiveName": false, + "name": "Min Xie" + }, + { + "ForeName": "Xuewen", + "LastName": "Gou", + "abbrevName": "Gou X", + "email": null, + "isCollectiveName": false, + "name": "Xuewen Gou" + }, + { + "ForeName": "Philbert", + "LastName": "Lee", + "abbrevName": "Lee P", + "email": null, + "isCollectiveName": false, + "name": "Philbert Lee" + }, + { + "ForeName": "Michael", + "LastName": "Schneider", + "abbrevName": "Schneider MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schneider" + }, + { + "ForeName": "Xiaoyang", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": "xiaoyangwu@uchicago.edu", + "isCollectiveName": false, + "name": "Xiaoyang Wu" + } + ], + "contacts": [ + { + "ForeName": "Xiaoyang", + "LastName": "Wu", + "email": [ + "xiaoyangwu@uchicago.edu" + ], + "name": "Xiaoyang Wu" + } + ] + }, + "doi": "10.1016/j.devcel.2014.10.025", + "pmid": "25490267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 31 2014", + "title": "Microtubules regulate focal adhesion dynamics through MAP4K4." + } + }, + { + "pmid": "25231989", + "pubmed": { + "ISODate": "2014-10-31T00:00:00.000Z", + "abstract": "The postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2, a MT plus-end-tracking protein (+TIP), increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases, including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends, and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. How CLASP2 phosphorylation regulates MT capture at the NMJ and how this controls the size of AChR clusters are not yet understood. To examine this, we used myotubes cultured on agrin patches that induce AChR clustering in a two-dimensional manner. We show that expression of a CLASP2 mutant, in which the nine GSK3 target serines are mutated to alanine (CLASP2-9XS/9XA) and are resistant to GSK3β-dependent phosphorylation, promotes MT capture at clusters and increases AChR cluster size, compared with myotubes that express similar levels of wild type CLASP2 or that are noninfected. Conversely, myotubes expressing a phosphomimetic form of CLASP2 (CLASP2-8XS/D) show enrichment of immobile mutant CLASP2 in clusters, but MT capture and AChR cluster size are reduced. Taken together, our data suggest that both GSK3β-dependent phosphorylation and the level of CLASP2 play a role in the maintenance of AChR cluster size through the regulated capture and release of MT plus-ends. ", + "authors": { + "abbreviation": "Sreya Basu, Stefan Sladecek, Hayley Pemble, ..., Niels Galjart", + "authorList": [ + { + "ForeName": "Sreya", + "LastName": "Basu", + "abbrevName": "Basu S", + "email": null, + "isCollectiveName": false, + "name": "Sreya Basu" + }, + { + "ForeName": "Stefan", + "LastName": "Sladecek", + "abbrevName": "Sladecek S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Sladecek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + }, + { + "ForeName": "Johan", + "LastName": "Slotman", + "abbrevName": "Slotman JA", + "email": null, + "isCollectiveName": false, + "name": "Johan A Slotman" + }, + { + "ForeName": "Wiggert", + "LastName": "van Cappellen", + "abbrevName": "van Cappellen W", + "email": null, + "isCollectiveName": false, + "name": "Wiggert van Cappellen" + }, + { + "ForeName": "Hans-Rudolf", + "LastName": "Brenner", + "abbrevName": "Brenner HR", + "email": "Hans-Rudolf.Brenner@unibas.ch", + "isCollectiveName": false, + "name": "Hans-Rudolf Brenner" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": "n.galjart@erasmusmc.nl", + "isCollectiveName": false, + "name": "Niels Galjart" + } + ], + "contacts": [ + { + "ForeName": "Hans-Rudolf", + "LastName": "Brenner", + "email": [ + "Hans-Rudolf.Brenner@unibas.ch" + ], + "name": "Hans-Rudolf Brenner" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "email": [ + "n.galjart@erasmusmc.nl" + ], + "name": "Niels Galjart" + } + ] + }, + "doi": "10.1074/jbc.M114.589457", + "pmid": "25231989", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 289 2014", + "title": "Acetylcholine receptor (AChR) clustering is regulated both by glycogen synthase kinase 3β (GSK3β)-dependent phosphorylation and the level of CLIP-associated protein 2 (CLASP2) mediating the capture of microtubule plus-ends." + } + }, + { + "pmid": "24982445", + "pubmed": { + "ISODate": "2014-09-01T00:00:00.000Z", + "abstract": "Cell migration during development and metastatic invasion requires the coordination of actin and adhesion dynamics to promote protrusive activity at the front of the cell. The knowledge of the molecular mechanisms required to achieve such coordination is fragmentary. Here, we identify a new functional complex that drives cell motility. ERC1a (an isoform of ERC1) and the LL5 proteins LL5α and LL5β (encoded by PHLDB1 and PHLDB2, respectively) are required, together with liprin-α1, for effective migration and tumor cell invasion, and do so by stabilizing the protrusive activity at the cell front. Depletion of either protein negatively affects invasion, migration on extracellular matrix, lamellipodial persistence and the internalization of active integrin β1 receptors needed for adhesion turnover at the front of the cell. Liprin-α1, ERC1a and LL5 also define new highly polarized and dynamic cytoplasmic structures uniquely localized near the protruding cell edge. Our results indicate that the functional complex and the associated structures described here represent an important mechanism to drive tumor cell migration. ", + "authors": { + "abbreviation": "Veronica Astro, Sara Chiaretti, Elisa Magistrati, ..., Ivan de Curtis", + "authorList": [ + { + "ForeName": "Veronica", + "LastName": "Astro", + "abbrevName": "Astro V", + "email": null, + "isCollectiveName": false, + "name": "Veronica Astro" + }, + { + "ForeName": "Sara", + "LastName": "Chiaretti", + "abbrevName": "Chiaretti S", + "email": null, + "isCollectiveName": false, + "name": "Sara Chiaretti" + }, + { + "ForeName": "Elisa", + "LastName": "Magistrati", + "abbrevName": "Magistrati E", + "email": null, + "isCollectiveName": false, + "name": "Elisa Magistrati" + }, + { + "ForeName": "Marc", + "LastName": "Fivaz", + "abbrevName": "Fivaz M", + "email": null, + "isCollectiveName": false, + "name": "Marc Fivaz" + }, + { + "ForeName": "Ivan", + "LastName": "de Curtis", + "abbrevName": "de Curtis I", + "email": "decurtis.ivan@hsr.it", + "isCollectiveName": false, + "name": "Ivan de Curtis" + } + ], + "contacts": [ + { + "ForeName": "Ivan", + "LastName": "de Curtis", + "email": [ + "decurtis.ivan@hsr.it" + ], + "name": "Ivan de Curtis" + } + ] + }, + "doi": "10.1242/jcs.155663", + "pmid": "24982445", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 127 2014", + "title": "Liprin-α1, ERC1 and LL5 define polarized and dynamic structures that are implicated in cell migration." + } + }, + { + "pmid": "24870021", + "pubmed": { + "ISODate": "2014-06-15T00:00:00.000Z", + "abstract": "LD motifs (leucine-aspartic acid motifs) are short helical protein-protein interaction motifs that have emerged as key players in connecting cell adhesion with cell motility and survival. LD motifs are required for embryogenesis, wound healing and the evolution of multicellularity. LD motifs also play roles in disease, such as in cancer metastasis or viral infection. First described in the paxillin family of scaffolding proteins, LD motifs and similar acidic LXXLL interaction motifs have been discovered in several other proteins, whereas 16 proteins have been reported to contain LDBDs (LD motif-binding domains). Collectively, structural and functional analyses have revealed a surprising multivalency in LD motif interactions and a wide diversity in LDBD architectures. In the present review, we summarize the molecular basis for function, regulation and selectivity of LD motif interactions that has emerged from more than a decade of research. This overview highlights the intricate multi-level regulation and the inherently noisy and heterogeneous nature of signalling through short protein-protein interaction motifs.", + "authors": { + "abbreviation": "Tanvir Alam, Meshari Alazmi, Xin Gao, Stefan T Arold", + "authorList": [ + { + "ForeName": "Tanvir", + "LastName": "Alam", + "abbrevName": "Alam T", + "email": null, + "isCollectiveName": false, + "name": "Tanvir Alam" + }, + { + "ForeName": "Meshari", + "LastName": "Alazmi", + "abbrevName": "Alazmi M", + "email": null, + "isCollectiveName": false, + "name": "Meshari Alazmi" + }, + { + "ForeName": "Xin", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xin Gao" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + } + ], + "contacts": [] + }, + "doi": "10.1042/BJ20140298", + "pmid": "24870021", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochem J 460 2014", + "title": "How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "24714394", + "pubmed": { + "ISODate": "2014-04-09T00:00:00.000Z", + "abstract": "The force-dependent interaction between talin and vinculin plays a crucial role in the initiation and growth of focal adhesions. Here we use magnetic tweezers to characterise the mechano-sensitive compact N-terminal region of the talin rod, and show that the three helical bundles R1-R3 in this region unfold in three distinct steps consistent with the domains unfolding independently. Mechanical stretching of talin R1-R3 enhances its binding to vinculin and vinculin binding inhibits talin refolding after force is released. Mutations that stabilize R3 identify it as the initial mechano-sensing domain in talin, unfolding at ∼5 pN, suggesting that 5 pN is the force threshold for vinculin binding and adhesion progression. ", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Hu Chen, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Hu", + "LastName": "Chen", + "abbrevName": "Chen H", + "email": null, + "isCollectiveName": false, + "name": "Hu Chen" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/srep04610", + "pmid": "24714394", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 4 2014", + "title": "Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation." + } + }, + { + "pmid": "24368804", + "pubmed": { + "ISODate": "2013-12-23T00:00:00.000Z", + "abstract": "The coordinated growth of cells and their organelles is a fundamental and poorly understood problem, with implications for processes ranging from embryonic development to oncogenesis. Recent experiments have shed light on the cell size-dependent assembly of membrane-less cytoplasmic and nucleoplasmic structures, including ribonucleoprotein (RNP) granules and other intracellular bodies. Many of these structures behave as condensed liquid-like phases of the cytoplasm/nucleoplasm. The phase transitions that appear to govern their assembly exhibit an intrinsic dependence on cell size, and may explain the size scaling reported for a number of structures. This size scaling could, in turn, play a role in cell growth and size control. ", + "authors": { + "abbreviation": "Clifford P Brangwynne", + "authorList": [ + { + "ForeName": "Clifford", + "LastName": "Brangwynne", + "abbrevName": "Brangwynne CP", + "email": null, + "isCollectiveName": false, + "name": "Clifford P Brangwynne" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201308087", + "pmid": "24368804", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 203 2013", + "title": "Phase transitions and size scaling of membrane-less organelles." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "23940118", + "pubmed": { + "ISODate": "2013-08-19T00:00:00.000Z", + "abstract": "Amniote epiblast cells differentiate into mesoderm and endoderm lineages during gastrulation through a process called epithelial-to-mesenchymal transition (EMT). Molecular regulation of gastrulation EMT is poorly understood. Here we show that epiblast epithelial status was maintained by anchoring microtubules to the basal cortex via CLIP-associated protein (CLASP), a microtubule plus-end tracking protein, and Dystroglycan, a transmembrane protein that bridges the cytoskeleton and basement membrane (BM). Mesoderm formation required down-regulation of CLASP and Dystroglycan, and reducing CLASP activity in pregastrulation epiblast cells caused ectopic BM breakdown and disrupted epiblast integrity. These effects were mediated through the CLASP-binding partner LL5. Live-imaging using EB1-enhanced GFP (eGFP) revealed that reducing CLASP and LL5 levels in the epiblast destabilized basal microtubules. We further show that Dystroglycan is localized to basolateral membrane in epiblast cells. Basal but not lateral localization of Dystroglycan was regulated by CLASP. We propose that epiblast-BM interaction requires CLASP- and Dystroglycan-mediated cortical microtubule anchoring, the disruption of which initiates gastrulation EMT. ", + "authors": { + "abbreviation": "Yukiko Nakaya, Erike W Sukowati, Guojun Sheng", + "authorList": [ + { + "ForeName": "Yukiko", + "LastName": "Nakaya", + "abbrevName": "Nakaya Y", + "email": null, + "isCollectiveName": false, + "name": "Yukiko Nakaya" + }, + { + "ForeName": "Erike", + "LastName": "Sukowati", + "abbrevName": "Sukowati EW", + "email": null, + "isCollectiveName": false, + "name": "Erike W Sukowati" + }, + { + "ForeName": "Guojun", + "LastName": "Sheng", + "abbrevName": "Sheng G", + "email": null, + "isCollectiveName": false, + "name": "Guojun Sheng" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201302075", + "pmid": "23940118", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 202 2013", + "title": "Epiblast integrity requires CLASP and Dystroglycan-mediated microtubule anchoring to the basal cortex." + } + }, + { + "pmid": "23860236", + "pubmed": { + "ISODate": "2013-08-01T00:00:00.000Z", + "abstract": "Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling. ", + "authors": { + "abbreviation": "David A Calderwood, Iain D Campbell, David R Critchley", + "authorList": [ + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm3624", + "pmid": "23860236", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 14 2013", + "title": "Talins and kindlins: partners in integrin-mediated adhesion." + } + }, + { + "pmid": "23525008", + "pubmed": { + "ISODate": "2013-05-15T00:00:00.000Z", + "abstract": "Neuromuscular junctions (NMJs) in mammalian skeletal muscle undergo a postnatal topological transformation from a simple oval plaque to a complex branched structure. We previously showed that podosomes, actin-rich adhesive organelles, promote the remodeling process, and demonstrated a key role for one podosome component, LL5β. To further investigate molecular mechanisms of postsynaptic maturation, we purified LL5β-associated proteins from myotubes and showed that three regulators of the actin cytoskeleton--Amotl2, Asef2 and Flii--interact with LL5β. These and other LL5β-interacting proteins are associated with conventional podosomes in macrophages and podosome-like invadopodia in fibroblasts, strengthening the close relationship between synaptic and non-synaptic podosomes. We then focused on Amotl2, showing that it is associated with synaptic podosomes in cultured myotubes and with NMJs in vivo. Depletion of Amotl2 in myotubes leads to increased size of synaptic podosomes and corresponding alterations in postsynaptic topology. Depletion of Amotl2 from fibroblasts disrupts invadopodia in these cells. These results demonstrate a role for Amotl2 in synaptic maturation and support the involvement of podosomes in this process.", + "authors": { + "abbreviation": "Tomasz J Proszynski, Joshua R Sanes", + "authorList": [ + { + "ForeName": "Tomasz", + "LastName": "Proszynski", + "abbrevName": "Proszynski TJ", + "email": null, + "isCollectiveName": false, + "name": "Tomasz J Proszynski" + }, + { + "ForeName": "Joshua", + "LastName": "Sanes", + "abbrevName": "Sanes JR", + "email": null, + "isCollectiveName": false, + "name": "Joshua R Sanes" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.121327", + "pmid": "23525008", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 126 2013", + "title": "Amotl2 interacts with LL5β, localizes to podosomes and regulates postsynaptic differentiation in muscle." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "23237952", + "pubmed": { + "ISODate": "2012-12-11T00:00:00.000Z", + "abstract": "Directional cell migration requires the establishment and maintenance of long-term differences in structure and function between the front and back of a cell. Here, we show that the microtubule motor Kif1C contributes to persistent cell migration primarily through stabilization of an extended cell rear. Kif1C-mediated transport of α5β1-integrins is required for the proper maturation of trailing focal adhesions and resistance to tail retraction. Tail retraction precedes and induces changes in migration direction. Stabilization of cell tails through inhibition of myosin II activity suppresses the Kif1C depletion phenotype and results in longer-lived tails and higher directional stability of migrating cells. Taken together, these findings indicate that the maintenance of an extended, tense cell tail facilitates directional migration. We propose a rear drag mechanism for directional persistence of migration whereby the counterforce originating from a well-anchored tail serves to maintain directionality of the force-generating leading edge of the cell.", + "authors": { + "abbreviation": "Ulrike Theisen, Ekkehard Straube, Anne Straube", + "authorList": [ + { + "ForeName": "Ulrike", + "LastName": "Theisen", + "abbrevName": "Theisen U", + "email": null, + "isCollectiveName": false, + "name": "Ulrike Theisen" + }, + { + "ForeName": "Ekkehard", + "LastName": "Straube", + "abbrevName": "Straube E", + "email": null, + "isCollectiveName": false, + "name": "Ekkehard Straube" + }, + { + "ForeName": "Anne", + "LastName": "Straube", + "abbrevName": "Straube A", + "email": null, + "isCollectiveName": false, + "name": "Anne Straube" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2012.11.005", + "pmid": "23237952", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 23 2012", + "title": "Directional persistence of migrating cells requires Kif1C-mediated stabilization of trailing adhesions." + } + }, + { + "pmid": "22936764", + "pubmed": { + "ISODate": "2012-08-31T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Anthony A Hyman, Kai Simons", + "authorList": [ + { + "ForeName": "Anthony", + "LastName": "Hyman", + "abbrevName": "Hyman AA", + "email": "hyman@mpi-cbg.de", + "isCollectiveName": false, + "name": "Anthony A Hyman" + }, + { + "ForeName": "Kai", + "LastName": "Simons", + "abbrevName": "Simons K", + "email": null, + "isCollectiveName": false, + "name": "Kai Simons" + } + ], + "contacts": [ + { + "ForeName": "Anthony", + "LastName": "Hyman", + "email": [ + "hyman@mpi-cbg.de" + ], + "name": "Anthony A Hyman" + } + ] + }, + "doi": "10.1126/science.1223728", + "pmid": "22936764", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Science 337 2012", + "title": "Cell biology. Beyond oil and water--phase transitions in cells." + } + }, + { + "pmid": "22908306", + "pubmed": { + "ISODate": "2012-08-20T00:00:00.000Z", + "abstract": "Directional cell migration requires force generation that relies on the coordinated remodeling of interactions with the extracellular matrix (ECM), which is mediated by integrin-based focal adhesions (FAs). Normal FA turnover requires dynamic microtubules, and three members of the diverse group of microtubule plus-end-tracking proteins are principally involved in mediating microtubule interactions with FAs. Microtubules also alter the assembly state of FAs by modulating Rho GTPase signaling, and recent evidence suggests that microtubule-mediated clathrin-dependent and -independent endocytosis regulates FA dynamics. In addition, FA-associated microtubules may provide a polarized microtubule track for localized secretion of matrix metalloproteases (MMPs). Thus, different aspects of the molecular mechanisms by which microtubules control FA turnover in migrating cells are beginning to emerge.", + "authors": { + "abbreviation": "Samantha Stehbens, Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens S", + "email": null, + "isCollectiveName": false, + "name": "Samantha Stehbens" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201206050", + "pmid": "22908306", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 198 2012", + "title": "Targeting and transport: how microtubules control focal adhesion dynamics." + } + }, + { + "pmid": "22851317", + "pubmed": { + "ISODate": "2012-08-06T00:00:00.000Z", + "abstract": "Agrin is the major factor mediating the neuronal regulation of postsynaptic structures at the vertebrate neuromuscular junction, but the details of how it orchestrates this unique three-dimensional structure remain unknown. Here, we show that agrin induces the formation of the dense network of microtubules in the subsynaptic cytoplasm and that this, in turn, regulates acetylcholine receptor insertion into the postsynaptic membrane. Agrin acted in part by locally activating phosphatidylinositol 3-kinase and inactivating GSK3β, which led to the local capturing of dynamic microtubules at agrin-induced acetylcholine receptor (AChR) clusters, mediated to a large extent by the microtubule plus-end tracking proteins CLASP2 and CLIP-170. Indeed, in the absence of CLASP2, microtubule plus ends at the subsynaptic muscle membrane, the density of synaptic AChRs, the size of AChR clusters, and the numbers of subsynaptic muscle nuclei with their selective gene expression programs were all reduced. Thus, the cascade linking agrin to CLASP2-mediated microtubule capturing at the synaptic membrane is essential for the maintenance of a normal neuromuscular phenotype.", + "authors": { + "abbreviation": "Nadine Schmidt, Sreya Basu, Stefan Sladecek, ..., Hans Rudolf Brenner", + "authorList": [ + { + "ForeName": "Nadine", + "LastName": "Schmidt", + "abbrevName": "Schmidt N", + "email": null, + "isCollectiveName": false, + "name": "Nadine Schmidt" + }, + { + "ForeName": "Sreya", + "LastName": "Basu", + "abbrevName": "Basu S", + "email": null, + "isCollectiveName": false, + "name": "Sreya Basu" + }, + { + "ForeName": "Stefan", + "LastName": "Sladecek", + "abbrevName": "Sladecek S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Sladecek" + }, + { + "ForeName": "Sabrina", + "LastName": "Gatti", + "abbrevName": "Gatti S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Gatti" + }, + { + "ForeName": "Jeffrey", + "LastName": "van Haren", + "abbrevName": "van Haren J", + "email": null, + "isCollectiveName": false, + "name": "Jeffrey van Haren" + }, + { + "ForeName": "Susan", + "LastName": "Treves", + "abbrevName": "Treves S", + "email": null, + "isCollectiveName": false, + "name": "Susan Treves" + }, + { + "ForeName": "Jan", + "LastName": "Pielage", + "abbrevName": "Pielage J", + "email": null, + "isCollectiveName": false, + "name": "Jan Pielage" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Hans", + "LastName": "Brenner", + "abbrevName": "Brenner HR", + "email": null, + "isCollectiveName": false, + "name": "Hans Rudolf Brenner" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201111130", + "pmid": "22851317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 198 2012", + "title": "Agrin regulates CLASP2-mediated capture of microtubules at the neuromuscular junction synaptic membrane." + } + }, + { + "pmid": "22819514", + "pubmed": { + "ISODate": "2012-10-01T00:00:00.000Z", + "abstract": "The formation of tissues and organs requires cells to adhere to each other and/or to migrate and polarize in contact with components of the extracellular matrix. The connection between the cytoskeleton and the extracellular environment is provided by heterodimeric transmembrane receptors of the integrin family. In response to extracellular ligand binding, integrins undergo a conformational switch that permits the recruitment of cytoplasmic adapter proteins, eventually linking the integrin receptors to the actin cytoskeleton, progressively forming highly complex cell-matrix adhesions. A major challenge in the field consists in identifying the regulatory mechanisms, which drive the assembly of cell-matrix adhesions as they are based on posttranslational modifications as well as allosteric conformational changes caused by protein-protein as well as protein-lipid interactions. In response to mechanical tension, generated either by intra-cellular acto-myosin contraction, shear stress or mechanical strain on the extracellular scaffold, the composition and signaling of cell-matrix adhesion changes, leading either to increased anchorage or controlled disassembly of cell matrix adhesions, both processes critically involved in cell migration. The aim of this review is to provide insight into the mechanisms leading to the progressive assembly of focal adhesions, how they are modulated in response to mechanical challenges and which mechanisms are used for their disassembly.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2012.06.010", + "pmid": "22819514", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Assembly and disassembly of cell matrix adhesions." + } + }, + { + "pmid": "22351767", + "pubmed": { + "ISODate": "2012-04-20T00:00:00.000Z", + "abstract": "Talin, which is composed of head (THD) and rod domains, plays an important role in cell adhesion events in diverse species including most metazoans and Dictyostelium discoideum. Talin is abundant in the cytosol; however, it mediates adhesion by associating with integrins in the plasma membrane where it forms a primary link between integrins and the actin cytoskeleton. Cells modulate the partitioning of talin between the plasma membrane and the cytosol to control cell adhesion. Here, we combine nuclear magnetic resonance spectroscopy (NMR) with subcellular fractionation to characterize two distinct THD-rod domain interactions that control the interaction of talin with the actin cytoskeleton or its localization to the plasma membrane. An interaction between a discrete vinculin-binding region of the rod (VBS1/2a; Tln1(482-787)), and the THD restrains talin from interacting with the plasma membrane. Furthermore, we show that vinculin binding to VBS1/2a results in talin recruitment to the plasma membrane. Thus, we have structurally defined specific inter-domain interactions between THD and the talin rod domain that regulate the subcellular localization of talin.", + "authors": { + "abbreviation": "Asoka Banno, Benjamin T Goult, HoSup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Asoka", + "LastName": "Banno", + "abbrevName": "Banno A", + "email": null, + "isCollectiveName": false, + "name": "Asoka Banno" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "HoSup", + "LastName": "Lee", + "abbrevName": "Lee H", + "email": null, + "isCollectiveName": false, + "name": "HoSup Lee" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M112.341214", + "pmid": "22351767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 287 2012", + "title": "Subcellular localization of talin is regulated by inter-domain interactions." + } + }, + { + "pmid": "22291038", + "pubmed": { + "ISODate": "2012-02-06T00:00:00.000Z", + "abstract": "Focal adhesion composition and size are modulated in a myosin II-dependent maturation process that controls adhesion, migration, and matrix remodeling. As myosin II activity drives stress fiber assembly and enhanced tension at adhesions simultaneously, the extent to which adhesion maturation is driven by tension or altered actin architecture is unknown. We show that perturbations to formin and α-actinin 1 activity selectively inhibited stress fiber assembly at adhesions but retained a contractile lamella that generated large tension on adhesions. Despite relatively unperturbed adhesion dynamics and force transmission, impaired stress fiber assembly impeded focal adhesion compositional maturation and fibronectin remodeling. Finally, we show that compositional maturation of focal adhesions could occur even when myosin II-dependent cellular tension was reduced by 80%. We propose that stress fiber assembly at the adhesion site serves as a structural template that facilitates adhesion maturation over a wide range of tensions. This work identifies the essential role of lamellar actin architecture in adhesion maturation.", + "authors": { + "abbreviation": "Patrick W Oakes, Yvonne Beckham, Jonathan Stricker, Margaret L Gardel", + "authorList": [ + { + "ForeName": "Patrick", + "LastName": "Oakes", + "abbrevName": "Oakes PW", + "email": null, + "isCollectiveName": false, + "name": "Patrick W Oakes" + }, + { + "ForeName": "Yvonne", + "LastName": "Beckham", + "abbrevName": "Beckham Y", + "email": null, + "isCollectiveName": false, + "name": "Yvonne Beckham" + }, + { + "ForeName": "Jonathan", + "LastName": "Stricker", + "abbrevName": "Stricker J", + "email": null, + "isCollectiveName": false, + "name": "Jonathan Stricker" + }, + { + "ForeName": "Margaret", + "LastName": "Gardel", + "abbrevName": "Gardel ML", + "email": null, + "isCollectiveName": false, + "name": "Margaret L Gardel" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.201107042", + "pmid": "22291038", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 196 2012", + "title": "Tension is required but not sufficient for focal adhesion maturation without a stress fiber template." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "22030346", + "pubmed": { + "ISODate": "2012-06-01T00:00:00.000Z", + "abstract": "Regulated neurotransmitter release from presynaptic boutons is crucial for the functioning of chemical synapses, what in turn governs the functional performance of the nervous system. Release occurs at the active zone (AZ), a specialized region of the presynaptic plasma membrane that is defined by a unique and complex meshwork of proteins--the cytomatrix at the AZ (CAZ). Important functions of CAZ proteins include recruitment, docking and priming of synaptic vesicles as well as appropriate localization of voltage-gated calcium channels near vesicle docking sites. We will discuss recent progress in the understanding of the topological localization and the molecular functions of characteristic CAZ proteins as well as emerging molecular mechanisms underlying presynaptic plasticity that involve significant structural CAZ remodeling.", + "authors": { + "abbreviation": "Eckart D Gundelfinger, Anna Fejtova", + "authorList": [ + { + "ForeName": "Eckart", + "LastName": "Gundelfinger", + "abbrevName": "Gundelfinger ED", + "email": "gundelfi@lin-magdeburg.de", + "isCollectiveName": false, + "name": "Eckart D Gundelfinger" + }, + { + "ForeName": "Anna", + "LastName": "Fejtova", + "abbrevName": "Fejtova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Fejtova" + } + ], + "contacts": [ + { + "ForeName": "Eckart", + "LastName": "Gundelfinger", + "email": [ + "gundelfi@lin-magdeburg.de" + ], + "name": "Eckart D Gundelfinger" + } + ] + }, + "doi": "10.1016/j.conb.2011.10.005", + "pmid": "22030346", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Neurobiol 22 2012", + "title": "Molecular organization and plasticity of the cytomatrix at the active zone." + } + }, + { + "pmid": "22001384", + "pubmed": { + "ISODate": "2011-12-01T00:00:00.000Z", + "abstract": "Microtubules define the architecture and internal organization of cells by positioning organelles and activities, as well as by supporting cell shape and mechanics. One of the major functions of microtubules is the control of polarized cell motility. In order to support the asymmetry of polarized cells, microtubules have to be organized asymmetrically themselves. Asymmetry in microtubule distribution and stability is regulated by multiple molecular factors, most of which are microtubule-associated proteins that locally control microtubule nucleation and dynamics. At the same time, the dynamic state of microtubules is key to the regulatory mechanisms by which microtubules regulate cell polarity, modulate cell adhesion and control force-production by the actin cytoskeleton. Here, we propose that even small alterations in microtubule dynamics can influence cell migration via several different microtubule-dependent pathways. We discuss regulatory factors, potential feedback mechanisms due to functional microtubule-actin crosstalk and implications for cancer cell motility.", + "authors": { + "abbreviation": "Irina Kaverina, Anne Straube", + "authorList": [ + { + "ForeName": "Irina", + "LastName": "Kaverina", + "abbrevName": "Kaverina I", + "email": "Irina.Kaverina@Vanderbilt.Edu", + "isCollectiveName": false, + "name": "Irina Kaverina" + }, + { + "ForeName": "Anne", + "LastName": "Straube", + "abbrevName": "Straube A", + "email": null, + "isCollectiveName": false, + "name": "Anne Straube" + } + ], + "contacts": [ + { + "ForeName": "Irina", + "LastName": "Kaverina", + "email": [ + "Irina.Kaverina@Vanderbilt.Edu" + ], + "name": "Irina Kaverina" + } + ] + }, + "doi": "10.1016/j.semcdb.2011.09.017", + "pmid": "22001384", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Semin Cell Dev Biol 22 2011", + "title": "Regulation of cell migration by dynamic microtubules." + } + }, + { + "pmid": "21596566", + "pubmed": { + "ISODate": "2011-06-07T00:00:00.000Z", + "abstract": "Rab6 is a conserved small GTPase that localizes to the Golgi apparatus and cytoplasmic vesicles and controls transport and fusion of secretory carriers [1]. Another Rab implicated in trafficking from the trans-Golgi to the plasma membrane is Rab8 [2-5]. Here we show that Rab8A stably associates with exocytotic vesicles in a Rab6-dependent manner. Rab8A function is not needed for budding or motility of exocytotic carriers but is required for their docking and fusion. These processes also depend on the Rab6-interacting cortical factor ELKS [1], suggesting that Rab8A and ELKS act in the same pathway. We show that Rab8A and ELKS can be linked by MICAL3, a member of the MICAL family of flavoprotein monooxygenases [6]. Expression of a MICAL3 mutant with an inactive monooxygenase domain resulted in a strong accumulation of secretory vesicles that were docked at the cell cortex but failed to fuse with the plasma membrane, an effect that correlated with the strongly reduced mobility of MICAL3. We propose that the monooxygenase activity of MICAL3 is required to regulate its own turnover and the concomitant remodeling of vesicle-docking protein complexes in which it is engaged. Taken together, the results of our study illustrate cooperation of two Rab proteins in constitutive exocytosis and implicates a redox enzyme in this process.", + "authors": { + "abbreviation": "Ilya Grigoriev, Ka Lou Yu, Emma Martinez-Sanchez, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Emma", + "LastName": "Martinez-Sanchez", + "abbrevName": "Martinez-Sanchez E", + "email": null, + "isCollectiveName": false, + "name": "Emma Martinez-Sanchez" + }, + { + "ForeName": "Andrea", + "LastName": "Serra-Marques", + "abbrevName": "Serra-Marques A", + "email": null, + "isCollectiveName": false, + "name": "Andrea Serra-Marques" + }, + { + "ForeName": "Ihor", + "LastName": "Smal", + "abbrevName": "Smal I", + "email": null, + "isCollectiveName": false, + "name": "Ihor Smal" + }, + { + "ForeName": "Erik", + "LastName": "Meijering", + "abbrevName": "Meijering E", + "email": null, + "isCollectiveName": false, + "name": "Erik Meijering" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Johan", + "LastName": "Peränen", + "abbrevName": "Peränen J", + "email": null, + "isCollectiveName": false, + "name": "Johan Peränen" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Peter", + "LastName": "van der Sluijs", + "abbrevName": "van der Sluijs P", + "email": null, + "isCollectiveName": false, + "name": "Peter van der Sluijs" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": null, + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2011.04.030", + "pmid": "21596566", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 21 2011", + "title": "Rab6, Rab8, and MICAL3 cooperate in controlling docking and fusion of exocytotic carriers." + } + }, + { + "pmid": "21572423", + "pubmed": { + "ISODate": "2011-06-01T00:00:00.000Z", + "abstract": "Large gaps in basement membrane occur at sites of cell invasion and tissue remodelling in development and cancer. Though never followed directly in vivo, basement membrane dissolution or reduced synthesis have been postulated to create these gaps. Using landmark photobleaching and optical highlighting of laminin and type IV collagen, we find that a new mechanism, basement membrane sliding, underlies basement membrane gap enlargement during uterine-vulval attachment in Caenorhabditis elegans. Laser ablation and mutant analysis reveal that the invaginating vulval cells promote basement membrane movement. Further, an RNA interference and expression screen identifies the integrin INA-1/PAT-3 and VAB-19, homologue of the tumour suppressor Kank, as regulators of basement membrane opening. Both concentrate within vulval cells at the basement membrane gap boundary and halt expansion of the shifting basement membrane. Basement membrane sliding followed by targeted adhesion represents a new mechanism for creating precise basement membrane breaches that can be used by cells to break down compartment boundaries.", + "authors": { + "abbreviation": "Shinji Ihara, Elliott J Hagedorn, Meghan A Morrissey, ..., David R Sherwood", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Ihara", + "abbrevName": "Ihara S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Ihara" + }, + { + "ForeName": "Elliott", + "LastName": "Hagedorn", + "abbrevName": "Hagedorn EJ", + "email": null, + "isCollectiveName": false, + "name": "Elliott J Hagedorn" + }, + { + "ForeName": "Meghan", + "LastName": "Morrissey", + "abbrevName": "Morrissey MA", + "email": null, + "isCollectiveName": false, + "name": "Meghan A Morrissey" + }, + { + "ForeName": "Qiuyi", + "LastName": "Chi", + "abbrevName": "Chi Q", + "email": null, + "isCollectiveName": false, + "name": "Qiuyi Chi" + }, + { + "ForeName": "Fumio", + "LastName": "Motegi", + "abbrevName": "Motegi F", + "email": null, + "isCollectiveName": false, + "name": "Fumio Motegi" + }, + { + "ForeName": "James", + "LastName": "Kramer", + "abbrevName": "Kramer JM", + "email": null, + "isCollectiveName": false, + "name": "James M Kramer" + }, + { + "ForeName": "David", + "LastName": "Sherwood", + "abbrevName": "Sherwood DR", + "email": null, + "isCollectiveName": false, + "name": "David R Sherwood" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2233", + "pmid": "21572423", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 13 2011", + "title": "Basement membrane sliding and targeted adhesion remodels tissue boundaries during uterine-vulval attachment in Caenorhabditis elegans." + } + }, + { + "pmid": "21561680", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "Despite its frequent inactivation in human breast cancers, the role of p21(Cip1) (p21) in morphological plasticity of normal mammary epithelial cells is still poorly understood. To address this question, we have investigated the consequences of p21 silencing in two-dimensional (2D) morphogenesis of untransformed human mammary epithelial cells. Here we show that p21 inactivation causes a reduction of 2D cell spreading and suppresses focal adhesion. In order to investigate the cytoskeletal modifications associated with this altered morphology, we have analyzed the microtubule dynamics in interphase p21-depleted cells. Our results demonstrate that interphase microtubule dynamic instability is strongly increased by p21 silencing. This alteration correlates with severe microtubule hypoacetylation. Next, we show that these microtubule defects in p21-depleted cells can be reversed by the use of the small molecule tubacin, a specific inhibitor of the α-tubulin deacetylase HDAC6. Tubacin-induced microtubule dynamics decrease also correlates with a partial recovery of cell spreading and focal adhesion in those cells. Collectively, these data indicate that p21 regulates the morphological plasticity of normal mammary epithelial cells by modulating dynamics of key cytoskeletal components.", + "authors": { + "abbreviation": "Benjamin Pierre Bouchet, Frédérique Fauvet, Gaël Grelier, ..., Alain Puisieux", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": "bouchetben@gmail.com", + "isCollectiveName": false, + "name": "Benjamin Pierre Bouchet" + }, + { + "ForeName": "Frédérique", + "LastName": "Fauvet", + "abbrevName": "Fauvet F", + "email": null, + "isCollectiveName": false, + "name": "Frédérique Fauvet" + }, + { + "ForeName": "Gaël", + "LastName": "Grelier", + "abbrevName": "Grelier G", + "email": null, + "isCollectiveName": false, + "name": "Gaël Grelier" + }, + { + "ForeName": "Carlos", + "LastName": "Galmarini", + "abbrevName": "Galmarini CM", + "email": null, + "isCollectiveName": false, + "name": "Carlos María Galmarini" + }, + { + "ForeName": "Alain", + "LastName": "Puisieux", + "abbrevName": "Puisieux A", + "email": null, + "isCollectiveName": false, + "name": "Alain Puisieux" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "email": [ + "bouchetben@gmail.com" + ], + "name": "Benjamin Pierre Bouchet" + } + ] + }, + "doi": "10.1016/j.ejcb.2011.03.002", + "pmid": "21561680", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Cell Biol 90 2011", + "title": "p21(Cip1) regulates cell-substrate adhesion and interphase microtubule dynamics in untransformed human mammary epithelial cells." + } + }, + { + "pmid": "20729930", + "pubmed": { + "ISODate": "2010-09-01T00:00:00.000Z", + "abstract": "Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease. For most cells in most environments, movement begins with protrusion of the cell membrane followed by the formation of new adhesions at the cell front that link the actin cytoskeleton to the substratum, generation of traction forces that move the cell forwards and disassembly of adhesions at the cell rear. Adhesion formation and disassembly drive the migration cycle by activating Rho GTPases, which in turn regulate actin polymerization and myosin II activity, and therefore adhesion dynamics.", + "authors": { + "abbreviation": "J Thomas Parsons, Alan Rick Horwitz, Martin A Schwartz", + "authorList": [ + { + "ForeName": "J", + "LastName": "Parsons", + "abbrevName": "Parsons JT", + "email": "jtp@virginia.edu", + "isCollectiveName": false, + "name": "J Thomas Parsons" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AR", + "email": null, + "isCollectiveName": false, + "name": "Alan Rick Horwitz" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "J", + "LastName": "Parsons", + "email": [ + "jtp@virginia.edu" + ], + "name": "J Thomas Parsons" + } + ] + }, + "doi": "10.1038/nrm2957", + "pmid": "20729930", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 11 2010", + "title": "Cell adhesion: integrating cytoskeletal dynamics and cellular tension." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "20581014", + "pubmed": { + "ISODate": "2010-08-01T00:00:00.000Z", + "abstract": "Cytomatrix at the active zone-associated structural protein (CAST) was first purified from rat brain. It belongs to a protein family with the protein ELKS being its close relative. In nerve terminals, these proteins are specifically localized in the active zone (AZ). They have been shown to directly interact with other AZ proteins, including RIM1, Piccolo and Bassoon, and indirectly with Munc13-1 through RIM1, forming a large molecular complex at AZ. Moreover, the direct interaction of CAST with RIM1 and Bassoon appears to be involved in the release of neurotransmitters. However, it still remains elusive how CAST and ELKS regulate the assembly and function of AZ during synapse maturation. This review focuses on recent findings about the ELKS/CAST family revealed by biochemical strategies and genetic studies, and discusses the potential roles of this protein family in the function and organization of the presynaptic AZ.", + "authors": { + "abbreviation": "Yamato Hida, Toshihisa Ohtsuka", + "authorList": [ + { + "ForeName": "Yamato", + "LastName": "Hida", + "abbrevName": "Hida Y", + "email": null, + "isCollectiveName": false, + "name": "Yamato Hida" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + } + ], + "contacts": [] + }, + "doi": "10.1093/jb/mvq065", + "pmid": "20581014", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Biochem 148 2010", + "title": "CAST and ELKS proteins: structural and functional determinants of the presynaptic active zone." + } + }, + { + "pmid": "20513769", + "pubmed": { + "ISODate": "2010-05-31T00:00:00.000Z", + "abstract": "LL5beta has been identified as a microtubule-anchoring factor that attaches EB1/CLIP-associating protein (CLASP)-bound microtubule plus ends to the cell cortex. In this study, we show that LL5beta and its homologue LL5alpha (LL5s) colocalize with autocrine laminin-5 and its receptors, integrins alpha3beta1 and alpha6beta4, at the basal side of fully polarized epithelial sheets. Depletion of both laminin receptor integrins abolishes the cortical localization of LL5s, whereas LL5 depletion reduces the amount of integrin alpha3 at the basal cell cortex. Activation of integrin alpha3 is sufficient to initiate LL5 accumulation at the cell cortex. LL5s form a complex with the cytoplasmic tails of these integrins, but their interaction might be indirect. Analysis of the three-dimensional distribution of microtubule growth by visualizing EB1-GFP in epithelial sheets in combination with RNA interference reveals that LL5s are required to maintain the density of growing microtubules selectively at the basal cortex. These findings reveal that signaling from laminin-integrin associations attaches microtubule plus ends to the epithelial basal cell cortex.", + "authors": { + "abbreviation": "Azusa Hotta, Tomomi Kawakatsu, Tomoya Nakatani, ..., Yuko Mimori-Kiyosue", + "authorList": [ + { + "ForeName": "Azusa", + "LastName": "Hotta", + "abbrevName": "Hotta A", + "email": null, + "isCollectiveName": false, + "name": "Azusa Hotta" + }, + { + "ForeName": "Tomomi", + "LastName": "Kawakatsu", + "abbrevName": "Kawakatsu T", + "email": null, + "isCollectiveName": false, + "name": "Tomomi Kawakatsu" + }, + { + "ForeName": "Tomoya", + "LastName": "Nakatani", + "abbrevName": "Nakatani T", + "email": null, + "isCollectiveName": false, + "name": "Tomoya Nakatani" + }, + { + "ForeName": "Toshitaka", + "LastName": "Sato", + "abbrevName": "Sato T", + "email": null, + "isCollectiveName": false, + "name": "Toshitaka Sato" + }, + { + "ForeName": "Chiyuki", + "LastName": "Matsui", + "abbrevName": "Matsui C", + "email": null, + "isCollectiveName": false, + "name": "Chiyuki Matsui" + }, + { + "ForeName": "Taiko", + "LastName": "Sukezane", + "abbrevName": "Sukezane T", + "email": null, + "isCollectiveName": false, + "name": "Taiko Sukezane" + }, + { + "ForeName": "Tsuyoshi", + "LastName": "Akagi", + "abbrevName": "Akagi T", + "email": null, + "isCollectiveName": false, + "name": "Tsuyoshi Akagi" + }, + { + "ForeName": "Tomoko", + "LastName": "Hamaji", + "abbrevName": "Hamaji T", + "email": null, + "isCollectiveName": false, + "name": "Tomoko Hamaji" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Yoshimi", + "LastName": "Takai", + "abbrevName": "Takai Y", + "email": null, + "isCollectiveName": false, + "name": "Yoshimi Takai" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200910095", + "pmid": "20513769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Laminin-based cell adhesion anchors microtubule plus ends to the epithelial cell basal cortex through LL5alpha/beta." + } + }, + { + "pmid": "19822767", + "pubmed": { + "ISODate": "2009-10-27T00:00:00.000Z", + "abstract": "A critical step in synapse formation is the clustering of neurotransmitter receptors in the postsynaptic membrane, directly opposite the nerve terminal. At the neuromuscular junction, a widely studied model synapse, acetylcholine receptors (AChRs) initially aggregate to form an ovoid postsynaptic plaque. As the synapse matures, the plaque becomes perforated and is eventually transformed into a complex, branched structure. We found that this transformation also occurs in myotubes cultured in the absence of neurons, and used this system to seek machinery that orchestrates postsynaptic maturation. We show that perforations in the AChR aggregate bear structures resembling podosomes, dynamic actin-rich adhesive organelles involved in matrix remodeling in non-neuronal cells but not described in neural structures. The location and dynamics of synaptic podosomes are spatiotemporally correlated with changes in AChR aggregate topology, and pharmacological disruption of podosomes leads to rapid alterations in AChR organization. Our results indicate that synaptic podosomes play critical roles in maturation of the postsynaptic membrane.", + "authors": { + "abbreviation": "Tomasz J Proszynski, Jacinthe Gingras, Gregorio Valdez, ..., Joshua R Sanes", + "authorList": [ + { + "ForeName": "Tomasz", + "LastName": "Proszynski", + "abbrevName": "Proszynski TJ", + "email": null, + "isCollectiveName": false, + "name": "Tomasz J Proszynski" + }, + { + "ForeName": "Jacinthe", + "LastName": "Gingras", + "abbrevName": "Gingras J", + "email": null, + "isCollectiveName": false, + "name": "Jacinthe Gingras" + }, + { + "ForeName": "Gregorio", + "LastName": "Valdez", + "abbrevName": "Valdez G", + "email": null, + "isCollectiveName": false, + "name": "Gregorio Valdez" + }, + { + "ForeName": "Konrad", + "LastName": "Krzewski", + "abbrevName": "Krzewski K", + "email": null, + "isCollectiveName": false, + "name": "Konrad Krzewski" + }, + { + "ForeName": "Joshua", + "LastName": "Sanes", + "abbrevName": "Sanes JR", + "email": null, + "isCollectiveName": false, + "name": "Joshua R Sanes" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.0910391106", + "pmid": "19822767", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Proc Natl Acad Sci U S A 106 2009", + "title": "Podosomes are present in a postsynaptic apparatus and participate in its maturation." + } + }, + { + "pmid": "19798053", + "pubmed": { + "ISODate": "2009-11-18T00:00:00.000Z", + "abstract": "Fundamental to cell adhesion and migration, integrins are large heterodimeric membrane proteins that uniquely mediate inside-out signal transduction, whereby adhesion to the extracellular matrix is activated from within the cell by direct binding of talin to the cytoplasmic tail of the beta integrin subunit. Here, we report the first structure of talin bound to an authentic full-length beta integrin tail. Using biophysical and whole cell measurements, we show that a specific ionic interaction between the talin F3 domain and the membrane-proximal helix of the beta tail disrupts an integrin alpha/beta salt bridge that helps maintain the integrin inactive state. Second, we identify a positively charged surface on the talin F2 domain that precisely orients talin to disrupt the heterodimeric integrin transmembrane (TM) complex. These results show key structural features that explain the ability of talin to mediate inside-out TM signalling.", + "authors": { + "abbreviation": "Nicholas J Anthis, Kate L Wegener, Feng Ye, ..., Iain D Campbell", + "authorList": [ + { + "ForeName": "Nicholas", + "LastName": "Anthis", + "abbrevName": "Anthis NJ", + "email": "nick.anthis@gmail.com", + "isCollectiveName": false, + "name": "Nicholas J Anthis" + }, + { + "ForeName": "Kate", + "LastName": "Wegener", + "abbrevName": "Wegener KL", + "email": null, + "isCollectiveName": false, + "name": "Kate L Wegener" + }, + { + "ForeName": "Feng", + "LastName": "Ye", + "abbrevName": "Ye F", + "email": null, + "isCollectiveName": false, + "name": "Feng Ye" + }, + { + "ForeName": "Chungho", + "LastName": "Kim", + "abbrevName": "Kim C", + "email": null, + "isCollectiveName": false, + "name": "Chungho Kim" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Edward", + "LastName": "Lowe", + "abbrevName": "Lowe ED", + "email": null, + "isCollectiveName": false, + "name": "Edward D Lowe" + }, + { + "ForeName": "Ioannis", + "LastName": "Vakonakis", + "abbrevName": "Vakonakis I", + "email": null, + "isCollectiveName": false, + "name": "Ioannis Vakonakis" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + } + ], + "contacts": [ + { + "ForeName": "Nicholas", + "LastName": "Anthis", + "email": [ + "nick.anthis@gmail.com" + ], + "name": "Nicholas J Anthis" + } + ] + }, + "doi": "10.1038/emboj.2009.287", + "pmid": "19798053", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 28 2009", + "title": "The structure of an integrin/talin complex reveals the basis of inside-out signal transduction." + } + }, + { + "pmid": "19632184", + "pubmed": { + "ISODate": "2009-07-23T00:00:00.000Z", + "abstract": "Microtubules are filamentous polymers essential for cell viability. Microtubule plus-end tracking proteins (+TIPs) associate with growing microtubule plus ends and control microtubule dynamics and interactions with different cellular structures during cell division, migration, and morphogenesis. EB1 and its homologs are highly conserved proteins that play an important role in the targeting of +TIPs to microtubule ends, but the underlying molecular mechanism remains elusive. By using live cell experiments and in vitro reconstitution assays, we demonstrate that a short polypeptide motif, Ser-x-Ile-Pro (SxIP), is used by numerous +TIPs, including the tumor suppressor APC, the transmembrane protein STIM1, and the kinesin MCAK, for localization to microtubule tips in an EB1-dependent manner. Structural and biochemical data reveal the molecular basis of the EB1-SxIP interaction and explain its negative regulation by phosphorylation. Our findings establish a general \"microtubule tip localization signal\" (MtLS) and delineate a unifying mechanism for this subcellular protein targeting process.", + "authors": { + "abbreviation": "Srinivas Honnappa, Susana Montenegro Gouveia, Anke Weisbrich, ..., Michel O Steinmetz", + "authorList": [ + { + "ForeName": "Srinivas", + "LastName": "Honnappa", + "abbrevName": "Honnappa S", + "email": null, + "isCollectiveName": false, + "name": "Srinivas Honnappa" + }, + { + "ForeName": "Susana", + "LastName": "Gouveia", + "abbrevName": "Gouveia SM", + "email": null, + "isCollectiveName": false, + "name": "Susana Montenegro Gouveia" + }, + { + "ForeName": "Anke", + "LastName": "Weisbrich", + "abbrevName": "Weisbrich A", + "email": null, + "isCollectiveName": false, + "name": "Anke Weisbrich" + }, + { + "ForeName": "Fred", + "LastName": "Damberger", + "abbrevName": "Damberger FF", + "email": null, + "isCollectiveName": false, + "name": "Fred F Damberger" + }, + { + "ForeName": "Neel", + "LastName": "Bhavesh", + "abbrevName": "Bhavesh NS", + "email": null, + "isCollectiveName": false, + "name": "Neel S Bhavesh" + }, + { + "ForeName": "Hatim", + "LastName": "Jawhari", + "abbrevName": "Jawhari H", + "email": null, + "isCollectiveName": false, + "name": "Hatim Jawhari" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Frederik", + "LastName": "van Rijssel", + "abbrevName": "van Rijssel FJ", + "email": null, + "isCollectiveName": false, + "name": "Frederik J A van Rijssel" + }, + { + "ForeName": "Ruben", + "LastName": "Buey", + "abbrevName": "Buey RM", + "email": null, + "isCollectiveName": false, + "name": "Ruben M Buey" + }, + { + "ForeName": "Aleksandra", + "LastName": "Lawera", + "abbrevName": "Lawera A", + "email": null, + "isCollectiveName": false, + "name": "Aleksandra Lawera" + }, + { + "ForeName": "Ilian", + "LastName": "Jelesarov", + "abbrevName": "Jelesarov I", + "email": null, + "isCollectiveName": false, + "name": "Ilian Jelesarov" + }, + { + "ForeName": "Fritz", + "LastName": "Winkler", + "abbrevName": "Winkler FK", + "email": null, + "isCollectiveName": false, + "name": "Fritz K Winkler" + }, + { + "ForeName": "Kurt", + "LastName": "Wüthrich", + "abbrevName": "Wüthrich K", + "email": null, + "isCollectiveName": false, + "name": "Kurt Wüthrich" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Michel", + "LastName": "Steinmetz", + "abbrevName": "Steinmetz MO", + "email": null, + "isCollectiveName": false, + "name": "Michel O Steinmetz" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2009.04.065", + "pmid": "19632184", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 138 2009", + "title": "An EB1-binding motif acts as a microtubule tip localization signal." + } + }, + { + "pmid": "19575647", + "pubmed": { + "ISODate": "2010-01-01T00:00:00.000Z", + "abstract": "Directed cell migration is a physical process that requires dramatic changes in cell shape and adhesion to the extracellular matrix. For efficient movement, these processes must be spatiotemporally coordinated. To a large degree, the morphological changes and physical forces that occur during migration are generated by a dynamic filamentous actin (F-actin) cytoskeleton. Adhesion is regulated by dynamic assemblies of structural and signaling proteins that couple the F-actin cytoskeleton to the extracellular matrix. Here, we review current knowledge of the dynamic organization of the F-actin cytoskeleton in cell migration and the regulation of focal adhesion assembly and disassembly with an emphasis on how mechanical and biochemical signaling between these two systems regulate the coordination of physical processes in cell migration.", + "authors": { + "abbreviation": "Margaret L Gardel, Ian C Schneider, Yvonne Aratyn-Schaus, Clare M Waterman", + "authorList": [ + { + "ForeName": "Margaret", + "LastName": "Gardel", + "abbrevName": "Gardel ML", + "email": null, + "isCollectiveName": false, + "name": "Margaret L Gardel" + }, + { + "ForeName": "Ian", + "LastName": "Schneider", + "abbrevName": "Schneider IC", + "email": null, + "isCollectiveName": false, + "name": "Ian C Schneider" + }, + { + "ForeName": "Yvonne", + "LastName": "Aratyn-Schaus", + "abbrevName": "Aratyn-Schaus Y", + "email": null, + "isCollectiveName": false, + "name": "Yvonne Aratyn-Schaus" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + } + ], + "contacts": [] + }, + "doi": "10.1146/annurev.cellbio.011209.122036", + "pmid": "19575647", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Annu Rev Cell Dev Biol 26 2010", + "title": "Mechanical integration of actin and adhesion dynamics in cell migration." + } + }, + { + "pmid": "19559006", + "pubmed": { + "ISODate": "2009-09-04T00:00:00.000Z", + "abstract": "Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is associated with heterozygous mutations in the KIF21A gene, including a major (R954W) and a minor (M947T) mutation. Kank1, which regulates actin polymerization, cell migration and neurite outgrowth, interacted with the third and fourth coiled-coil domains of KIF21A protein at its ankyrin-repeat domain. While both KIF21A(R954W) and KIF21A(M947T) enhanced the formation of a heterodimer with the wild type, KIF21A(WT), these mutants also enhanced the interaction with Kank1. Knockdown of KIF21A resulted in Kank1 predominantly occurring in the cytosolic fraction, while KIF21A(WT) slightly enhanced the translocation of Kank1 to the membrane fraction. Moreover, KIF21A(R954W) significantly enhanced the translocation of Kank1 to the membrane fraction. These results suggest that KIF21A regulates the distribution of Kank1 and that KIF21A mutations associated with CFEOM1 enhanced the accumulation of Kank1 in the membrane fraction. This might cause an abrogation of neuronal development in cases of CFEOM1 through over-regulation of actin polymerization by Kank1.", + "authors": { + "abbreviation": "Naoto Kakinuma, Ryoiti Kiyama", + "authorList": [ + { + "ForeName": "Naoto", + "LastName": "Kakinuma", + "abbrevName": "Kakinuma N", + "email": null, + "isCollectiveName": false, + "name": "Naoto Kakinuma" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbrc.2009.06.109", + "pmid": "19559006", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem Biophys Res Commun 386 2009", + "title": "A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane." + } + }, + { + "pmid": "19554261", + "pubmed": { + "ISODate": "2009-08-01T00:00:00.000Z", + "abstract": "The Kank family of proteins, Kank1-Kank4, are characterized by their unique structure, coiled-coil motifs in the N-terminal region, and ankyrin-repeats in the C-terminal region, with an additional motif, the KN motif, at the N-terminus. Kank1 was obtained by positional cloning of a tumor suppressor gene in renal cell carcinoma, while the other members were found by homology search. The family is involved in the regulation of actin polymerization and cell motility through signaling pathways containing PI3K/Akt and/or unidentified modulators/effectors. Their relationship to diseases such as cancer, and to neuronal and developmental disorders, will be an important subject of future study.", + "authors": { + "abbreviation": "N Kakinuma, Y Zhu, Y Wang, ..., R Kiyama", + "authorList": [ + { + "ForeName": "N", + "LastName": "Kakinuma", + "abbrevName": "Kakinuma N", + "email": null, + "isCollectiveName": false, + "name": "N Kakinuma" + }, + { + "ForeName": "Y", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Y Zhu" + }, + { + "ForeName": "Y", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Y Wang" + }, + { + "ForeName": "B", + "LastName": "Roy", + "abbrevName": "Roy BC", + "email": null, + "isCollectiveName": false, + "name": "B C Roy" + }, + { + "ForeName": "R", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "R Kiyama" + } + ], + "contacts": [] + }, + "doi": "10.1007/s00018-009-0038-y", + "pmid": "19554261", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell Mol Life Sci 66 2009", + "title": "Kank proteins: structure, functions and diseases." + } + }, + { + "pmid": "19179532", + "pubmed": { + "ISODate": "2009-01-30T00:00:00.000Z", + "abstract": "The molecular mechanism by which a mechanical stimulus is translated into a chemical response in biological systems is still unclear. We show that mechanical stretching of single cytoplasmic proteins can activate binding of other molecules. We used magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy to investigate the effect of force on the interaction between talin, a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system. Such protein stretching may be a more general mechanism for force transduction.", + "authors": { + "abbreviation": "Armando del Rio, Raul Perez-Jimenez, Ruchuan Liu, ..., Michael P Sheetz", + "authorList": [ + { + "ForeName": "Armando", + "LastName": "del Rio", + "abbrevName": "del Rio A", + "email": null, + "isCollectiveName": false, + "name": "Armando del Rio" + }, + { + "ForeName": "Raul", + "LastName": "Perez-Jimenez", + "abbrevName": "Perez-Jimenez R", + "email": null, + "isCollectiveName": false, + "name": "Raul Perez-Jimenez" + }, + { + "ForeName": "Ruchuan", + "LastName": "Liu", + "abbrevName": "Liu R", + "email": null, + "isCollectiveName": false, + "name": "Ruchuan Liu" + }, + { + "ForeName": "Pere", + "LastName": "Roca-Cusachs", + "abbrevName": "Roca-Cusachs P", + "email": null, + "isCollectiveName": false, + "name": "Pere Roca-Cusachs" + }, + { + "ForeName": "Julio", + "LastName": "Fernandez", + "abbrevName": "Fernandez JM", + "email": null, + "isCollectiveName": false, + "name": "Julio M Fernandez" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1162912", + "pmid": "19179532", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Science 323 2009", + "title": "Stretching single talin rod molecules activates vinculin binding." + } + }, + { + "pmid": "19175539", + "pubmed": { + "ISODate": "2009-03-01T00:00:00.000Z", + "abstract": "Cross-talk between microtubule networks and sites of cell-matrix and cell-cell adhesion has profound impact on these structures and is essential for proper cell organization, polarization and motility. Components of adhesion sites can interact directly with microtubules or with proteins that specifically associate with microtubule plus ends and minus ends and in this way capture, stabilize or destabilize microtubules. In their turn, microtubules can serve as routes for delivery of structural and regulatory factors that control adhesion site turnover. In addition, the microtubule lattice or growing microtubule plus ends can serve as diffusional sinks that accumulate and scaffold regulatory molecules, thereby affecting their activity in the vicinity of adhesions. Combination of these mechanisms underlies the functional co-operation between microtubules and adhesion sites and defines their dynamic behavior.", + "authors": { + "abbreviation": "Anna Akhmanova, Samantha J Stehbens, Alpha S Yap", + "authorList": [ + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@erasmusmc.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Alpha", + "LastName": "Yap", + "abbrevName": "Yap AS", + "email": null, + "isCollectiveName": false, + "name": "Alpha S Yap" + } + ], + "contacts": [ + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@erasmusmc.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1111/j.1600-0854.2008.00869.x", + "pmid": "19175539", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Traffic 10 2009", + "title": "Touch, grasp, deliver and control: functional cross-talk between microtubules and cell adhesions." + } + }, + { + "pmid": "19171758", + "pubmed": { + "ISODate": "2009-01-26T00:00:00.000Z", + "abstract": "In this study, insulin receptor substrate (IRS) p53 is identified as a binding partner for Kank, a kidney ankyrin repeat-containing protein that functions to suppress cell proliferation and regulate the actin cytoskeleton. Kank specifically inhibits the binding of IRSp53 with active Rac1 (Rac1(G12V)) but not Cdc42 (cdc42(G12V)) and thus inhibits the IRSp53-dependent development of lamellipodia without affecting the formation of filopodia. Knockdown (KD) of Kank by RNA interference results in increased lamellipodial development, whereas KD of both Kank and IRSp53 has little effect. Moreover, insulin-induced membrane ruffling is inhibited by overexpression of Kank. Kank also suppresses integrin-dependent cell spreading and IRSp53-induced neurite outgrowth. Our results demonstrate that Kank negatively regulates the formation of lamellipodia by inhibiting the interaction between Rac1 and IRSp53.", + "authors": { + "abbreviation": "Badal Chandra Roy, Naoto Kakinuma, Ryoiti Kiyama", + "authorList": [ + { + "ForeName": "Badal", + "LastName": "Roy", + "abbrevName": "Roy BC", + "email": null, + "isCollectiveName": false, + "name": "Badal Chandra Roy" + }, + { + "ForeName": "Naoto", + "LastName": "Kakinuma", + "abbrevName": "Kakinuma N", + "email": null, + "isCollectiveName": false, + "name": "Naoto Kakinuma" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200805147", + "pmid": "19171758", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 184 2009", + "title": "Kank attenuates actin remodeling by preventing interaction between IRSp53 and Rac1." + } + }, + { + "pmid": "18458160", + "pubmed": { + "ISODate": "2008-05-05T00:00:00.000Z", + "abstract": "Phosphoinositide-3 kinase (PI3K)/Akt signaling is activated by growth factors such as insulin and epidermal growth factor (EGF) and regulates several functions such as cell cycling, apoptosis, cell growth, and cell migration. Here, we find that Kank is an Akt substrate located downstream of PI3K and a 14-3-3-binding protein. The interaction between Kank and 14-3-3 is regulated by insulin and EGF and is mediated through phosphorylation of Kank by Akt. In NIH3T3 cells expressing Kank, the amount of actin stress fibers is reduced, and the coexpression of 14-3-3 disrupted this effect. Kank also inhibits insulin-induced cell migration via 14-3-3 binding. Furthermore, Kank inhibits insulin and active Akt-dependent activation of RhoA through binding to 14-3-3. Based on these findings, we hypothesize that Kank negatively regulates the formation of actin stress fibers and cell migration through the inhibition of RhoA activity, which is controlled by binding of Kank to 14-3-3 in PI3K-Akt signaling.", + "authors": { + "abbreviation": "Naoto Kakinuma, Badal Chandra Roy, Yun Zhu, ..., Ryoiti Kiyama", + "authorList": [ + { + "ForeName": "Naoto", + "LastName": "Kakinuma", + "abbrevName": "Kakinuma N", + "email": null, + "isCollectiveName": false, + "name": "Naoto Kakinuma" + }, + { + "ForeName": "Badal", + "LastName": "Roy", + "abbrevName": "Roy BC", + "email": null, + "isCollectiveName": false, + "name": "Badal Chandra Roy" + }, + { + "ForeName": "Yun", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yun Zhu" + }, + { + "ForeName": "Yong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Wang" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200707022", + "pmid": "18458160", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 181 2008", + "title": "Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K-Akt signaling." + } + }, + { + "pmid": "17956329", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Synapses are specialized communication junctions between neurons whose plasticity provides the structural and functional basis for information processing and storage in the brain. Recent biochemical, genetic and imaging studies in diverse model systems are beginning to reveal the molecular mechanisms by which synaptic vesicles, ion channels, receptors and other synaptic components assemble to make a functional synapse. Recent evidence has shown that the formation and function of synapses are critically regulated by the liprin-alpha family of scaffolding proteins. The liprin-alphas have been implicated in pre- and post-synaptic development by recruiting synaptic proteins and regulating synaptic cargo transport. Here, we will summarize the diversity of liprin binding partners, highlight the factors that control the function of liprin-alphas at the synapse and discuss how liprin-alpha family proteins regulate synapse formation and synaptic transmission.", + "authors": { + "abbreviation": "S A Spangler, C C Hoogenraad", + "authorList": [ + { + "ForeName": "S", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "S A Spangler" + }, + { + "ForeName": "C", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": null, + "isCollectiveName": false, + "name": "C C Hoogenraad" + } + ], + "contacts": [] + }, + "doi": "10.1042/BST0351278", + "pmid": "17956329", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochem Soc Trans 35 2007", + "title": "Liprin-alpha proteins: scaffold molecules for synapse maturation." + } + }, + { + "pmid": "17952086", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Shotgun proteomics uses liquid chromatography-tandem mass spectrometry to identify proteins in complex biological samples. We describe an algorithm, called Percolator, for improving the rate of confident peptide identifications from a collection of tandem mass spectra. Percolator uses semi-supervised machine learning to discriminate between correct and decoy spectrum identifications, correctly assigning peptides to 17% more spectra from a tryptic Saccharomyces cerevisiae dataset, and up to 77% more spectra from non-tryptic digests, relative to a fully supervised approach.", + "authors": { + "abbreviation": "Lukas Käll, Jesse D Canterbury, Jason Weston, ..., Michael J MacCoss", + "authorList": [ + { + "ForeName": "Lukas", + "LastName": "Käll", + "abbrevName": "Käll L", + "email": null, + "isCollectiveName": false, + "name": "Lukas Käll" + }, + { + "ForeName": "Jesse", + "LastName": "Canterbury", + "abbrevName": "Canterbury JD", + "email": null, + "isCollectiveName": false, + "name": "Jesse D Canterbury" + }, + { + "ForeName": "Jason", + "LastName": "Weston", + "abbrevName": "Weston J", + "email": null, + "isCollectiveName": false, + "name": "Jason Weston" + }, + { + "ForeName": "William", + "LastName": "Noble", + "abbrevName": "Noble WS", + "email": null, + "isCollectiveName": false, + "name": "William Stafford Noble" + }, + { + "ForeName": "Michael", + "LastName": "MacCoss", + "abbrevName": "MacCoss MJ", + "email": null, + "isCollectiveName": false, + "name": "Michael J MacCoss" + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth1113", + "pmid": "17952086", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Methods 4 2007", + "title": "Semi-supervised learning for peptide identification from shotgun proteomics datasets." + } + }, + { + "pmid": "17681140", + "pubmed": { + "ISODate": "2007-08-01T00:00:00.000Z", + "abstract": "Constitutive exocytosis delivers newly synthesized proteins, lipids, and other molecules from the Golgi apparatus to the cell surface. This process is mediated by vesicles, which bud off the trans-Golgi network, move along cytoskeletal filaments, and fuse with the plasma membrane. Here, we show that the small GTPase Rab6 marks exocytotic vesicles and, together with the microtubule plus-end-directed motor kinesin-1, stimulates their processive microtubule-based transport to the cell periphery. Furthermore, Rab6 directs targeting of secretory vesicles to plasma-membrane sites enriched in the cortical protein ELKS, a known Rab6 binding partner. Our data demonstrate that although Rab6 is not essential for secretion, it controls the organization of exocytosis within the cellular space.", + "authors": { + "abbreviation": "Ilya Grigoriev, Daniël Splinter, Nanda Keijzer, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Daniël", + "LastName": "Splinter", + "abbrevName": "Splinter D", + "email": null, + "isCollectiveName": false, + "name": "Daniël Splinter" + }, + { + "ForeName": "Nanda", + "LastName": "Keijzer", + "abbrevName": "Keijzer N", + "email": null, + "isCollectiveName": false, + "name": "Nanda Keijzer" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Mauro", + "LastName": "Modesti", + "abbrevName": "Modesti M", + "email": null, + "isCollectiveName": false, + "name": "Mauro Modesti" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": null, + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2007.06.010", + "pmid": "17681140", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 13 2007", + "title": "Rab6 regulates transport and targeting of exocytotic carriers." + } + }, + { + "pmid": "17113391", + "pubmed": { + "ISODate": "2006-11-21T00:00:00.000Z", + "abstract": "In motile fibroblasts, stable microtubules (MTs) are oriented toward the leading edge of cells. How these polarized MT arrays are established and maintained, and the cellular processes they control, have been the subject of many investigations. Several MT \"plus-end-tracking proteins,\" or +TIPs, have been proposed to regulate selective MT stabilization, including the CLASPs, a complex of CLIP-170, IQGAP1, activated Cdc42 or Rac1, a complex of APC, EB1, and mDia1, and the actin-MT crosslinking factor ACF7. By using mouse embryonic fibroblasts (MEFs) in a wound-healing assay, we show here that CLASP2 is required for the formation of a stable, polarized MT array but that CLIP-170 and an APC-EB1 interaction are not essential. Persistent motility is also hampered in CLASP2-deficient MEFs. We find that ACF7 regulates cortical CLASP localization in HeLa cells, indicating it acts upstream of CLASP2. Fluorescence-based approaches show that GFP-CLASP2 is immobilized in a bimodal manner in regions near cell edges. Our results suggest that the regional immobilization of CLASP2 allows MT stabilization and promotes directionally persistent motility in fibroblasts.", + "authors": { + "abbreviation": "Ksenija Drabek, Marco van Ham, Tatiana Stepanova, ..., Niels Galjart", + "authorList": [ + { + "ForeName": "Ksenija", + "LastName": "Drabek", + "abbrevName": "Drabek K", + "email": null, + "isCollectiveName": false, + "name": "Ksenija Drabek" + }, + { + "ForeName": "Marco", + "LastName": "van Ham", + "abbrevName": "van Ham M", + "email": null, + "isCollectiveName": false, + "name": "Marco van Ham" + }, + { + "ForeName": "Tatiana", + "LastName": "Stepanova", + "abbrevName": "Stepanova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Stepanova" + }, + { + "ForeName": "Katharina", + "LastName": "Draegestein", + "abbrevName": "Draegestein K", + "email": null, + "isCollectiveName": false, + "name": "Katharina Draegestein" + }, + { + "ForeName": "Remco", + "LastName": "van Horssen", + "abbrevName": "van Horssen R", + "email": null, + "isCollectiveName": false, + "name": "Remco van Horssen" + }, + { + "ForeName": "Carmen", + "LastName": "Sayas", + "abbrevName": "Sayas CL", + "email": null, + "isCollectiveName": false, + "name": "Carmen Laura Sayas" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Timo", + "LastName": "Ten Hagen", + "abbrevName": "Ten Hagen T", + "email": null, + "isCollectiveName": false, + "name": "Timo Ten Hagen" + }, + { + "ForeName": "Ron", + "LastName": "Smits", + "abbrevName": "Smits R", + "email": null, + "isCollectiveName": false, + "name": "Ron Smits" + }, + { + "ForeName": "Riccardo", + "LastName": "Fodde", + "abbrevName": "Fodde R", + "email": null, + "isCollectiveName": false, + "name": "Riccardo Fodde" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2006.09.065", + "pmid": "17113391", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 16 2006", + "title": "Role of CLASP2 in microtubule stabilization and the regulation of persistent motility." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "16254238", + "pubmed": { + "ISODate": "2005-11-01T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "Boris Ratnikov, Celeste Ptak, Jaewon Han, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Boris", + "LastName": "Ratnikov", + "abbrevName": "Ratnikov B", + "email": null, + "isCollectiveName": false, + "name": "Boris Ratnikov" + }, + { + "ForeName": "Celeste", + "LastName": "Ptak", + "abbrevName": "Ptak C", + "email": null, + "isCollectiveName": false, + "name": "Celeste Ptak" + }, + { + "ForeName": "Jaewon", + "LastName": "Han", + "abbrevName": "Han J", + "email": null, + "isCollectiveName": false, + "name": "Jaewon Han" + }, + { + "ForeName": "Jeffrey", + "LastName": "Shabanowitz", + "abbrevName": "Shabanowitz J", + "email": null, + "isCollectiveName": false, + "name": "Jeffrey Shabanowitz" + }, + { + "ForeName": "Donald", + "LastName": "Hunt", + "abbrevName": "Hunt DF", + "email": null, + "isCollectiveName": false, + "name": "Donald F Hunt" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.02682", + "pmid": "16254238", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Sci 118 2005", + "title": "Talin phosphorylation sites mapped by mass spectrometry." + } + }, + { + "pmid": "15895076", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Imaging studies implicate microtubule targeting of focal adhesions in focal adhesion disassembly, although the molecular mechanism is unknown. Here, we develop a model system of focal adhesion disassembly based on the finding that microtubule regrowth after nocodazole washout induces disassembly of focal adhesions, and that this disassembly occurs independently of Rho and Rac, but depends on focal adhesion kinase (FAK) and dynamin. During disassembly, dynamin interacts with FAK and colocalizes with focal adhesions. Inhibition of dynamin prevents migration of cells with a focal adhesion phenotype. Our results show that focal adhesion disassembly involves microtubules, dynamin and FAK, and is not simply the reversal of focal adhesion formation.", + "authors": { + "abbreviation": "Ellen J Ezratty, Michael A Partridge, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Michael", + "LastName": "Partridge", + "abbrevName": "Partridge MA", + "email": null, + "isCollectiveName": false, + "name": "Michael A Partridge" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1262", + "pmid": "15895076", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nat Cell Biol 7 2005", + "title": "Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase." + } + }, + { + "pmid": "15851520", + "pubmed": { + "ISODate": "2005-04-25T00:00:00.000Z", + "abstract": "In both neurons and muscle fibers, specific mRNAs are concentrated beneath and locally translated at synaptic sites. At the skeletal neuromuscular junction, all synaptic RNAs identified to date encode synaptic components. Using microarrays, we compared RNAs in synapse-rich and -free regions of muscles, thereby identifying transcripts that are enriched near synapses and that encode soluble membrane and nuclear proteins. One gene product, LL5beta, binds to both phosphoinositides and a cytoskeletal protein, filamin, one form of which is concentrated at synaptic sites. LL5beta is itself associated with the cytoplasmic face of the postsynaptic membrane; its highest levels border regions of highest acetylcholine receptor (AChR) density, which suggests a role in \"corraling\" AChRs. Consistent with this idea, perturbing LL5beta expression in myotubes inhibits AChR aggregation. Thus, a strategy designed to identify novel synaptic components led to identification of a protein required for assembly of the postsynaptic apparatus.", + "authors": { + "abbreviation": "Masashi Kishi, Terrance T Kummer, Stephen J Eglen, Joshua R Sanes", + "authorList": [ + { + "ForeName": "Masashi", + "LastName": "Kishi", + "abbrevName": "Kishi M", + "email": null, + "isCollectiveName": false, + "name": "Masashi Kishi" + }, + { + "ForeName": "Terrance", + "LastName": "Kummer", + "abbrevName": "Kummer TT", + "email": null, + "isCollectiveName": false, + "name": "Terrance T Kummer" + }, + { + "ForeName": "Stephen", + "LastName": "Eglen", + "abbrevName": "Eglen SJ", + "email": null, + "isCollectiveName": false, + "name": "Stephen J Eglen" + }, + { + "ForeName": "Joshua", + "LastName": "Sanes", + "abbrevName": "Sanes JR", + "email": null, + "isCollectiveName": false, + "name": "Joshua R Sanes" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200411012", + "pmid": "15851520", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 169 2005", + "title": "LL5beta: a regulator of postsynaptic differentiation identified in a screen for synaptically enriched transcripts at the neuromuscular junction." + } + }, + { + "pmid": "15631994", + "pubmed": { + "ISODate": "2005-01-03T00:00:00.000Z", + "abstract": "CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115. Using RNA interference in HeLa cells, we show that the two CLASPs play redundant roles in regulating the density, length distribution and stability of interphase MTs. In HeLa cells, both CLASPs concentrate on the distal MT ends in a narrow region at the cell margin. CLASPs stabilize MTs by promoting pauses and restricting MT growth and shortening episodes to this peripheral cell region. We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. Furthermore, we show that the association of CLASP2 with the cell cortex is MT independent and relies on its COOH-terminal domain. Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. We propose that CLASPs can mediate interactions between MT plus ends and the cell cortex and act as local rescue factors, possibly through forming a complex with EB1 at MT tips.", + "authors": { + "abbreviation": "Yuko Mimori-Kiyosue, Ilya Grigoriev, Gideon Lansbergen, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Hiroyuki", + "LastName": "Sasaki", + "abbrevName": "Sasaki H", + "email": null, + "isCollectiveName": false, + "name": "Hiroyuki Sasaki" + }, + { + "ForeName": "Chiyuki", + "LastName": "Matsui", + "abbrevName": "Matsui C", + "email": null, + "isCollectiveName": false, + "name": "Chiyuki Matsui" + }, + { + "ForeName": "Fedor", + "LastName": "Severin", + "abbrevName": "Severin F", + "email": null, + "isCollectiveName": false, + "name": "Fedor Severin" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Ivan", + "LastName": "Vorobjev", + "abbrevName": "Vorobjev I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Vorobjev" + }, + { + "ForeName": "Shoichiro", + "LastName": "Tsukita", + "abbrevName": "Tsukita S", + "email": null, + "isCollectiveName": false, + "name": "Shoichiro Tsukita" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200405094", + "pmid": "15631994", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biol 168 2005", + "title": "CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex." + } + }, + { + "pmid": "15448700", + "pubmed": { + "ISODate": "2004-10-01T00:00:00.000Z", + "abstract": "Dynamic regulation of adhesion complexes is required for cell migration and has therefore emerged as a key issue in the study of cell motility. Recent progress has been made in defining some of the molecular mechanisms by which adhesion disassembly is regulated, including the contributions of adhesion adaptor proteins and tyrosine kinases. However, little is known about the potential contribution of proteolytic mechanisms to the regulation of adhesion complex dynamics. Here, we show that proteolysis of talin by the intracellular calcium-dependent protease calpain is critical for focal adhesion disassembly. We have generated a single point mutation in talin that renders it resistant to proteolysis by calpain. Quantification of adhesion assembly and disassembly rates demonstrates that calpain-mediated talin proteolysis is a rate-limiting step during adhesion turnover. Furthermore, we demonstrate that disassembly of other adhesion components, including paxillin, vinculin and zyxin, is also dependent on the ability of calpain to cleave talin, suggesting a general role for talin proteolysis in regulating adhesion turnover. Together, these findings identify calpain-mediated proteolysis of talin as a mechanism by which adhesion dynamics are regulated.", + "authors": { + "abbreviation": "Santos J Franco, Mary A Rodgers, Benjamin J Perrin, ..., Anna Huttenlocher", + "authorList": [ + { + "ForeName": "Santos", + "LastName": "Franco", + "abbrevName": "Franco SJ", + "email": null, + "isCollectiveName": false, + "name": "Santos J Franco" + }, + { + "ForeName": "Mary", + "LastName": "Rodgers", + "abbrevName": "Rodgers MA", + "email": null, + "isCollectiveName": false, + "name": "Mary A Rodgers" + }, + { + "ForeName": "Benjamin", + "LastName": "Perrin", + "abbrevName": "Perrin BJ", + "email": null, + "isCollectiveName": false, + "name": "Benjamin J Perrin" + }, + { + "ForeName": "Jaewon", + "LastName": "Han", + "abbrevName": "Han J", + "email": null, + "isCollectiveName": false, + "name": "Jaewon Han" + }, + { + "ForeName": "David", + "LastName": "Bennin", + "abbrevName": "Bennin DA", + "email": null, + "isCollectiveName": false, + "name": "David A Bennin" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Anna", + "LastName": "Huttenlocher", + "abbrevName": "Huttenlocher A", + "email": null, + "isCollectiveName": false, + "name": "Anna Huttenlocher" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1175", + "pmid": "15448700", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nat Cell Biol 6 2004", + "title": "Calpain-mediated proteolysis of talin regulates adhesion dynamics." + } + }, + { + "pmid": "14636561", + "pubmed": { + "ISODate": "2003-10-31T00:00:00.000Z", + "abstract": "ACF7 is a member of the spectraplakin family of cytoskeletal crosslinking proteins possessing actin and microtubule binding domains. Here, we show that ACF7 is an essential integrator of MT-actin dynamics. In endodermal cells, ACF7 binds along microtubules but concentrates at their distal ends and at cell borders when polarized. In ACF7's absence, microtubules still bind EB1 and CLIP170, but they no longer grow along polarized actin bundles, nor do they pause and tether to actin-rich cortical sites. The consequences are less stable, long microtubules with skewed cytoplasmic trajectories and altered dynamic instability. In response to wounding, ACF7 null cultures activate polarizing signals, but fail to maintain them and coordinate migration. Rescue of these defects requires ACF7's actin and microtubule binding domains. Thus, spectraplakins are important for controlling microtubule dynamics and reinforcing links between microtubules and polarized F-actin, so that cellular polarization and coordinated cell movements can be sustained.", + "authors": { + "abbreviation": "Atsuko Kodama, Iakowos Karakesisoglou, Ellen Wong, ..., Elaine Fuchs", + "authorList": [ + { + "ForeName": "Atsuko", + "LastName": "Kodama", + "abbrevName": "Kodama A", + "email": null, + "isCollectiveName": false, + "name": "Atsuko Kodama" + }, + { + "ForeName": "Iakowos", + "LastName": "Karakesisoglou", + "abbrevName": "Karakesisoglou I", + "email": null, + "isCollectiveName": false, + "name": "Iakowos Karakesisoglou" + }, + { + "ForeName": "Ellen", + "LastName": "Wong", + "abbrevName": "Wong E", + "email": null, + "isCollectiveName": false, + "name": "Ellen Wong" + }, + { + "ForeName": "Alec", + "LastName": "Vaezi", + "abbrevName": "Vaezi A", + "email": null, + "isCollectiveName": false, + "name": "Alec Vaezi" + }, + { + "ForeName": "Elaine", + "LastName": "Fuchs", + "abbrevName": "Fuchs E", + "email": null, + "isCollectiveName": false, + "name": "Elaine Fuchs" + } + ], + "contacts": [] + }, + "doi": "10.1016/s0092-8674(03)00813-4", + "pmid": "14636561", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Cell 115 2003", + "title": "ACF7: an essential integrator of microtubule dynamics." + } + }, + { + "pmid": "12782685", + "pubmed": { + "ISODate": "2003-06-09T00:00:00.000Z", + "abstract": "Although cell movement is driven by actin, polarization and directional locomotion require an intact microtubule cytoskeleton that influences polarization by modulating substrate adhesion via specific targeting interactions with adhesion complexes. The fidelity of adhesion site targeting is precise; using total internal reflection fluorescence microscopy (TIRFM), we now show microtubule ends (visualized by incorporation of GFP tubulin) are within 50 nm of the substrate when polymerizing toward the cell periphery, but not when shrinking from it. Multiple microtubules sometimes followed similar tracks, suggesting guidance along a common cytoskeletal element. Use of TIRFM with GFP- or DsRed-zyxin in combination with either GFP-tubulin or GFP-CLIP-170 further revealed that the polymerizing microtubule plus ends that tracked close to the dorsal surface consistently targeted substrate adhesion complexes. This supports a central role for the microtubule tip complex in the guidance of microtubules into adhesion foci, and provides evidence for an intimate cross-talk between microtubule tips and substrate adhesions in the range of molecular dimensions.", + "authors": { + "abbreviation": "Olga Krylyshkina, Kurt I Anderson, Irina Kaverina, ..., Derek K Toomre", + "authorList": [ + { + "ForeName": "Olga", + "LastName": "Krylyshkina", + "abbrevName": "Krylyshkina O", + "email": null, + "isCollectiveName": false, + "name": "Olga Krylyshkina" + }, + { + "ForeName": "Kurt", + "LastName": "Anderson", + "abbrevName": "Anderson KI", + "email": null, + "isCollectiveName": false, + "name": "Kurt I Anderson" + }, + { + "ForeName": "Irina", + "LastName": "Kaverina", + "abbrevName": "Kaverina I", + "email": null, + "isCollectiveName": false, + "name": "Irina Kaverina" + }, + { + "ForeName": "Irene", + "LastName": "Upmann", + "abbrevName": "Upmann I", + "email": null, + "isCollectiveName": false, + "name": "Irene Upmann" + }, + { + "ForeName": "Dietmar", + "LastName": "Manstein", + "abbrevName": "Manstein DJ", + "email": null, + "isCollectiveName": false, + "name": "Dietmar J Manstein" + }, + { + "ForeName": "J", + "LastName": "Small", + "abbrevName": "Small JV", + "email": null, + "isCollectiveName": false, + "name": "J Victor Small" + }, + { + "ForeName": "Derek", + "LastName": "Toomre", + "abbrevName": "Toomre DK", + "email": null, + "isCollectiveName": false, + "name": "Derek K Toomre" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200301102", + "pmid": "12782685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 161 2003", + "title": "Nanometer targeting of microtubules to focal adhesions." + } + }, + { + "pmid": "12517702", + "pubmed": { + "ISODate": "2003-02-01T00:00:00.000Z", + "abstract": "Cell movement is driven by the regulated and polarised turnover of the actin cytoskeleton and of the adhesion complexes that link it to the extracellular matrix. For most cells, polarisation requires the engagement of microtubules, which exert their effect by mediating changes in the activity of the Rho GTPases. Evidence suggests that these changes are effected in a very localised fashion at sites of substrate adhesion, via specific microtubule-targeting interactions. Targeting serves to bring molecular complexes bound at the tips and along microtubules in close proximity with adhesion complexes, to promote adhesion disassembly and remodelling of the actin cytoskeleton.", + "authors": { + "abbreviation": "J Victor Small, Irina Kaverina", + "authorList": [ + { + "ForeName": "J", + "LastName": "Small", + "abbrevName": "Small JV", + "email": "jvsmall@imb.oeaw.ac.at", + "isCollectiveName": false, + "name": "J Victor Small" + }, + { + "ForeName": "Irina", + "LastName": "Kaverina", + "abbrevName": "Kaverina I", + "email": null, + "isCollectiveName": false, + "name": "Irina Kaverina" + } + ], + "contacts": [ + { + "ForeName": "J", + "LastName": "Small", + "email": [ + "jvsmall@imb.oeaw.ac.at" + ], + "name": "J Victor Small" + } + ] + }, + "doi": "10.1016/s0955-0674(02)00008-x", + "pmid": "12517702", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 15 2003", + "title": "Microtubules meet substrate adhesions to arrange cell polarity." + } + }, + { + "pmid": "12376540", + "pubmed": { + "ISODate": "2003-01-10T00:00:00.000Z", + "abstract": "We identified a potential phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P(3)) binding pleckstrin homology domain in the data bases and have cloned and expressed its full coding sequence (LL5beta). The protein bound PtdIns(3,4,5)P(3) selectively in vitro. Strikingly, a substantial proportion of LL5beta became associated with an unidentified intracellular vesicle population in the context of low PtdIns(3,4,5)P(3) levels produced by the addition of wortmannin or LY294002. In addition, expression of platelet-derived growth factor-receptor mutants unable to activate type 1A phosphoinositide 3-kinase (PI3K) or serum starvation in porcine aortic endothelial cells lead to redistribution of LL5beta to this vesicle population. Importantly, pleckstrin homology domain mutants of LL5beta that could not bind PtdIns(3,4,5)P(3) were constitutively localized to this vesicle population. At increased PtdIns(3,4,5)P(3) levels, LL5beta was redirected to a predominantly cytoplasmic distribution, presumably through a PI3K-dependent block on its targeting to the vesicular compartment. Furthermore, at high, hormone-stimulated PtdIns(3,4,5)P(3) levels, it became significantly plasma-membrane localized. The distribution of LL5beta is thus dramatically and uniquely sensitive to low levels of PtdIns(3,4,5)P(3) indicating it can act as a sensor of both low and hormone-stimulated levels of PtdIns(3,4,5)P(3). In addition, LL5beta bound to the cytoskeletal adaptor, gamma-filamin, tightly and in a PI3K-independent fashion, both in vitro and in vivo. This interaction could co-localize heterologously expressed gamma-filamin with GFP-LL5beta in the unidentified vesicles.", + "authors": { + "abbreviation": "Varuni Paranavitane, W John Coadwell, Alicia Eguinoa, ..., Len Stephens", + "authorList": [ + { + "ForeName": "Varuni", + "LastName": "Paranavitane", + "abbrevName": "Paranavitane V", + "email": null, + "isCollectiveName": false, + "name": "Varuni Paranavitane" + }, + { + "ForeName": "W", + "LastName": "Coadwell", + "abbrevName": "Coadwell WJ", + "email": null, + "isCollectiveName": false, + "name": "W John Coadwell" + }, + { + "ForeName": "Alicia", + "LastName": "Eguinoa", + "abbrevName": "Eguinoa A", + "email": null, + "isCollectiveName": false, + "name": "Alicia Eguinoa" + }, + { + "ForeName": "Phillip", + "LastName": "Hawkins", + "abbrevName": "Hawkins PT", + "email": null, + "isCollectiveName": false, + "name": "Phillip T Hawkins" + }, + { + "ForeName": "Len", + "LastName": "Stephens", + "abbrevName": "Stephens L", + "email": null, + "isCollectiveName": false, + "name": "Len Stephens" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M208352200", + "pmid": "12376540", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 278 2003", + "title": "LL5beta is a phosphatidylinositol (3,4,5)-trisphosphate sensor that can bind the cytoskeletal adaptor, gamma-filamin." + } + }, + { + "pmid": "10477757", + "pubmed": { + "ISODate": "1999-09-06T00:00:00.000Z", + "abstract": "We recently showed that substrate contact sites in living fibroblasts are specifically targeted by microtubules (Kaverina, I., K. Rottner, and J.V. Small. 1998. J. Cell Biol. 142:181-190). Evidence is now provided that microtubule contact targeting plays a role in the modulation of substrate contact dynamics. The results are derived from spreading and polarized goldfish fibroblasts in which microtubules and contact sites were simultaneously visualized using proteins conjugated with Cy-3, rhodamine, or green fluorescent protein. For cells allowed to spread in the presence of nocodazole the turnover of contacts was retarded, as compared with controls and adhesions that were retained under the cell body were dissociated after microtubule reassembly. In polarized cells, small focal complexes were found at the protruding cell front and larger adhesions, corresponding to focal adhesions, at the retracting flanks and rear. At retracting edges, multiple microtubule contact targeting preceded contact release and cell edge retraction. The same effect could be observed in spread cells, in which microtubules were allowed to reassemble after local disassembly by the application of nocodazole to one cell edge. At the protruding front of polarized cells, focal complexes were also targeted and as a result remained either unchanged in size or, more rarely, were disassembled. Conversely, when contact targeting at the cell front was prevented by freezing microtubule growth with 20 nM taxol and protrusion stimulated by the injection of constitutively active Rac, peripheral focal complexes became abnormally enlarged. We further found that the local application of inhibitors of myosin contractility to cell edges bearing focal adhesions induced the same contact dissociation and edge retraction as observed after microtubule targeting. Our data are consistent with a mechanism whereby microtubules deliver localized doses of relaxing signals to contact sites to retard or reverse their development. We propose that it is via this route that microtubules exert their well-established control on cell polarity.", + "authors": { + "abbreviation": "I Kaverina, O Krylyshkina, J V Small", + "authorList": [ + { + "ForeName": "I", + "LastName": "Kaverina", + "abbrevName": "Kaverina I", + "email": null, + "isCollectiveName": false, + "name": "I Kaverina" + }, + { + "ForeName": "O", + "LastName": "Krylyshkina", + "abbrevName": "Krylyshkina O", + "email": null, + "isCollectiveName": false, + "name": "O Krylyshkina" + }, + { + "ForeName": "J", + "LastName": "Small", + "abbrevName": "Small JV", + "email": null, + "isCollectiveName": false, + "name": "J V Small" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.146.5.1033", + "pmid": "10477757", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 146 1999", + "title": "Microtubule targeting of substrate contacts promotes their relaxation and dissociation." + } + }, + { + "pmid": "9660872", + "pubmed": { + "ISODate": "1998-07-13T00:00:00.000Z", + "abstract": "By co-injecting fluorescent tubulin and vinculin into fish fibroblasts we have revealed a \"cross talk\" between microtubules and early sites of substrate contact. This mutuality was first indicated by the targeting of vinculin-rich foci by microtubules during their growth towards the cell periphery. In addition to passing directly over contact sites, the ends of single microtubules could be observed to target several contacts in succession or the same contact repetitively, with intermittent withdrawals. Targeting sometimes involved side-stepping, or the major re-routing of a microtubule, indicative of a guided, rather than a random process. The paths that microtubules followed into contacts were unrelated to the orientation of stress fiber assemblies and targeting occurred also in mouse fibroblasts that lacked a system of intermediate filaments. Further experiments with microtubule inhibitors showed that adhesion foci can: (a) capture microtubules and stabilize them against disassembly by nocodazole; and (b), act as preferred sites of microtubule polymerization, during either early recovery from nocodazole, or brief treatment with taxol. From these and other findings we speculate that microtubules are guided into substrate contact sites and through the motor-dependent delivery of signaling molecules serve to modulate their development. It is further proposed this modulation provides the route whereby microtubules exert their influence on cell shape and polarity.", + "authors": { + "abbreviation": "I Kaverina, K Rottner, J V Small", + "authorList": [ + { + "ForeName": "I", + "LastName": "Kaverina", + "abbrevName": "Kaverina I", + "email": null, + "isCollectiveName": false, + "name": "I Kaverina" + }, + { + "ForeName": "K", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "K Rottner" + }, + { + "ForeName": "J", + "LastName": "Small", + "abbrevName": "Small JV", + "email": null, + "isCollectiveName": false, + "name": "J V Small" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.142.1.181", + "pmid": "9660872", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 142 1998", + "title": "Targeting, capture, and stabilization of microtubules at early focal adhesions." + } + }, + { + "pmid": "8589602", + "pubmed": { + "ISODate": "1995-09-01T00:00:00.000Z", + "abstract": "A considerable degree of variability exists in the way that 1H, 13C and 15N chemical shifts are reported and referenced for biomolecules. In this article we explore some of the reasons for this situation and propose guidelines for future chemical shift referencing and for conversion from many common 1H, 13C and 15N chemical shift standards, now used in biomolecular NMR, to those proposed here.", + "authors": { + "abbreviation": "D S Wishart, C G Bigam, J Yao, ..., B D Sykes", + "authorList": [ + { + "ForeName": "D", + "LastName": "Wishart", + "abbrevName": "Wishart DS", + "email": null, + "isCollectiveName": false, + "name": "D S Wishart" + }, + { + "ForeName": "C", + "LastName": "Bigam", + "abbrevName": "Bigam CG", + "email": null, + "isCollectiveName": false, + "name": "C G Bigam" + }, + { + "ForeName": "J", + "LastName": "Yao", + "abbrevName": "Yao J", + "email": null, + "isCollectiveName": false, + "name": "J Yao" + }, + { + "ForeName": "F", + "LastName": "Abildgaard", + "abbrevName": "Abildgaard F", + "email": null, + "isCollectiveName": false, + "name": "F Abildgaard" + }, + { + "ForeName": "H", + "LastName": "Dyson", + "abbrevName": "Dyson HJ", + "email": null, + "isCollectiveName": false, + "name": "H J Dyson" + }, + { + "ForeName": "E", + "LastName": "Oldfield", + "abbrevName": "Oldfield E", + "email": null, + "isCollectiveName": false, + "name": "E Oldfield" + }, + { + "ForeName": "J", + "LastName": "Markley", + "abbrevName": "Markley JL", + "email": null, + "isCollectiveName": false, + "name": "J L Markley" + }, + { + "ForeName": "B", + "LastName": "Sykes", + "abbrevName": "Sykes BD", + "email": null, + "isCollectiveName": false, + "name": "B D Sykes" + } + ], + "contacts": [] + }, + "doi": "10.1007/BF00211777", + "pmid": "8589602", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Biomol NMR 6 1995", + "title": "1H, 13C and 15N chemical shift referencing in biomolecular NMR." + } + }, + { + "pmid": "1555235", + "pubmed": { + "ISODate": "1992-04-03T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "R O Hynes", + "authorList": [ + { + "ForeName": "R", + "LastName": "Hynes", + "abbrevName": "Hynes RO", + "email": null, + "isCollectiveName": false, + "name": "R O Hynes" + } + ], + "contacts": [] + }, + "doi": "10.1016/0092-8674(92)90115-s", + "pmid": "1555235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell 69 1992", + "title": "Integrins: versatility, modulation, and signaling in cell adhesion." + } + } + ], + "relatedPapers": [ + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + } + ], + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2022-02-02T21:55:38.058Z", + "_newestOpId": "c98c8632-34f0-4aaf-a585-ba3af2eb84a1", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "3687b1d5-e08d-45e2-b63f-f0de188511a5" + }, + { + "group": "unsigned", + "id": "ff1f0206-ea65-408c-9b1c-16ddb3dfa365" + } + ], + "id": "e56263d8-d5b6-4812-bc2f-8d905a66f0f9", + "liveId": "d99b593e-c421-4295-a057-2c790d90e1d1", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T21:53:53.331Z", + "_newestOpId": "f0a67ffb-36ff-4e30-a080-ecdef6276c03", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "607704" + }, + { + "db": "HGNC", + "id": "HGNC:19309" + }, + { + "db": "Ensembl", + "id": "ENSG00000107104" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.344946, + "id": "23189", + "name": "KANK1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "ANKRD15", + "CPSQ2", + "KANK", + "KN motif and ankyrin repeat domain-containing protein 1", + "ankyrin repeat domain-containing protein 15", + "kidney ankyrin repeat-containing protein", + "KN motif and ankyrin repeat domains 1" + ], + "synonyms": [ + "ANKRD15", + "CPSQ2", + "KANK", + "KN motif and ankyrin repeat domain-containing protein 1", + "ankyrin repeat domain-containing protein 15", + "kidney ankyrin repeat-containing protein", + "KN motif and ankyrin repeat domains 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "ff1f0206-ea65-408c-9b1c-16ddb3dfa365", + "liveId": "fdae362f-8c96-482e-84e2-e75ddacdcdc9", + "lock": null, + "locked": false, + "name": "KANK1", + "position": { + "x": 409.62025316455697, + "y": 181.77215189873417 + }, + "relatedPapers": [ + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T21:55:44.273Z", + "_newestOpId": "ccaea3f9-374f-4ec7-ac26-f80e76ea6eb8", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "3687b1d5-e08d-45e2-b63f-f0de188511a5" + }, + { + "group": "unsigned", + "id": "6bf463a2-7eb9-4c8e-8507-ca5182b04c8a" + } + ], + "id": "013b7e2a-7240-4668-b628-2653c60f47e9", + "liveId": "094ef6e6-f1e2-4e75-9561-07493e3e2e3d", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 60.75949367088607, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T21:55:54.073Z", + "_newestOpId": "fcc97d78-582c-49b1-912a-966a3d999758", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "b6d9c0fb-154b-4810-84c1-b14772f00228" + }, + { + "group": "unsigned", + "id": "ff1f0206-ea65-408c-9b1c-16ddb3dfa365" + } + ], + "id": "5a374667-a51d-4aa3-bf93-526fe203b04e", + "liveId": "5e73c125-bebc-4354-87e3-ca5f7fc06caa", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T21:55:16.344Z", + "_newestOpId": "0af99342-c9a5-4280-9d43-e162c8794153", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "607349" + }, + { + "db": "HGNC", + "id": "HGNC:15447" + }, + { + "db": "Ensembl", + "id": "ENSG00000171914" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.352453, + "id": "83660", + "name": "TLN2", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "ILWEQ", + "talin-2", + "talin 2" + ], + "synonyms": [ + "ILWEQ", + "talin-2", + "talin 2" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "b6d9c0fb-154b-4810-84c1-b14772f00228", + "liveId": "cb2c70d7-b0bc-445c-87f9-fb1206a132e5", + "lock": null, + "locked": false, + "name": "Tln2", + "position": { + "x": 422.7848101265823, + "y": 266.83544303797464 + }, + "relatedPapers": [ + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T21:53:44.488Z", + "_newestOpId": "a305a38b-9c9d-4f6f-9385-4a994455ee10", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "186745" + }, + { + "db": "HGNC", + "id": "HGNC:11845" + }, + { + "db": "Ensembl", + "id": "ENSG00000137076" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.344946, + "id": "7094", + "name": "TLN1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "ILWEQ", + "TLN", + "talin-1", + "talin 1" + ], + "synonyms": [ + "ILWEQ", + "TLN", + "talin-1", + "talin 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "3687b1d5-e08d-45e2-b63f-f0de188511a5", + "liveId": "ce51f9c9-4175-4d64-b46b-dfe5d508ea9b", + "lock": null, + "locked": false, + "name": "Tln1", + "position": { + "x": 265.3164556962026, + "y": 125.56962025316454 + }, + "relatedPapers": [ + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T21:56:04.546Z", + "_newestOpId": "bc161228-5646-4b5e-93db-804df8d04f8f", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "b6d9c0fb-154b-4810-84c1-b14772f00228" + }, + { + "group": "unsigned", + "id": "6bf463a2-7eb9-4c8e-8507-ca5182b04c8a" + } + ], + "id": "651326eb-3d90-40be-a8d7-2ece04e82226", + "liveId": "a6e1c16a-93dd-475f-92a3-e1ffd2c79efd", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 60.75949367088607, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T21:55:24.890Z", + "_newestOpId": "29f6130a-98a1-4d2a-a7be-ec1b7e0a8063", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "614610" + }, + { + "db": "HGNC", + "id": "HGNC:29300" + }, + { + "db": "Ensembl", + "id": "ENSG00000197256" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.852278, + "id": "25959", + "name": "KANK2", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "ANKRD25", + "MXRA3", + "NPHS16", + "PPKWH", + "SIP", + "KN motif and ankyrin repeat domains 2", + "kidney ankyrin repeat-containing protein 2", + "ankyrin repeat domain-containing protein 25", + "KN motif and ankyrin repeat domain-containing protein 2", + "matrix-remodeling-associated protein 3" + ], + "synonyms": [ + "ANKRD25", + "MXRA3", + "NPHS16", + "PPKWH", + "SIP", + "KN motif and ankyrin repeat domain-containing protein 2", + "SRC-interacting protein", + "SRC1-interacting protein", + "ankyrin repeat domain-containing protein 25", + "kidney ankyrin repeat-containing protein 2", + "matrix-remodeling-associated protein 3", + "KN motif and ankyrin repeat domains 2" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "6bf463a2-7eb9-4c8e-8507-ca5182b04c8a", + "liveId": "d7ab9cbc-bfb5-4e87-a0e1-58ffa297ba9b", + "lock": null, + "locked": false, + "name": "KANK2", + "position": { + "x": 282.53164556962025, + "y": 252.1518987341772 + }, + "relatedPapers": [ + { + "pmid": "24120883", + "pubmed": { + "ISODate": "2013-10-28T00:00:00.000Z", + "abstract": "Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.", + "authors": { + "abbreviation": "Babet van der Vaart, Wilhelmina E van Riel, Harinath Doodhi, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Babet", + "LastName": "van der Vaart", + "abbrevName": "van der Vaart B", + "email": null, + "isCollectiveName": false, + "name": "Babet van der Vaart" + }, + { + "ForeName": "Wilhelmina", + "LastName": "van Riel", + "abbrevName": "van Riel WE", + "email": null, + "isCollectiveName": false, + "name": "Wilhelmina E van Riel" + }, + { + "ForeName": "Harinath", + "LastName": "Doodhi", + "abbrevName": "Doodhi H", + "email": null, + "isCollectiveName": false, + "name": "Harinath Doodhi" + }, + { + "ForeName": "Josta", + "LastName": "Kevenaar", + "abbrevName": "Kevenaar JT", + "email": null, + "isCollectiveName": false, + "name": "Josta T Kevenaar" + }, + { + "ForeName": "Eugene", + "LastName": "Katrukha", + "abbrevName": "Katrukha EA", + "email": null, + "isCollectiveName": false, + "name": "Eugene A Katrukha" + }, + { + "ForeName": "Laura", + "LastName": "Gumy", + "abbrevName": "Gumy L", + "email": null, + "isCollectiveName": false, + "name": "Laura Gumy" + }, + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Samantha", + "LastName": "Spangler", + "abbrevName": "Spangler SA", + "email": null, + "isCollectiveName": false, + "name": "Samantha A Spangler" + }, + { + "ForeName": "Ka", + "LastName": "Yu", + "abbrevName": "Yu KL", + "email": null, + "isCollectiveName": false, + "name": "Ka Lou Yu" + }, + { + "ForeName": "Phebe", + "LastName": "Wulf", + "abbrevName": "Wulf PS", + "email": null, + "isCollectiveName": false, + "name": "Phebe S Wulf" + }, + { + "ForeName": "Jingchao", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingchao Wu" + }, + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Eljo", + "LastName": "van Battum", + "abbrevName": "van Battum EY", + "email": null, + "isCollectiveName": false, + "name": "Eljo Y van Battum" + }, + { + "ForeName": "R", + "LastName": "Pasterkamp", + "abbrevName": "Pasterkamp RJ", + "email": null, + "isCollectiveName": false, + "name": "R Jeroen Pasterkamp" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Natacha", + "LastName": "Olieric", + "abbrevName": "Olieric N", + "email": null, + "isCollectiveName": false, + "name": "Natacha Olieric" + }, + { + "ForeName": "Ivan", + "LastName": "Maly", + "abbrevName": "Maly IV", + "email": null, + "isCollectiveName": false, + "name": "Ivan V Maly" + }, + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "abbrevName": "Hoogenraad CC", + "email": "c.hoogenraad@uu.nl", + "isCollectiveName": false, + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": "a.akhmanova@uu.nl", + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [ + { + "ForeName": "Casper", + "LastName": "Hoogenraad", + "email": [ + "c.hoogenraad@uu.nl" + ], + "name": "Casper C Hoogenraad" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "email": [ + "a.akhmanova@uu.nl" + ], + "name": "Anna Akhmanova" + } + ] + }, + "doi": "10.1016/j.devcel.2013.09.010", + "pmid": "24120883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 27 2013", + "title": "CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor." + } + }, + { + "pmid": "25530216", + "pubmed": { + "ISODate": "2015-03-01T00:00:00.000Z", + "abstract": "Adhesion complex formation and disassembly is crucial for maintaining efficient cell movement. During migration, several proteins act in concert to promote remodeling of the actin cytoskeleton and we have previously shown that in highly invasive breast cancer cells, this process is regulated by small GTP-binding proteins of the ADP-ribosylation factor (ARF) family. These are overexpressed and highly activated in these cells. Here, we report that one mechanism by which ARF1 regulates migration is by controlling assembly of focal adhesions. In cells depleted of ARF1, paxillin is no longer colocalized with actin at focal adhesion sites. In addition, we demonstrate that this occurs through the ability of ARF1 to regulate the recruitment of key proteins such as paxillin, talin and FAK to ß1-integrin. Furthermore, we show that the interactions between paxillin and talin together and with FAK are significantly impaired in ARF1 knocked down cells. Our findings also indicate that ARF1 is essential for EGF-mediated phosphorylation of FAK and Src. Finally, we report that ARF1 can be found in complex with key focal adhesion proteins such as ß1-integrin, paxillin, talin and FAK. Together our findings uncover a new mechanism by which ARF1 regulates cell migration and provide this GTPase as a target for the development of new therapeutics in triple negative breast cancer. ", + "authors": { + "abbreviation": "Sabrina Schlienger, Rodrigo Alain Migueles Ramirez, Audrey Claing", + "authorList": [ + { + "ForeName": "Sabrina", + "LastName": "Schlienger", + "abbrevName": "Schlienger S", + "email": null, + "isCollectiveName": false, + "name": "Sabrina Schlienger" + }, + { + "ForeName": "Rodrigo", + "LastName": "Ramirez", + "abbrevName": "Ramirez RA", + "email": null, + "isCollectiveName": false, + "name": "Rodrigo Alain Migueles Ramirez" + }, + { + "ForeName": "Audrey", + "LastName": "Claing", + "abbrevName": "Claing A", + "email": "audrey.claing@umontreal.ca", + "isCollectiveName": false, + "name": "Audrey Claing" + } + ], + "contacts": [ + { + "ForeName": "Audrey", + "LastName": "Claing", + "email": [ + "audrey.claing@umontreal.ca" + ], + "name": "Audrey Claing" + } + ] + }, + "doi": "10.1016/j.cellsig.2014.11.032", + "pmid": "25530216", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Signal 27 2015", + "title": "ARF1 regulates adhesion of MDA-MB-231 invasive breast cancer cells through formation of focal adhesions." + } + }, + { + "pmid": "31389241", + "pubmed": { + "ISODate": "2019-09-11T00:00:00.000Z", + "abstract": "KANK proteins mediate cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix. KANKs interact with the integrin/actin-binding protein talin and with several components of microtubule-stabilizing cortical complexes. Because of actomyosin contractility, the talin-KANK complex is likely under mechanical force, and its mechanical stability is expected to be a critical determinant of KANK recruitment to focal adhesions. Here, we quantified the lifetime of the complex of the talin rod domain R7 and the KN domain of KANK1 under shear-force geometry and found that it can withstand forces for seconds to minutes over a physiological force range up to 10 pN. Complex stability measurements combined with cell biological experiments suggest that shear-force stretching promotes KANK1 localization to the periphery of focal adhesions. These results indicate that the talin-KANK1 complex is mechanically strong, enabling it to support the cross-talk between microtubule and actin cytoskeleton at focal adhesions.", + "authors": { + "abbreviation": "Miao Yu, Shimin Le, York-Christoph Ammon, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1021/acs.nanolett.9b01732", + "pmid": "31389241", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nano Lett 19 2019", + "title": "Force-Dependent Regulation of Talin-KANK1 Complex at Focal Adhesions." + } + }, + { + "pmid": "30361699", + "pubmed": { + "ISODate": "2018-11-01T00:00:00.000Z", + "abstract": "Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvβ5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin β5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.", + "authors": { + "abbreviation": "John G Lock, Matthew C Jones, Janet A Askari, ..., Staffan Strömblad", + "authorList": [ + { + "ForeName": "John", + "LastName": "Lock", + "abbrevName": "Lock JG", + "email": "john.lock@unsw.edu.au", + "isCollectiveName": false, + "name": "John G Lock" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Janet", + "LastName": "Askari", + "abbrevName": "Askari JA", + "email": null, + "isCollectiveName": false, + "name": "Janet A Askari" + }, + { + "ForeName": "Xiaowei", + "LastName": "Gong", + "abbrevName": "Gong X", + "email": null, + "isCollectiveName": false, + "name": "Xiaowei Gong" + }, + { + "ForeName": "Anna", + "LastName": "Oddone", + "abbrevName": "Oddone A", + "email": null, + "isCollectiveName": false, + "name": "Anna Oddone" + }, + { + "ForeName": "Helene", + "LastName": "Olofsson", + "abbrevName": "Olofsson H", + "email": null, + "isCollectiveName": false, + "name": "Helene Olofsson" + }, + { + "ForeName": "Sara", + "LastName": "Göransson", + "abbrevName": "Göransson S", + "email": null, + "isCollectiveName": false, + "name": "Sara Göransson" + }, + { + "ForeName": "Melike", + "LastName": "Lakadamyali", + "abbrevName": "Lakadamyali M", + "email": null, + "isCollectiveName": false, + "name": "Melike Lakadamyali" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "abbrevName": "Strömblad S", + "email": "staffan.stromblad@ki.se", + "isCollectiveName": false, + "name": "Staffan Strömblad" + } + ], + "contacts": [ + { + "ForeName": "John", + "LastName": "Lock", + "email": [ + "john.lock@unsw.edu.au" + ], + "name": "John G Lock" + }, + { + "ForeName": "Staffan", + "LastName": "Strömblad", + "email": [ + "staffan.stromblad@ki.se" + ], + "name": "Staffan Strömblad" + } + ] + }, + "doi": "10.1038/s41556-018-0220-2", + "pmid": "30361699", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Cell Biol 20 2018", + "title": "Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis." + } + }, + { + "pmid": "27043085", + "pubmed": { + "ISODate": "2016-05-01T00:00:00.000Z", + "abstract": "Integrin endocytic recycling is critical for cell migration, yet how recycled integrins assemble into new adhesions is unclear. By synchronizing endocytic disassembly of focal adhesions (FAs), we find that recycled integrins reassemble FAs coincident with their return to the cell surface and dependent on Rab5 and Rab11. Unexpectedly, endocytosed integrins remained in an active but unliganded state in endosomes. FAK and Src kinases co-localized with endocytosed integrin and were critical for FA reassembly by regulating integrin activation and recycling, respectively. FAK sustained the active integrin conformation by maintaining talin association with Rab11 endosomes in a type I phosphatidylinositol phosphate kinase (PIPKIγ)-dependent manner. In migrating cells, endocytosed integrins reassembled FAs polarized towards the leading edge, and this polarization required FAK. These studies identify unanticipated roles for FA proteins in maintaining endocytosed integrin in an active conformation. We propose that the conformational memory of endocytosed integrin enhances polarized reassembly of FAs to enable directional cell migration.", + "authors": { + "abbreviation": "Guilherme P F Nader, Ellen J Ezratty, Gregg G Gundersen", + "authorList": [ + { + "ForeName": "Guilherme", + "LastName": "Nader", + "abbrevName": "Nader GP", + "email": null, + "isCollectiveName": false, + "name": "Guilherme P F Nader" + }, + { + "ForeName": "Ellen", + "LastName": "Ezratty", + "abbrevName": "Ezratty EJ", + "email": null, + "isCollectiveName": false, + "name": "Ellen J Ezratty" + }, + { + "ForeName": "Gregg", + "LastName": "Gundersen", + "abbrevName": "Gundersen GG", + "email": null, + "isCollectiveName": false, + "name": "Gregg G Gundersen" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3333", + "pmid": "27043085", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly." + } + }, + { + "pmid": "30485809", + "pubmed": { + "ISODate": "2018-11-27T00:00:00.000Z", + "abstract": "Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo.", + "authors": { + "abbreviation": "Amanda Haage, Katharine Goodwin, Austin Whitewood, ..., Guy Tanentzapf", + "authorList": [ + { + "ForeName": "Amanda", + "LastName": "Haage", + "abbrevName": "Haage A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Haage" + }, + { + "ForeName": "Katharine", + "LastName": "Goodwin", + "abbrevName": "Goodwin K", + "email": null, + "isCollectiveName": false, + "name": "Katharine Goodwin" + }, + { + "ForeName": "Austin", + "LastName": "Whitewood", + "abbrevName": "Whitewood A", + "email": null, + "isCollectiveName": false, + "name": "Austin Whitewood" + }, + { + "ForeName": "Darius", + "LastName": "Camp", + "abbrevName": "Camp D", + "email": null, + "isCollectiveName": false, + "name": "Darius Camp" + }, + { + "ForeName": "Aaron", + "LastName": "Bogutz", + "abbrevName": "Bogutz A", + "email": null, + "isCollectiveName": false, + "name": "Aaron Bogutz" + }, + { + "ForeName": "Christopher", + "LastName": "Turner", + "abbrevName": "Turner CT", + "email": null, + "isCollectiveName": false, + "name": "Christopher T Turner" + }, + { + "ForeName": "David", + "LastName": "Granville", + "abbrevName": "Granville DJ", + "email": null, + "isCollectiveName": false, + "name": "David J Granville" + }, + { + "ForeName": "Louis", + "LastName": "Lefebvre", + "abbrevName": "Lefebvre L", + "email": null, + "isCollectiveName": false, + "name": "Louis Lefebvre" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov S", + "email": null, + "isCollectiveName": false, + "name": "Sergey Plotnikov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "abbrevName": "Tanentzapf G", + "email": "tanentz@mail.ubc.ca", + "isCollectiveName": false, + "name": "Guy Tanentzapf" + } + ], + "contacts": [ + { + "ForeName": "Guy", + "LastName": "Tanentzapf", + "email": [ + "tanentz@mail.ubc.ca" + ], + "name": "Guy Tanentzapf" + } + ] + }, + "doi": "10.1016/j.celrep.2018.10.098", + "pmid": "30485809", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Rep 25 2018", + "title": "Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo." + } + }, + { + "pmid": "29158259", + "pubmed": { + "ISODate": "2018-01-05T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1·KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.", + "authors": { + "abbreviation": "Zhuangfeng Weng, Yuan Shang, Deqiang Yao, ..., Rongguang Zhang", + "authorList": [ + { + "ForeName": "Zhuangfeng", + "LastName": "Weng", + "abbrevName": "Weng Z", + "email": null, + "isCollectiveName": false, + "name": "Zhuangfeng Weng" + }, + { + "ForeName": "Yuan", + "LastName": "Shang", + "abbrevName": "Shang Y", + "email": null, + "isCollectiveName": false, + "name": "Yuan Shang" + }, + { + "ForeName": "Deqiang", + "LastName": "Yao", + "abbrevName": "Yao D", + "email": null, + "isCollectiveName": false, + "name": "Deqiang Yao" + }, + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "abbrevName": "Zhu J", + "email": "jinwei.zhu@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "abbrevName": "Zhang R", + "email": "rgzhang@sibcb.ac.cn", + "isCollectiveName": false, + "name": "Rongguang Zhang" + } + ], + "contacts": [ + { + "ForeName": "Jinwei", + "LastName": "Zhu", + "email": [ + "jinwei.zhu@sibcb.ac.cn" + ], + "name": "Jinwei Zhu" + }, + { + "ForeName": "Rongguang", + "LastName": "Zhang", + "email": [ + "rgzhang@sibcb.ac.cn" + ], + "name": "Rongguang Zhang" + } + ] + }, + "doi": "10.1074/jbc.M117.816017", + "pmid": "29158259", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." + } + }, + { + "pmid": "24859005", + "pubmed": { + "ISODate": "2014-06-01T00:00:00.000Z", + "abstract": "Turnover of integrin-based focal adhesions (FAs) with the extracellular matrix (ECM) is essential for coordinated cell movement. In collectively migrating human keratinocytes, FAs assemble near the leading edge, grow and mature as a result of contractile forces and disassemble underneath the advancing cell body. We report that clustering of microtubule-associated CLASP1 and CLASP2 proteins around FAs temporally correlates with FA turnover. CLASPs and LL5β (also known as PHLDB2), which recruits CLASPs to FAs, facilitate FA disassembly. CLASPs are further required for FA-associated ECM degradation, and matrix metalloprotease inhibition slows FA disassembly similarly to CLASP or PHLDB2 (LL5β) depletion. Finally, CLASP-mediated microtubule tethering at FAs establishes an FA-directed transport pathway for delivery, docking and localized fusion of exocytic vesicles near FAs. We propose that CLASPs couple microtubule organization, vesicle transport and cell interactions with the ECM, establishing a local secretion pathway that facilitates FA turnover by severing cell-matrix connections. ", + "authors": { + "abbreviation": "Samantha J Stehbens, Matthew Paszek, Hayley Pemble, ..., Torsten Wittmann", + "authorList": [ + { + "ForeName": "Samantha", + "LastName": "Stehbens", + "abbrevName": "Stehbens SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J Stehbens" + }, + { + "ForeName": "Matthew", + "LastName": "Paszek", + "abbrevName": "Paszek M", + "email": null, + "isCollectiveName": false, + "name": "Matthew Paszek" + }, + { + "ForeName": "Hayley", + "LastName": "Pemble", + "abbrevName": "Pemble H", + "email": null, + "isCollectiveName": false, + "name": "Hayley Pemble" + }, + { + "ForeName": "Andreas", + "LastName": "Ettinger", + "abbrevName": "Ettinger A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Ettinger" + }, + { + "ForeName": "Sarah", + "LastName": "Gierke", + "abbrevName": "Gierke S", + "email": null, + "isCollectiveName": false, + "name": "Sarah Gierke" + }, + { + "ForeName": "Torsten", + "LastName": "Wittmann", + "abbrevName": "Wittmann T", + "email": null, + "isCollectiveName": false, + "name": "Torsten Wittmann" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb2975", + "pmid": "24859005", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Cell Biol 16 2014", + "title": "CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover." + } + }, + { + "pmid": "21763488", + "pubmed": { + "ISODate": "2011-07-29T00:00:00.000Z", + "abstract": "Many of the early events in retroviral infection are not well understood, but it is known that the host cytoskeleton and signaling pathways play integral roles in various entry and post-entry processes. Focal adhesion complexes act as sites of integration for both cytoskeletal organization and integrin signaling at the cell surface. Here, we show that talin-1 and vinculin, two interacting proteins that localize in focal adhesions to mediate integrin linkage to the actin cytoskeleton, function during retroviral infection. Transient overexpression of either talin-1 or vinculin reduced the susceptibility of human cells to infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) and Moloney murine leukemia virus. In contrast, transient short interfering RNA-mediated knockdown of talin-1 or vinculin increased infection by pseudotyped HIV-1 and simian immunodeficiency virus, demonstrating that the endogenous forms of these proteins also impaired retroviral infection. Talin-1 or vinculin overexpression inhibited infection by retroviruses that entered the cell by either fusion or endocytosis, while analysis of HIV-1 DNA synthesis demonstrated that the block occurred early in infection and prior to the initiation of reverse transcription. Both factors retained antiviral activity in the presence of actin or microtubule depolymerizing agents. Finally, talin-1 and vinculin expression was found to negatively influence tyrosine phosphorylation of paxillin, a major focal adhesion scaffolding protein whose transient knockdown decreased pseudotyped HIV-1 infection. Together, these findings demonstrate that talin-1 and vinculin negatively affect tyrosine phosphorylation of paxillin, a novel positive regulator of HIV-1 infection, and impose an early block to infection by distinct retroviruses.", + "authors": { + "abbreviation": "Craig Brown, Scott G Morham, Derek Walsh, Mojgan H Naghavi", + "authorList": [ + { + "ForeName": "Craig", + "LastName": "Brown", + "abbrevName": "Brown C", + "email": null, + "isCollectiveName": false, + "name": "Craig Brown" + }, + { + "ForeName": "Scott", + "LastName": "Morham", + "abbrevName": "Morham SG", + "email": null, + "isCollectiveName": false, + "name": "Scott G Morham" + }, + { + "ForeName": "Derek", + "LastName": "Walsh", + "abbrevName": "Walsh D", + "email": null, + "isCollectiveName": false, + "name": "Derek Walsh" + }, + { + "ForeName": "Mojgan", + "LastName": "Naghavi", + "abbrevName": "Naghavi MH", + "email": null, + "isCollectiveName": false, + "name": "Mojgan H Naghavi" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2011.03.076", + "pmid": "21763488", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 410 2011", + "title": "Focal adhesion proteins talin-1 and vinculin negatively affect paxillin phosphorylation and limit retroviral infection." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "30837291", + "pubmed": { + "ISODate": "2019-04-03T00:00:00.000Z", + "abstract": "Talin protein is one of the key components in integrin-mediated adhesion complexes. Talins transmit mechanical forces between β-integrin and actin, and regulate adhesion complex composition and signaling through the force-regulated unfolding of talin rod domain. Using modified talin proteins, we demonstrate that these functions contribute to different cellular processes and can be dissected. The transmission of mechanical forces regulates adhesion complex composition and phosphotyrosine signaling even in the absence of the mechanically regulated talin rod subdomains. However, the presence of the rod subdomains and their mechanical activation are required for the reinforcement of the adhesion complex, cell polarization and migration. Talin rod domain unfolding was also found to be essential for the generation of cellular signaling anisotropy, since both insufficient and excess activity of the rod domain severely inhibited cell polarization. Utilizing proteomics tools, we identified adhesome components that are recruited and activated either in a talin rod-dependent manner or independently of the rod subdomains. This study clarifies the division of roles between the force-regulated unfolding of a talin protein (talin 1) and its function as a physical linker between integrins and the cytoskeleton.", + "authors": { + "abbreviation": "Rolle Rahikainen, Tiina Öhman, Paula Turkki, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Rolle", + "LastName": "Rahikainen", + "abbrevName": "Rahikainen R", + "email": null, + "isCollectiveName": false, + "name": "Rolle Rahikainen" + }, + { + "ForeName": "Tiina", + "LastName": "Öhman", + "abbrevName": "Öhman T", + "email": null, + "isCollectiveName": false, + "name": "Tiina Öhman" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": null, + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Markku", + "LastName": "Varjosalo", + "abbrevName": "Varjosalo M", + "email": null, + "isCollectiveName": false, + "name": "Markku Varjosalo" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1242/jcs.226514", + "pmid": "30837291", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Talin-mediated force transmission and talin rod domain unfolding independently regulate adhesion signaling." + } + }, + { + "pmid": "27378169", + "pubmed": { + "ISODate": "2016-08-15T00:00:00.000Z", + "abstract": "Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.", + "authors": { + "abbreviation": "Boon Cheng Lim, Shinji Matsumoto, Hideki Yamamoto, ..., Akira Kikuchi", + "authorList": [ + { + "ForeName": "Boon", + "LastName": "Lim", + "abbrevName": "Lim BC", + "email": null, + "isCollectiveName": false, + "name": "Boon Cheng Lim" + }, + { + "ForeName": "Shinji", + "LastName": "Matsumoto", + "abbrevName": "Matsumoto S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Matsumoto" + }, + { + "ForeName": "Hideki", + "LastName": "Yamamoto", + "abbrevName": "Yamamoto H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Yamamoto" + }, + { + "ForeName": "Hiroki", + "LastName": "Mizuno", + "abbrevName": "Mizuno H", + "email": null, + "isCollectiveName": false, + "name": "Hiroki Mizuno" + }, + { + "ForeName": "Junichi", + "LastName": "Kikuta", + "abbrevName": "Kikuta J", + "email": null, + "isCollectiveName": false, + "name": "Junichi Kikuta" + }, + { + "ForeName": "Masaru", + "LastName": "Ishii", + "abbrevName": "Ishii M", + "email": null, + "isCollectiveName": false, + "name": "Masaru Ishii" + }, + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "abbrevName": "Kikuchi A", + "email": "akikuchi@molbiobc.med.osaka-u.ac.jp", + "isCollectiveName": false, + "name": "Akira Kikuchi" + } + ], + "contacts": [ + { + "ForeName": "Akira", + "LastName": "Kikuchi", + "email": [ + "akikuchi@molbiobc.med.osaka-u.ac.jp" + ], + "name": "Akira Kikuchi" + } + ] + }, + "doi": "10.1242/jcs.185439", + "pmid": "27378169", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Sci 129 2016", + "title": "Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells." + } + }, + { + "pmid": "30003879", + "pubmed": { + "ISODate": "2018-09-15T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) play an important role in cancer cell migration and metastasis by linking the actin cytoskeleton to the extracellular matrix, allowing the cell to generate traction. SUMOylation is a post-translational modification of proteins on lysine residues that can affect protein localisation, turnover and protein-protein interactions. In this study, we demonstrate that talin, a key component of FAs, can be post-translationally modified by SUMOylation in MDA-MB-231 breast cancer cells and U2OS osteosarcoma cells. Furthermore we demonstrate that SUMOylation regulates the dynamic activities of FAs including their number, size and turnover rate. Inhibiting SUMOylation significantly reduced the speed of cell migration. The identification of talin as a SUMO target provides insight into the mechanisms regulating focal adhesion formation and turnover and potentially identifies a novel mechanism underlying cell migration.", + "authors": { + "abbreviation": "Zhiyao Huang, Diana Barker, Jonathan M Gibbins, Philip R Dash", + "authorList": [ + { + "ForeName": "Zhiyao", + "LastName": "Huang", + "abbrevName": "Huang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiyao Huang" + }, + { + "ForeName": "Diana", + "LastName": "Barker", + "abbrevName": "Barker D", + "email": null, + "isCollectiveName": false, + "name": "Diana Barker" + }, + { + "ForeName": "Jonathan", + "LastName": "Gibbins", + "abbrevName": "Gibbins JM", + "email": null, + "isCollectiveName": false, + "name": "Jonathan M Gibbins" + }, + { + "ForeName": "Philip", + "LastName": "Dash", + "abbrevName": "Dash PR", + "email": "p.r.dash@reading.ac.uk", + "isCollectiveName": false, + "name": "Philip R Dash" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Dash", + "email": [ + "p.r.dash@reading.ac.uk" + ], + "name": "Philip R Dash" + } + ] + }, + "doi": "10.1016/j.yexcr.2018.07.005", + "pmid": "30003879", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Exp Cell Res 370 2018", + "title": "Talin is a substrate for SUMOylation in migrating cancer cells." + } + }, + { + "pmid": "19363486", + "pubmed": { + "ISODate": "2009-05-01T00:00:00.000Z", + "abstract": "Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly/disassembly. Talin, an actin and beta-integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin has a key role in focal adhesion turnover; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant tal(S425A), which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.", + "authors": { + "abbreviation": "Cai Huang, Zenon Rajfur, Nima Yousefi, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Cai", + "LastName": "Huang", + "abbrevName": "Huang C", + "email": null, + "isCollectiveName": false, + "name": "Cai Huang" + }, + { + "ForeName": "Zenon", + "LastName": "Rajfur", + "abbrevName": "Rajfur Z", + "email": null, + "isCollectiveName": false, + "name": "Zenon Rajfur" + }, + { + "ForeName": "Nima", + "LastName": "Yousefi", + "abbrevName": "Yousefi N", + "email": null, + "isCollectiveName": false, + "name": "Nima Yousefi" + }, + { + "ForeName": "Zaozao", + "LastName": "Chen", + "abbrevName": "Chen Z", + "email": null, + "isCollectiveName": false, + "name": "Zaozao Chen" + }, + { + "ForeName": "Ken", + "LastName": "Jacobson", + "abbrevName": "Jacobson K", + "email": null, + "isCollectiveName": false, + "name": "Ken Jacobson" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb1868", + "pmid": "19363486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Cell Biol 11 2009", + "title": "Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration." + } + }, + { + "pmid": "22138388", + "pubmed": { + "ISODate": "2012-02-01T00:00:00.000Z", + "abstract": "Integrin-dependent cell adhesions come in different shapes and serve in different cell types for tasks ranging from cell-adhesion, migration, and the remodeling of the extracellular matrix to the formation and stabilization of immunological and chemical synapses. A major challenge consists in the identification of adhesion-specific as well as common regulatory mechanisms, motivating the need for a deeper analysis of protein-protein interactions in the context of intact focal adhesions. Specifically, it is critical to understand how small differences in binding of integrins to extracellular ligands and/or cytoplasmic adapter proteins affect the assembly and function of an entire focal adhesion. By using the talin-integrin pair as a starting point, I would like to discuss how specific protein-protein and protein-lipid interactions can control the behavior and function of focal adhesions. By responding to chemical and mechanical cues several allosterically regulated proteins create a dynamic multifunctional protein network that provides both adhesion to the extracellular matrix as well as intracellular signaling in response to mechanical changes in the cellular environment.", + "authors": { + "abbreviation": "Bernhard Wehrle-Haller", + "authorList": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "abbrevName": "Wehrle-Haller B", + "email": "Bernhard.Wehrle-Haller@unige.ch", + "isCollectiveName": false, + "name": "Bernhard Wehrle-Haller" + } + ], + "contacts": [ + { + "ForeName": "Bernhard", + "LastName": "Wehrle-Haller", + "email": [ + "Bernhard.Wehrle-Haller@unige.ch" + ], + "name": "Bernhard Wehrle-Haller" + } + ] + }, + "doi": "10.1016/j.ceb.2011.11.001", + "pmid": "22138388", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 24 2012", + "title": "Structure and function of focal adhesions." + } + }, + { + "pmid": "33309958", + "pubmed": { + "ISODate": "2021-02-01T00:00:00.000Z", + "abstract": "The Kank (kidney or KN motif and ankyrin repeat domain-containing) family of proteins has been described as essential for crosstalk between actin and microtubules. Kank1, 2, 3 and 4 arose by gene duplication and diversification and share conserved structural domains. KANK proteins are localised mainly to the plasma membrane in focal adhesions, indirectly affecting RhoA and Rac1 thus regulating actin cytoskeleton. In addition, Kank proteins are part of the cortical microtubule stabilisation complex regulating microtubules. Most of the data have been collected for Kank1 protein whose expression promotes apoptosis and cell-cycle arrest while Kank3 was identified as hypoxia-inducible proapoptotic target of p53. A discrepancy in Kanks role in regulation of cell migration and sensitivity to antitumour drugs has been observed in different cell models. Since expression of Kank1 and 3 correlate positively with tumour progression and patient outcome, at least in some tumour types, they are candidates for tumour suppressors.", + "authors": { + "abbreviation": "Ana Tadijan, Ivana Samaržija, Jonathan D Humphries, ..., Andreja Ambriović-Ristov", + "authorList": [ + { + "ForeName": "Ana", + "LastName": "Tadijan", + "abbrevName": "Tadijan A", + "email": null, + "isCollectiveName": false, + "name": "Ana Tadijan" + }, + { + "ForeName": "Ivana", + "LastName": "Samaržija", + "abbrevName": "Samaržija I", + "email": null, + "isCollectiveName": false, + "name": "Ivana Samaržija" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "abbrevName": "Ambriović-Ristov A", + "email": "Andreja.Ambriovic.Ristov@irb.hr", + "isCollectiveName": false, + "name": "Andreja Ambriović-Ristov" + } + ], + "contacts": [ + { + "ForeName": "Andreja", + "LastName": "Ambriović-Ristov", + "email": [ + "Andreja.Ambriovic.Ristov@irb.hr" + ], + "name": "Andreja Ambriović-Ristov" + } + ] + }, + "doi": "10.1016/j.biocel.2020.105903", + "pmid": "33309958", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Biochem Cell Biol 131 2021", + "title": "KANK family proteins in cancer." + } + }, + { + "pmid": "31597743", + "pubmed": { + "ISODate": "2019-10-09T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.", + "authors": { + "abbreviation": "Shailaja Seetharaman, Sandrine Etienne-Manneville", + "authorList": [ + { + "ForeName": "Shailaja", + "LastName": "Seetharaman", + "abbrevName": "Seetharaman S", + "email": null, + "isCollectiveName": false, + "name": "Shailaja Seetharaman" + }, + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "abbrevName": "Etienne-Manneville S", + "email": "setienne@pasteur.fr", + "isCollectiveName": false, + "name": "Sandrine Etienne-Manneville" + } + ], + "contacts": [ + { + "ForeName": "Sandrine", + "LastName": "Etienne-Manneville", + "email": [ + "setienne@pasteur.fr" + ], + "name": "Sandrine Etienne-Manneville" + } + ] + }, + "doi": "10.1242/jcs.232843", + "pmid": "31597743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Sci 132 2019", + "title": "Microtubules at focal adhesions - a double-edged sword." + } + }, + { + "pmid": "27552250", + "pubmed": { + "ISODate": "2016-08-23T00:00:00.000Z", + "abstract": "A new study reveals that a protein called talin forms a vital link between microtubules and focal adhesions at the surface of cells.", + "authors": { + "abbreviation": "Sarah K Armitage, Sergey V Plotnikov", + "authorList": [ + { + "ForeName": "Sarah", + "LastName": "Armitage", + "abbrevName": "Armitage SK", + "email": null, + "isCollectiveName": false, + "name": "Sarah K Armitage" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.19733", + "pmid": "27552250", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016420", + "value": "Comment" + } + ], + "reference": "Elife 5 2016", + "title": "Bridging the gap." + } + }, + { + "pmid": "29217769", + "pubmed": { + "ISODate": "2018-02-09T00:00:00.000Z", + "abstract": "Kidney ankyrin repeat-containing proteins (KANK1/2/3/4) belong to a family of scaffold proteins, playing critical roles in cytoskeleton organization, cell polarity, and migration. Mutations in KANK proteins are implicated in cancers and genetic diseases, such as nephrotic syndrome. KANK proteins can bind various target proteins through different protein regions, including a highly conserved ankyrin repeat domain (ANKRD). However, the molecular basis for target recognition by the ANKRD remains elusive. In this study, we solved a high-resolution crystal structure of the ANKRD of KANK1 in complex with a short sequence of the motor protein kinesin family member 21A (KIF21A), revealing that the highly specific target-binding mode of the ANKRD involves combinatorial use of two interfaces. Mutations in either interface disrupted the KANK1-KIF21A interaction. Cellular immunofluorescence localization analysis indicated that binding-deficient mutations block recruitment of KIF21A to focal adhesions by KANK1. In conclusion, our structural study provides mechanistic explanations for the ANKRD-mediated recognition of KIF21A and for many disease-related mutations identified in human KANK proteins.", + "authors": { + "abbreviation": "Wenfei Pan, Kang Sun, Kun Tang, ..., Zhiyi Wei", + "authorList": [ + { + "ForeName": "Wenfei", + "LastName": "Pan", + "abbrevName": "Pan W", + "email": null, + "isCollectiveName": false, + "name": "Wenfei Pan" + }, + { + "ForeName": "Kang", + "LastName": "Sun", + "abbrevName": "Sun K", + "email": null, + "isCollectiveName": false, + "name": "Kang Sun" + }, + { + "ForeName": "Kun", + "LastName": "Tang", + "abbrevName": "Tang K", + "email": null, + "isCollectiveName": false, + "name": "Kun Tang" + }, + { + "ForeName": "Qingpin", + "LastName": "Xiao", + "abbrevName": "Xiao Q", + "email": null, + "isCollectiveName": false, + "name": "Qingpin Xiao" + }, + { + "ForeName": "Chenxue", + "LastName": "Ma", + "abbrevName": "Ma C", + "email": null, + "isCollectiveName": false, + "name": "Chenxue Ma" + }, + { + "ForeName": "Cong", + "LastName": "Yu", + "abbrevName": "Yu C", + "email": null, + "isCollectiveName": false, + "name": "Cong Yu" + }, + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "abbrevName": "Wei Z", + "email": "weizy@sustc.edu.cn", + "isCollectiveName": false, + "name": "Zhiyi Wei" + } + ], + "contacts": [ + { + "ForeName": "Zhiyi", + "LastName": "Wei", + "email": [ + "weizy@sustc.edu.cn" + ], + "name": "Zhiyi Wei" + } + ] + }, + "doi": "10.1074/jbc.M117.815779", + "pmid": "29217769", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "19278997", + "pubmed": { + "ISODate": "2009-05-15T00:00:00.000Z", + "abstract": "In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.", + "authors": { + "abbreviation": "Mirko Himmel, Anett Ritter, Sven Rothemund, ..., Wolfgang H Ziegler", + "authorList": [ + { + "ForeName": "Mirko", + "LastName": "Himmel", + "abbrevName": "Himmel M", + "email": null, + "isCollectiveName": false, + "name": "Mirko Himmel" + }, + { + "ForeName": "Anett", + "LastName": "Ritter", + "abbrevName": "Ritter A", + "email": null, + "isCollectiveName": false, + "name": "Anett Ritter" + }, + { + "ForeName": "Sven", + "LastName": "Rothemund", + "abbrevName": "Rothemund S", + "email": null, + "isCollectiveName": false, + "name": "Sven Rothemund" + }, + { + "ForeName": "Björg", + "LastName": "Pauling", + "abbrevName": "Pauling BV", + "email": null, + "isCollectiveName": false, + "name": "Björg V Pauling" + }, + { + "ForeName": "Klemens", + "LastName": "Rottner", + "abbrevName": "Rottner K", + "email": null, + "isCollectiveName": false, + "name": "Klemens Rottner" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "abbrevName": "Ziegler WH", + "email": "wolfgang.ziegler@medizin.uni-leipzig.de", + "isCollectiveName": false, + "name": "Wolfgang H Ziegler" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Ziegler", + "email": [ + "wolfgang.ziegler@medizin.uni-leipzig.de" + ], + "name": "Wolfgang H Ziegler" + } + ] + }, + "doi": "10.1074/jbc.M900266200", + "pmid": "19278997", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions." + } + }, + { + "pmid": "12422220", + "pubmed": { + "ISODate": "2002-11-07T00:00:00.000Z", + "abstract": "The ability of cells to form cell contacts, adhere to the extracellular matrix, change morphology, and migrate is essential for development, wound healing, metastasis, cell survival and the immune response. These events depend on the binding of integrin to the extracellular matrix, and assembly of focal adhesions, which are complexes comprising scaffolding and signalling proteins organized by adhesion to the extracellular matrix. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin. The binding of talin to beta-integrin is strengthened by PtdIns(4,5)P(2), suggesting that the basis of focal adhesion assembly is regulated by this lipid mediator. Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin. PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin. This defines a mechanism for spatial generation of PtdIns(4,5)P(2) at focal adhesions.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Ari J Firestone, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Matthew", + "LastName": "Bunce", + "abbrevName": "Bunce MW", + "email": null, + "isCollectiveName": false, + "name": "Matthew W Bunce" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1038/nature01082", + "pmid": "12422220", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Nature 420 2002", + "title": "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions." + } + }, + { + "pmid": "22084092", + "pubmed": { + "ISODate": "2011-11-29T00:00:00.000Z", + "abstract": "Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 activates class I ADP ribosylation factors (ARFs) by accelerating the replacement of bound GDP with GTP to initiate recruitment of coat proteins for membrane vesicle formation. Among proteins that interact with BIG1, kinesin family member 21A (KIF21A), a plus-end-directed motor protein, moves cargo away from the microtubule-organizing center (MTOC) on microtubules. Because KANK1, a protein containing N-terminal KN, C-terminal ankyrin-repeat, and intervening coiled-coil domains, has multiple actions in cells and also interacts with KIF21A, we explored a possible interaction between it and BIG1. We obtained evidence for a functional and physical association between these proteins, and found that the effects of BIG1 and KANK1 depletion on cell migration in wound-healing assays were remarkably similar. Treatment of cells with BIG1- or KANK1-specific siRNA interfered significantly with directed cell migration and initial orientation of Golgi/MTOC toward the leading edge, which was not mimicked by KIF21A depletion. Although colocalization of overexpressed KANK1 and endogenous BIG1 in HeLa cells was not clear microscopically, their reciprocal immunoprecipitation (IP) is compatible with the presence of small percentages of each protein in the same complexes. Depletion or overexpression of BIG1 protein appeared not to affect KANK1 distribution. Our data identify actions of both BIG1 and KANK1 in regulating cell polarity during directed migration; these actions are consistent with the presence of both BIG1 and KANK1 in dynamic multimolecular complexes that maintain Golgi/MTOC orientation, differ from those that might contain all three proteins (BIG1, KIF21A, and KANK1), and function in directed transport along microtubules.", + "authors": { + "abbreviation": "Chun-Chun Li, Jean-Cheng Kuo, Clare M Waterman, ..., Martha Vaughan", + "authorList": [ + { + "ForeName": "Chun-Chun", + "LastName": "Li", + "abbrevName": "Li CC", + "email": null, + "isCollectiveName": false, + "name": "Chun-Chun Li" + }, + { + "ForeName": "Jean-Cheng", + "LastName": "Kuo", + "abbrevName": "Kuo JC", + "email": null, + "isCollectiveName": false, + "name": "Jean-Cheng Kuo" + }, + { + "ForeName": "Clare", + "LastName": "Waterman", + "abbrevName": "Waterman CM", + "email": null, + "isCollectiveName": false, + "name": "Clare M Waterman" + }, + { + "ForeName": "Ryoiti", + "LastName": "Kiyama", + "abbrevName": "Kiyama R", + "email": null, + "isCollectiveName": false, + "name": "Ryoiti Kiyama" + }, + { + "ForeName": "Joel", + "LastName": "Moss", + "abbrevName": "Moss J", + "email": null, + "isCollectiveName": false, + "name": "Joel Moss" + }, + { + "ForeName": "Martha", + "LastName": "Vaughan", + "abbrevName": "Vaughan M", + "email": null, + "isCollectiveName": false, + "name": "Martha Vaughan" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1117011108", + "pmid": "22084092", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing." + } + }, + { + "pmid": "16824950", + "pubmed": { + "ISODate": "2006-07-01T00:00:00.000Z", + "abstract": "CLASPs are mammalian microtubule-stabilizing proteins that can mediate the interaction between distal microtubule ends and the cell cortex. Using mass spectrometry-based assays, we have identified two CLASP partners, LL5beta and ELKS. LL5beta and ELKS form a complex that colocalizes with CLASPs at the cortex of HeLa cells as well as at the leading edge of motile fibroblasts. LL5beta is required for cortical CLASP accumulation and microtubule stabilization in HeLa cells, while ELKS plays an accessory role in these processes. LL5beta is a phosphatidylinositol-3,4,5-triphosphate (PIP3) binding protein, and its recruitment to the cell cortex is influenced by PI3 kinase activity but does not require intact microtubules. Cortical clusters of LL5beta and ELKS do not overlap with focal adhesions but often form in their vicinity and can affect their size. We propose that LL5beta and ELKS can form a PIP3-regulated cortical platform to which CLASPs attach distal microtubule ends.", + "authors": { + "abbreviation": "Gideon Lansbergen, Ilya Grigoriev, Yuko Mimori-Kiyosue, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Gideon", + "LastName": "Lansbergen", + "abbrevName": "Lansbergen G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Lansbergen" + }, + { + "ForeName": "Ilya", + "LastName": "Grigoriev", + "abbrevName": "Grigoriev I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Grigoriev" + }, + { + "ForeName": "Yuko", + "LastName": "Mimori-Kiyosue", + "abbrevName": "Mimori-Kiyosue Y", + "email": null, + "isCollectiveName": false, + "name": "Yuko Mimori-Kiyosue" + }, + { + "ForeName": "Toshihisa", + "LastName": "Ohtsuka", + "abbrevName": "Ohtsuka T", + "email": null, + "isCollectiveName": false, + "name": "Toshihisa Ohtsuka" + }, + { + "ForeName": "Susumu", + "LastName": "Higa", + "abbrevName": "Higa S", + "email": null, + "isCollectiveName": false, + "name": "Susumu Higa" + }, + { + "ForeName": "Isao", + "LastName": "Kitajima", + "abbrevName": "Kitajima I", + "email": null, + "isCollectiveName": false, + "name": "Isao Kitajima" + }, + { + "ForeName": "Jeroen", + "LastName": "Demmers", + "abbrevName": "Demmers J", + "email": null, + "isCollectiveName": false, + "name": "Jeroen Demmers" + }, + { + "ForeName": "Niels", + "LastName": "Galjart", + "abbrevName": "Galjart N", + "email": null, + "isCollectiveName": false, + "name": "Niels Galjart" + }, + { + "ForeName": "Adriaan", + "LastName": "Houtsmuller", + "abbrevName": "Houtsmuller AB", + "email": null, + "isCollectiveName": false, + "name": "Adriaan B Houtsmuller" + }, + { + "ForeName": "Frank", + "LastName": "Grosveld", + "abbrevName": "Grosveld F", + "email": null, + "isCollectiveName": false, + "name": "Frank Grosveld" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.05.012", + "pmid": "16824950", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "CLASPs attach microtubule plus ends to the cell cortex through a complex with LL5beta." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "17150103", + "pubmed": { + "ISODate": "2006-12-06T00:00:00.000Z", + "abstract": "BACKGROUND: Talins are large, modular cytoskeletal proteins found in animals and amoebozoans such as Dictyostelium discoideum. Since the identification of a second talin gene in vertebrates, it has become increasingly clear that vertebrate Talin1 and Talin2 have non-redundant roles as essential links between integrins and the actin cytoskeleton in distinct plasma membrane-associated adhesion complexes. The conserved C-terminal I/LWEQ module is important for talin function. This structural element mediates the interaction of talins with F-actin. The I/LWEQ module also targets mammalian Talin1 to focal adhesion complexes, which are dynamic multicomponent assemblies required for cell adhesion and cell motility. Although Talin1 is essential for focal adhesion function, Talin2 is not targeted to focal adhesions. The nonvertebrate chordate Ciona intestinalis has only one talin gene, but alternative splicing of the talin mRNA produces two proteins with different C-terminal I/LWEQ modules. Thus, C. intestinalis contains two talins, Talin-a and Talin-b, with potentially different activities, despite having only one talin gene. RESULTS: We show here that, based on their distribution in cDNA libraries, Talin-a and Talin-b are differentially expressed during C. intestinalis development. The I/LWEQ modules of the two proteins also have different affinities for F-actin. Consistent with the hypothesis that Talin-a and Talin-b have different roles in cell adhesion, the distinct I/LWEQ modules of Talin-a and Talin-b possess different subcellular targeting determinants. The I/LWEQ module of Talin-a is targeted to focal adhesions, where it most likely serves as the link between integrin and the actin cytoskeleton. The Talin-b I/LWEQ module is not targeted to focal adhesions, but instead preferentially labels F-actin stress fibers. These different properties of C. intestinalis the Talin-a and Talin-b I/LWEQ modules mimic the differences between mammalian Talin1 and Talin2. CONCLUSION: Vertebrates and D. discoideum contain two talin genes that encode proteins with different functions. The urochordate C. intestinalis has a single talin gene but produces two separate talins by alternative splicing that vary in a domain crucial for talin function. This suggests that multicellular organisms require multiple talins as components of adhesion complexes. In C. intestinalis, alternative splicing, rather than gene duplication followed by neo-functionalization, accounts for the presence of multiple talins with different properties. Given that C. intestinalis is an excellent model system for chordate biology, the study of Talin-a and Talin-b will lead to a deeper understanding of cell adhesion in the chordate lineage and how talin functions have been parceled out to multiple proteins during metazoan evolution.", + "authors": { + "abbreviation": "Richard H Singiser, Richard O McCann", + "authorList": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "abbrevName": "Singiser RH", + "email": "rhsing2@uky.edu", + "isCollectiveName": false, + "name": "Richard H Singiser" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [ + { + "ForeName": "Richard", + "LastName": "Singiser", + "email": [ + "rhsing2@uky.edu", + "" + ], + "name": "Richard H Singiser" + } + ] + }, + "doi": "10.1186/1471-2121-7-40", + "pmid": "17150103", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cell Biol 7 2006", + "title": "Evidence that talin alternative splice variants from Ciona intestinalis have different roles in cell adhesion." + } + }, + { + "pmid": "26156744", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "Filamin plays a key role in cellular biomechanics as an actin cross-linker and as a versatile focal adhesion binding partner. It binds directly to integrins, a family of mechanosensitive transmembrane receptors that mediate attachment to several extracellular ligands such as fibronectin, collagen, and laminin. Filamin binds β-integrin at its cytoplasmic tail, competing with talin, a major integrin activator that plays a chief role in cell adhesion. Herein, we develop molecular dynamics models to study the mechanism of early binding of αIIbβ3 integrin with filamin A (FLNa). Our models predict three important electrostatic interactions and one stabilizing hydrophobic interaction that mediate binding between filamin and integrin. In its native conformation, filamin's integrin binding site is auto-inhibited. Our models help shed light on the role of integrin binding on regulating filamin activation. Finally, the effect of talin on the filamin-integrin interaction is explored and possible scenarios of the interplay among these molecules are examined. ", + "authors": { + "abbreviation": "Tiffany Truong, Hengameh Shams, Mohammad R K Mofrad", + "authorList": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "abbrevName": "Truong T", + "email": "mofrad@berkeley.edu", + "isCollectiveName": false, + "name": "Tiffany Truong" + }, + { + "ForeName": "Hengameh", + "LastName": "Shams", + "abbrevName": "Shams H", + "email": null, + "isCollectiveName": false, + "name": "Hengameh Shams" + }, + { + "ForeName": "Mohammad", + "LastName": "Mofrad", + "abbrevName": "Mofrad MR", + "email": null, + "isCollectiveName": false, + "name": "Mohammad R K Mofrad" + } + ], + "contacts": [ + { + "ForeName": "Tiffany", + "LastName": "Truong", + "email": [ + "mofrad@berkeley.edu" + ], + "name": "Tiffany Truong" + } + ] + }, + "doi": "10.1039/c5ib00133a", + "pmid": "26156744", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Integr Biol (Camb) 7 2015", + "title": "Mechanisms of integrin and filamin binding and their interplay with talin during early focal adhesion formation." + } + }, + { + "pmid": "31114072", + "pubmed": { + "ISODate": "2019-06-01T00:00:00.000Z", + "abstract": "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.", + "authors": { + "abbreviation": "Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V Plotnikov, ..., Alexander D Bershadsky", + "authorList": [ + { + "ForeName": "Nisha", + "LastName": "Rafiq", + "abbrevName": "Rafiq NBM", + "email": null, + "isCollectiveName": false, + "name": "Nisha Bte Mohd Rafiq" + }, + { + "ForeName": "Yukako", + "LastName": "Nishimura", + "abbrevName": "Nishimura Y", + "email": null, + "isCollectiveName": false, + "name": "Yukako Nishimura" + }, + { + "ForeName": "Sergey", + "LastName": "Plotnikov", + "abbrevName": "Plotnikov SV", + "email": null, + "isCollectiveName": false, + "name": "Sergey V Plotnikov" + }, + { + "ForeName": "Visalatchi", + "LastName": "Thiagarajan", + "abbrevName": "Thiagarajan V", + "email": null, + "isCollectiveName": false, + "name": "Visalatchi Thiagarajan" + }, + { + "ForeName": "Zhen", + "LastName": "Zhang", + "abbrevName": "Zhang Z", + "email": null, + "isCollectiveName": false, + "name": "Zhen Zhang" + }, + { + "ForeName": "Shidong", + "LastName": "Shi", + "abbrevName": "Shi S", + "email": null, + "isCollectiveName": false, + "name": "Shidong Shi" + }, + { + "ForeName": "Meenubharathi", + "LastName": "Natarajan", + "abbrevName": "Natarajan M", + "email": null, + "isCollectiveName": false, + "name": "Meenubharathi Natarajan" + }, + { + "ForeName": "Virgile", + "LastName": "Viasnoff", + "abbrevName": "Viasnoff V", + "email": null, + "isCollectiveName": false, + "name": "Virgile Viasnoff" + }, + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "abbrevName": "Kanchanawong P", + "email": "biekp@nus.edu.sg", + "isCollectiveName": false, + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "abbrevName": "Jones GE", + "email": "gareth.jones@kcl.ac.uk", + "isCollectiveName": false, + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "abbrevName": "Bershadsky AD", + "email": "alexander.bershadsky@weizmann.ac.il", + "isCollectiveName": false, + "name": "Alexander D Bershadsky" + } + ], + "contacts": [ + { + "ForeName": "Pakorn", + "LastName": "Kanchanawong", + "email": [ + "biekp@nus.edu.sg" + ], + "name": "Pakorn Kanchanawong" + }, + { + "ForeName": "Gareth", + "LastName": "Jones", + "email": [ + "gareth.jones@kcl.ac.uk" + ], + "name": "Gareth E Jones" + }, + { + "ForeName": "Alexander", + "LastName": "Bershadsky", + "email": [ + "alexander.bershadsky@weizmann.ac.il" + ], + "name": "Alexander D Bershadsky" + } + ] + }, + "doi": "10.1038/s41563-019-0371-y", + "pmid": "31114072", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Mater 18 2019", + "title": "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions." + } + }, + { + "pmid": "14691141", + "pubmed": { + "ISODate": "2003-12-22T00:00:00.000Z", + "abstract": "Engagement of integrin receptors with the extracellular matrix induces the formation of focal adhesions (FAs). Dynamic regulation of FAs is necessary for cells to polarize and migrate. Key interactions between FA scaffolding and signaling proteins are dependent on tyrosine phosphorylation. However, the precise role of tyrosine phosphorylation in FA development and maturation is poorly defined. Here, we show that phosphorylation of type Igamma phosphatidylinositol phosphate kinase (PIPKIgamma661) on tyrosine 644 (Y644) is critical for its interaction with talin, and consequently, localization to FAs. PIPKIgamma661 is specifically phosphorylated on Y644 by Src. Phosphorylation is regulated by focal adhesion kinase, which enhances the association between PIPKIgamma661 and Src. The phosphorylation of Y644 results in an approximately 15-fold increase in binding affinity to the talin head domain and blocks beta-integrin binding to talin. This defines a novel phosphotyrosine-binding site on the talin F3 domain and a \"molecular switch\" for talin binding between PIPKIgamma661 and beta-integrin that may regulate dynamic FA turnover.", + "authors": { + "abbreviation": "Kun Ling, Renee L Doughman, Vidhya V Iyer, ..., Richard A Anderson", + "authorList": [ + { + "ForeName": "Kun", + "LastName": "Ling", + "abbrevName": "Ling K", + "email": null, + "isCollectiveName": false, + "name": "Kun Ling" + }, + { + "ForeName": "Renee", + "LastName": "Doughman", + "abbrevName": "Doughman RL", + "email": null, + "isCollectiveName": false, + "name": "Renee L Doughman" + }, + { + "ForeName": "Vidhya", + "LastName": "Iyer", + "abbrevName": "Iyer VV", + "email": null, + "isCollectiveName": false, + "name": "Vidhya V Iyer" + }, + { + "ForeName": "Ari", + "LastName": "Firestone", + "abbrevName": "Firestone AJ", + "email": null, + "isCollectiveName": false, + "name": "Ari J Firestone" + }, + { + "ForeName": "Shawn", + "LastName": "Bairstow", + "abbrevName": "Bairstow SF", + "email": null, + "isCollectiveName": false, + "name": "Shawn F Bairstow" + }, + { + "ForeName": "Deane", + "LastName": "Mosher", + "abbrevName": "Mosher DF", + "email": null, + "isCollectiveName": false, + "name": "Deane F Mosher" + }, + { + "ForeName": "Michael", + "LastName": "Schaller", + "abbrevName": "Schaller MD", + "email": null, + "isCollectiveName": false, + "name": "Michael D Schaller" + }, + { + "ForeName": "Richard", + "LastName": "Anderson", + "abbrevName": "Anderson RA", + "email": null, + "isCollectiveName": false, + "name": "Richard A Anderson" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200310067", + "pmid": "14691141", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Biol 163 2003", + "title": "Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch." + } + }, + { + "pmid": "29183992", + "pubmed": { + "ISODate": "2018-01-12T00:00:00.000Z", + "abstract": "A well-controlled microtubule organization is essential for intracellular transport, cytoskeleton maintenance, and cell development. KN motif and ankyrin repeat domain-containing protein 1 (KANK1), a member of KANK family, recruits kinesin family member 21A (KIF21A) to the cell cortex to control microtubule growth via its C-terminal ankyrin domain. However, how the KANK1 ankyrin domain recognizes KIF21A and whether other KANK proteins can also bind KIF21A remain unknown. Here, using a combination of structural, site-directed mutagenesis, and biochemical studies, we found that a stretch of ∼22 amino acids in KIF21A is sufficient for binding to KANK1 and its close homolog KANK2. We further solved the complex structure of the KIF21A peptide with either the KANK1 ankyrin domain or the KANK2 ankyrin domain. In each complex, KIF21A is recognized by two distinct pockets of the ankyrin domain and adopts helical conformations upon binding to the ankyrin domain. The elucidated KANK structures may advance our understanding of the role of KANK1 as a scaffolding molecule in controlling microtubule growth at the cell periphery.", + "authors": { + "abbreviation": "Qiong Guo, Shanhui Liao, Zhongliang Zhu, ..., Chao Xu", + "authorList": [ + { + "ForeName": "Qiong", + "LastName": "Guo", + "abbrevName": "Guo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiong Guo" + }, + { + "ForeName": "Shanhui", + "LastName": "Liao", + "abbrevName": "Liao S", + "email": "ajsod@mail.ustc.edu.cn", + "isCollectiveName": false, + "name": "Shanhui Liao" + }, + { + "ForeName": "Zhongliang", + "LastName": "Zhu", + "abbrevName": "Zhu Z", + "email": null, + "isCollectiveName": false, + "name": "Zhongliang Zhu" + }, + { + "ForeName": "Yue", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yue Li" + }, + { + "ForeName": "Fudong", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fudong Li" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "abbrevName": "Xu C", + "email": "xuchaor@ustc.edu.cn", + "isCollectiveName": false, + "name": "Chao Xu" + } + ], + "contacts": [ + { + "ForeName": "Shanhui", + "LastName": "Liao", + "email": [ + "ajsod@mail.ustc.edu.cn" + ], + "name": "Shanhui Liao" + }, + { + "ForeName": "Chao", + "LastName": "Xu", + "email": [ + "xuchaor@ustc.edu.cn" + ], + "name": "Chao Xu" + } + ] + }, + "doi": "10.1074/jbc.M117.817494", + "pmid": "29183992", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins." + } + } + ], + "secret": "read-only", + "type": "protein" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/doct_tests_5.json b/neo4j-test/document/doct_tests_5.json new file mode 100644 index 000000000..d6052f3b3 --- /dev/null +++ b/neo4j-test/document/doct_tests_5.json @@ -0,0 +1,40460 @@ +{ + "document": [ + { + "_creationTimestamp": "2022-02-02T16:00:06.676Z", + "_newestOpId": "660ef3bf-4bae-494a-9159-2f452fb8f570", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Talin is a mechanosensitive adapter protein that couples integrins to the cytoskeleton. Talin rod domain-containing protein 1 (TLNRD1) shares 22% homology with the talin R7R8 rod domains, and is highly conserved throughout vertebrate evolution, although little is known about its function. Here we show that TLNRD1 is an α-helical protein structurally homologous to talin R7R8. Like talin R7R8, TLNRD1 binds F-actin, but because it forms a novel antiparallel dimer, it also bundles F-actin. In addition, it binds the same LD motif-containing proteins, RIAM and KANK, as talin R7R8. In cells, TLNRD1 localizes to actin bundles as well as to filopodia. Increasing TLNRD1 expression enhances filopodia formation and cell migration on 2D substrates, while TLNRD1 down-regulation has the opposite effect. Together, our results suggest that TLNRD1 has retained the diverse interactions of talin R7R8, but has developed distinct functionality as an actin-bundling protein that promotes filopodia assembly.", + "ArticleTitle": "Talin rod domain-containing protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Alana R", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0003-4614-9364" + } + ], + "Initials": "AR", + "LastName": "Cowell" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.", + "email": null + }, + { + "Affiliation": "Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Guillaume", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-9286-920X" + } + ], + "Initials": "G", + "LastName": "Jacquemet" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Abhimanyu K", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-9998-020X" + } + ], + "Initials": "AK", + "LastName": "Singh" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Lorena", + "Identifier": [], + "Initials": "L", + "LastName": "Varela" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.", + "email": null + }, + { + "Affiliation": "Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Anna S", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-0744-3600" + } + ], + "Initials": "AS", + "LastName": "Nylund" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "York-Christoph", + "Identifier": [], + "Initials": "YC", + "LastName": "Ammon" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "David G", + "Identifier": [], + "Initials": "DG", + "LastName": "Brown" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Anna", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-9048-8614" + } + ], + "Initials": "A", + "LastName": "Akhmanova" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.", + "email": null + }, + { + "Affiliation": "Department of Biochemistry, University of Turku, Turku, Finland.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Johanna", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-6295-6556" + } + ], + "Initials": "J", + "LastName": "Ivaska" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "School of Biosciences, University of Kent, Canterbury, UK.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Benjamin T", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-3438-2807" + } + ], + "Initials": "BT", + "LastName": "Goult" + } + ], + "Journal": 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Structure. 24:1130–1141. 10.1016/j.str.2016.04.016" + } + ], + "ReferenceList": [], + "Title": null + } + ] + } + }, + "authorProfiles": [ + { + "ForeName": "Alana", + "LastName": "Cowell", + "abbrevName": "Cowell AR", + "email": null, + "isCollectiveName": false, + "name": "Alana R Cowell", + "orcid": "0000-0003-4614-9364" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet", + "orcid": "0000-0002-9286-920X" + }, + { + "ForeName": "Abhimanyu", + "LastName": "Singh", + "abbrevName": "Singh AK", + "email": null, + "isCollectiveName": false, + "name": "Abhimanyu K Singh", + "orcid": "0000-0002-9998-020X" + }, + { + "ForeName": "Lorena", + "LastName": "Varela", + "abbrevName": "Varela L", + "email": null, + "isCollectiveName": false, + "name": "Lorena Varela", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Nylund", + "abbrevName": "Nylund AS", + "email": null, + "isCollectiveName": false, + "name": "Anna S Nylund", + "orcid": "0000-0002-0744-3600" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Brown", + "abbrevName": "Brown DG", + "email": null, + "isCollectiveName": false, + "name": "David G Brown", + "orcid": null + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova", + "orcid": "0000-0002-9048-8614" + }, + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "abbrevName": "Ivaska J", + "email": null, + "isCollectiveName": false, + "name": "Johanna Ivaska", + "orcid": "0000-0002-6295-6556" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult", + "orcid": "0000-0002-3438-2807" + } + ], + "caption": "Cancer, cell migration, filopodia", + "correspondence": { + "authorEmail": [], + "emails": [] + }, + "createdDate": 1643817606, + "entries": [ + { + "id": "93986510-92f8-45bd-a3f3-0eab34305361" + }, + { + "id": "d4a6eb78-7ac4-44eb-8257-c553e82b4ca3" + }, + { + "id": "d5d9fbcc-a1d9-4026-b1d3-d4a97faff36b" + }, + { + "id": "5e0f15cf-4601-4f69-bbe4-72c13d745cd0" + }, + { + "id": "0ce40cac-ced5-4b88-ba29-cd754a61937e" + }, + { + "id": "d38e87a9-a2ad-43f2-a026-63803cdd8120" + }, + { + "id": "13ab91d1-ee5f-46ca-a1ea-82ce72a938f4" + }, + { + "id": "401d53b5-520c-419c-84c4-b44829b8c259" + }, + { + "id": "d7b2a15d-43bf-4494-815b-a77e08cea59c" + }, + { + "id": "eec84ebe-eece-4143-b406-cd99cdbe2e43" + }, + { + "id": "e59c16c4-11e8-4755-8e2f-f88fe4a73b30" + } + ], + "id": "65781dc0-4605-4887-a6dd-d13ae63cd9ba", + "issues": { + "authorEmail": null, + "paperId": null + }, + "lastEditedDate": 1643817832, + "liveId": "91a2bd1a-e959-4d59-bd63-c38ee355a719", + "lock": null, + "locked": false, + "organisms": [], + "provided": { + "authorEmail": "user@email.org", + "authorName": "John Doe", + "name": "John Doe", + "paperId": "Some paper id" + }, + "referencedPapers": [ + { + "pmid": "34118235", + "pubmed": { + "ISODate": "2021-07-01T00:00:00.000Z", + "abstract": "Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.", + "authors": { + "abbreviation": "Rosemarie E Gough, Matthew C Jones, Thomas Zacharchenko, ..., Benjamin T Goult", + "authorList": [ + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "Matthew", + "LastName": "Jones", + "abbrevName": "Jones MC", + "email": null, + "isCollectiveName": false, + "name": "Matthew C Jones" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Shimin", + "LastName": "Le", + "abbrevName": "Le S", + "email": null, + "isCollectiveName": false, + "name": "Shimin Le" + }, + { + "ForeName": "Miao", + "LastName": "Yu", + "abbrevName": "Yu M", + "email": null, + "isCollectiveName": false, + "name": "Miao Yu" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ste", + "LastName": "Muench", + "abbrevName": "Muench SP", + "email": null, + "isCollectiveName": false, + "name": "Ste P Muench" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Jonathan", + "LastName": "Humphries", + "abbrevName": "Humphries JD", + "email": null, + "isCollectiveName": false, + "name": "Jonathan D Humphries" + }, + { + "ForeName": "Claus", + "LastName": "Jørgensen", + "abbrevName": "Jørgensen C", + "email": null, + "isCollectiveName": false, + "name": "Claus Jørgensen" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": "martin.humphries@manchester.ac.uk", + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Humphries", + "email": [ + "martin.humphries@manchester.ac.uk" + ], + "name": "Martin J Humphries" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1016/j.jbc.2021.100837", + "pmid": "34118235", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 297 2021", + "title": "Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1." + } + }, + { + "pmid": "33431906", + "pubmed": { + "ISODate": "2021-01-11T00:00:00.000Z", + "abstract": "Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. We analysed talin-1 mutations reported in the Catalogue of Somatic Mutations in Cancer database and developed a bioinformatics pipeline to predict the severity of each mutation. These predictions were then assessed using biochemistry and cell biology experiments. With this approach we were able to identify several talin-1 mutations affecting integrin activity, actin recruitment and Deleted in Liver Cancer 1 localization. We explored potential changes in talin-1 signalling responses by assessing impact on migration, invasion and proliferation. Altogether, this study describes a pipeline approach of experiments for crude characterization of talin-1 mutants in order to evaluate their functional effects and potential pathogenicity. Our findings suggest that cancer related point mutations in talin-1 can affect cell behaviour and so may contribute to cancer progression.", + "authors": { + "abbreviation": "Latifeh Azizi, Alana R Cowell, Vasyl V Mykuliak, ..., Vesa P Hytönen", + "authorList": [ + { + "ForeName": "Latifeh", + "LastName": "Azizi", + "abbrevName": "Azizi L", + "email": null, + "isCollectiveName": false, + "name": "Latifeh Azizi" + }, + { + "ForeName": "Alana", + "LastName": "Cowell", + "abbrevName": "Cowell AR", + "email": null, + "isCollectiveName": false, + "name": "Alana R Cowell" + }, + { + "ForeName": "Vasyl", + "LastName": "Mykuliak", + "abbrevName": "Mykuliak VV", + "email": null, + "isCollectiveName": false, + "name": "Vasyl V Mykuliak" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "B.T.Goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "abbrevName": "Turkki P", + "email": "paula.turkki@tuni.fi", + "isCollectiveName": false, + "name": "Paula Turkki" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "abbrevName": "Hytönen VP", + "email": "vesa.hytonen@tuni.fi", + "isCollectiveName": false, + "name": "Vesa P Hytönen" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "B.T.Goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + }, + { + "ForeName": "Paula", + "LastName": "Turkki", + "email": [ + "paula.turkki@tuni.fi" + ], + "name": "Paula Turkki" + }, + { + "ForeName": "Vesa", + "LastName": "Hytönen", + "email": [ + "vesa.hytonen@tuni.fi" + ], + "name": "Vesa P Hytönen" + } + ] + }, + "doi": "10.1038/s41598-020-77911-4", + "pmid": "33431906", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 11 2021", + "title": "Cancer associated talin point mutations disorganise cell adhesion and migration." + } + }, + { + "pmid": "31539492", + "pubmed": { + "ISODate": "2019-09-19T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) are protein machineries essential for cell adhesion, migration, and differentiation. Talin is an integrin-activating and tension-sensing FA component directly connecting integrins in the plasma membrane with the actomyosin cytoskeleton. To understand how talin function is regulated, we determined a cryoelectron microscopy (cryo-EM) structure of full-length talin1 revealing a two-way mode of autoinhibition. The actin-binding rod domains fold into a 15-nm globular arrangement that is interlocked by the integrin-binding FERM head. In turn, the rod domains R9 and R12 shield access of the FERM domain to integrin and the phospholipid PIP2 at the membrane. This mechanism likely ensures synchronous inhibition of integrin, membrane, and cytoskeleton binding. We also demonstrate that compacted talin1 reversibly unfolds to an ∼60-nm string-like conformation, revealing interaction sites for vinculin and actin. Our data explain how fast switching between active and inactive conformations of talin could regulate FA turnover, a process critical for cell adhesion and signaling.", + "authors": { + "abbreviation": "Dirk Dedden, Stephanie Schumacher, Charlotte F Kelley, ..., Naoko Mizuno", + "authorList": [ + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Stephanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stephanie Schumacher" + }, + { + "ForeName": "Charlotte", + "LastName": "Kelley", + "abbrevName": "Kelley CF", + "email": null, + "isCollectiveName": false, + "name": "Charlotte F Kelley" + }, + { + "ForeName": "Martin", + "LastName": "Zacharias", + "abbrevName": "Zacharias M", + "email": null, + "isCollectiveName": false, + "name": "Martin Zacharias" + }, + { + "ForeName": "Christian", + "LastName": "Biertümpfel", + "abbrevName": "Biertümpfel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Biertümpfel" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": "mizuno@biochem.mpg.de", + "isCollectiveName": false, + "name": "Naoko Mizuno" + } + ], + "contacts": [ + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "email": [ + "mizuno@biochem.mpg.de" + ], + "name": "Naoko Mizuno" + } + ] + }, + "doi": "10.1016/j.cell.2019.08.034", + "pmid": "31539492", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cell 179 2019", + "title": "The Architecture of Talin1 Reveals an Autoinhibition Mechanism." + } + }, + { + "pmid": "30917112", + "pubmed": { + "ISODate": "2019-03-01T00:00:00.000Z", + "abstract": "Reporting of the actual data in graphs and plots increases transparency and enables independent evaluation. On the other hand, data summaries are often used in graphs because they aid interpretation. To democratize state-of-the-art data visualization of raw data with a selection of statistical summaries, a freely available, open-source web app was written using R/shiny that uses the ggplot2 package for generating plots. Users can to choose how to display the data and which of the data summaries to add. In addition, the 95% confidence intervals (95CIs) can be added for visual inferences. By adjusting the visibility of the layers, the visualization of the raw data and their summaries can be tuned for optimal presentation and interpretation. The app is dubbed PlotsOfData and is available at https://huygens.science.uva.nl/PlotsOfData/.", + "authors": { + "abbreviation": "Marten Postma, Joachim Goedhart", + "authorList": [ + { + "ForeName": "Marten", + "LastName": "Postma", + "abbrevName": "Postma M", + "email": null, + "isCollectiveName": false, + "name": "Marten Postma" + }, + { + "ForeName": "Joachim", + "LastName": "Goedhart", + "abbrevName": "Goedhart J", + "email": null, + "isCollectiveName": false, + "name": "Joachim Goedhart" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.3000202", + "pmid": "30917112", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS Biol 17 2019", + "title": "PlotsOfData-A web app for visualizing data together with their summaries." + } + }, + { + "pmid": "30639111", + "pubmed": { + "ISODate": "2019-01-21T00:00:00.000Z", + "abstract": "Filopodia are adhesive cellular protrusions specialized in the detection of extracellular matrix (ECM)-derived cues. Although ECM engagement at focal adhesions is known to trigger the recruitment of hundreds of proteins (\"adhesome\") to fine-tune cellular behavior, the components of the filopodia adhesions remain undefined. Here, we performed a structured-illumination-microscopy-based screen to map the localization of 80 target proteins, linked to cell adhesion and migration, within myosin-X-induced filopodia. We demonstrate preferential enrichment of several adhesion proteins to either filopodia tips, filopodia shafts, or shaft subdomains, suggesting divergent, spatially restricted functions for these proteins. Moreover, proteins with phosphoinositide (PI) binding sites are particularly enriched in filopodia. This, together with the strong localization of PI(3,4)P2 in filopodia tips, predicts critical roles for PIs in regulating filopodia ultra-structure and function. Our mapping further reveals that filopodia adhesions consist of a unique set of proteins, the filopodome, that are distinct from classical nascent adhesions, focal adhesions, and fibrillar adhesions. Using live imaging, we observe that filopodia adhesions can give rise to nascent adhesions, which, in turn, form focal adhesions. We demonstrate that p130Cas (BCAR1) is recruited to filopodia tips via its C-terminal Cas family homology domain (CCHD) and acts as a mechanosensitive regulator of filopodia stability. Finally, we demonstrate that our map based on myosin-X-induced filopodia can be translated to endogenous filopodia and fascin- and IRSp53-mediated filopodia.", + "authors": { + "abbreviation": "Guillaume Jacquemet, Aki Stubb, Rafael Saup, ..., Johanna Ivaska", + "authorList": [ + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": "guillaume.jacquemet@utu.fi", + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Aki", + "LastName": "Stubb", + "abbrevName": "Stubb A", + "email": null, + "isCollectiveName": false, + "name": "Aki Stubb" + }, + { + "ForeName": "Rafael", + "LastName": "Saup", + "abbrevName": "Saup R", + "email": null, + "isCollectiveName": false, + "name": "Rafael Saup" + }, + { + "ForeName": "Mitro", + "LastName": "Miihkinen", + "abbrevName": "Miihkinen M", + "email": null, + "isCollectiveName": false, + "name": "Mitro Miihkinen" + }, + { + "ForeName": "Elena", + "LastName": "Kremneva", + "abbrevName": "Kremneva E", + "email": null, + "isCollectiveName": false, + "name": "Elena Kremneva" + }, + { + "ForeName": "Hellyeh", + "LastName": "Hamidi", + "abbrevName": "Hamidi H", + "email": null, + "isCollectiveName": false, + "name": "Hellyeh Hamidi" + }, + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "abbrevName": "Ivaska J", + "email": "johanna.ivaska@utu.fi", + "isCollectiveName": false, + "name": "Johanna Ivaska" + } + ], + "contacts": [ + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "email": [ + "guillaume.jacquemet@utu.fi" + ], + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "email": [ + "johanna.ivaska@utu.fi" + ], + "name": "Johanna Ivaska" + } + ] + }, + "doi": "10.1016/j.cub.2018.11.053", + "pmid": "30639111", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 29 2019", + "title": "Filopodome Mapping Identifies p130Cas as a Mechanosensitive Regulator of Filopodia Stability." + } + }, + { + "pmid": "30254032", + "pubmed": { + "ISODate": "2018-11-05T00:00:00.000Z", + "abstract": "Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.", + "authors": { + "abbreviation": "Benjamin T Goult, Jie Yan, Martin A Schwartz", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": "b.t.goult@kent.ac.uk", + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": null, + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "email": [ + "b.t.goult@kent.ac.uk" + ], + "name": "Benjamin T Goult" + } + ] + }, + "doi": "10.1083/jcb.201808061", + "pmid": "30254032", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "J Cell Biol 217 2018", + "title": "Talin as a mechanosensitive signaling hub." + } + }, + { + "pmid": "29907753", + "pubmed": { + "ISODate": "2018-06-15T00:00:00.000Z", + "abstract": "Multiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and hsa-miR-3677 in the RNA-seq and hsa-miR-146b-3p, hsa-miR-584, and hsa-miR-31 in the microarray dataset. Of the 223 miRNAs studied, the expression was significantly altered in 102 miRNAs in tumors compared to normal liver tissues. In summary, we set up an integrated miRNA expression database and validated prognostic miRNAs in HCC.", + "authors": { + "abbreviation": "Ádám Nagy, András Lánczky, Otília Menyhárt, Balázs Győrffy", + "authorList": [ + { + "ForeName": "Ádám", + "LastName": "Nagy", + "abbrevName": "Nagy Á", + "email": null, + "isCollectiveName": false, + "name": "Ádám Nagy" + }, + { + "ForeName": "András", + "LastName": "Lánczky", + "abbrevName": "Lánczky A", + "email": null, + "isCollectiveName": false, + "name": "András Lánczky" + }, + { + "ForeName": "Otília", + "LastName": "Menyhárt", + "abbrevName": "Menyhárt O", + "email": null, + "isCollectiveName": false, + "name": "Otília Menyhárt" + }, + { + "ForeName": "Balázs", + "LastName": "Győrffy", + "abbrevName": "Győrffy B", + "email": "gyorffy.balazs@ttk.mta.hu", + "isCollectiveName": false, + "name": "Balázs Győrffy" + } + ], + "contacts": [ + { + "ForeName": "Balázs", + "LastName": "Győrffy", + "email": [ + "gyorffy.balazs@ttk.mta.hu" + ], + "name": "Balázs Győrffy" + } + ] + }, + "doi": "10.1038/s41598-018-27521-y", + "pmid": "29907753", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Sci Rep 8 2018", + "title": "Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets." + } + }, + { + "pmid": "28808438", + "pubmed": { + "ISODate": "2017-08-01T00:00:00.000Z", + "abstract": "ATSAS is a comprehensive software suite for the analysis of small-angle scattering data from dilute solutions of biological macromolecules or nanoparticles. It contains applications for primary data processing and assessment, ab initio bead modelling, and model validation, as well as methods for the analysis of flexibility and mixtures. In addition, approaches are supported that utilize information from X-ray crystallography, nuclear magnetic resonance spectroscopy or atomistic homology modelling to construct hybrid models based on the scattering data. This article summarizes the progress made during the 2.5-2.8 ATSAS release series and highlights the latest developments. These include AMBIMETER, an assessment of the reconstruction ambiguity of experimental data; DATCLASS, a multiclass shape classification based on experimental data; SASRES, for estimating the resolution of ab initio model reconstructions; CHROMIXS, a convenient interface to analyse in-line size exclusion chromatography data; SHANUM, to evaluate the useful angular range in measured data; SREFLEX, to refine available high-resolution models using normal mode analysis; SUPALM for a rapid superposition of low- and high-resolution models; and SASPy, the ATSAS plugin for interactive modelling in PyMOL. All these features and other improvements are included in the ATSAS release 2.8, freely available for academic users from https://www.embl-hamburg.de/biosaxs/software.html.", + "authors": { + "abbreviation": "D Franke, M V Petoukhov, P V Konarev, ..., D I Svergun", + "authorList": [ + { + "ForeName": "D", + "LastName": "Franke", + "abbrevName": "Franke D", + "email": null, + "isCollectiveName": false, + "name": "D Franke" + }, + { + "ForeName": "M", + "LastName": "Petoukhov", + "abbrevName": "Petoukhov MV", + "email": null, + "isCollectiveName": false, + "name": "M V Petoukhov" + }, + { + "ForeName": "P", + "LastName": "Konarev", + "abbrevName": "Konarev PV", + "email": null, + "isCollectiveName": false, + "name": "P V Konarev" + }, + { + "ForeName": "A", + "LastName": "Panjkovich", + "abbrevName": "Panjkovich A", + "email": null, + "isCollectiveName": false, + "name": "A Panjkovich" + }, + { + "ForeName": "A", + "LastName": "Tuukkanen", + "abbrevName": "Tuukkanen A", + "email": null, + "isCollectiveName": false, + "name": "A Tuukkanen" + }, + { + "ForeName": "H", + "LastName": "Mertens", + "abbrevName": "Mertens HDT", + "email": null, + "isCollectiveName": false, + "name": "H D T Mertens" + }, + { + "ForeName": "A", + "LastName": "Kikhney", + "abbrevName": "Kikhney AG", + "email": null, + "isCollectiveName": false, + "name": "A G Kikhney" + }, + { + "ForeName": "N", + "LastName": "Hajizadeh", + "abbrevName": "Hajizadeh NR", + "email": null, + "isCollectiveName": false, + "name": "N R Hajizadeh" + }, + { + "ForeName": "J", + "LastName": "Franklin", + "abbrevName": "Franklin JM", + "email": null, + "isCollectiveName": false, + "name": "J M Franklin" + }, + { + "ForeName": "C", + "LastName": "Jeffries", + "abbrevName": "Jeffries CM", + "email": null, + "isCollectiveName": false, + "name": "C M Jeffries" + }, + { + "ForeName": "D", + "LastName": "Svergun", + "abbrevName": "Svergun DI", + "email": null, + "isCollectiveName": false, + "name": "D I Svergun" + } + ], + "contacts": [] + }, + "doi": "10.1107/S1600576717007786", + "pmid": "28808438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Appl Crystallogr 50 2017", + "title": "ATSAS 2.8: a comprehensive data analysis suite for small-angle scattering from macromolecular solutions." + } + }, + { + "pmid": "28765364", + "pubmed": { + "ISODate": "2017-10-02T00:00:00.000Z", + "abstract": "Defective filopodia formation is linked to pathologies such as cancer, wherein actively protruding filopodia, at the invasive front, accompany cancer cell dissemination. Despite wide biological significance, delineating filopodia function in complex systems remains challenging and is particularly hindered by lack of compatible methods to quantify filopodia properties. Here, we present FiloQuant, a freely available ImageJ plugin, to detect filopodia-like protrusions in both fixed- and live-cell microscopy data. We demonstrate that FiloQuant can extract quantifiable information, including protrusion dynamics, density, and length, from multiple cell types and in a range of microenvironments. In cellular models of breast ductal carcinoma in situ, we reveal a link between filopodia formation at the cell-matrix interface, in collectively invading cells and 3D tumor spheroids, and the in vitro invasive capacity of the carcinoma. Finally, using intravital microscopy, we observe that tumor spheroids display filopodia in vivo, supporting a potential role for these protrusions during tumorigenesis.", + "authors": { + "abbreviation": "Guillaume Jacquemet, Ilkka Paatero, Alexandre F Carisey, ..., Johanna Ivaska", + "authorList": [ + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": "guillaume.jacquemet@utu.fi", + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Ilkka", + "LastName": "Paatero", + "abbrevName": "Paatero I", + "email": null, + "isCollectiveName": false, + "name": "Ilkka Paatero" + }, + { + "ForeName": "Alexandre", + "LastName": "Carisey", + "abbrevName": "Carisey AF", + "email": null, + "isCollectiveName": false, + "name": "Alexandre F Carisey" + }, + { + "ForeName": "Artur", + "LastName": "Padzik", + "abbrevName": "Padzik A", + "email": null, + "isCollectiveName": false, + "name": "Artur Padzik" + }, + { + "ForeName": "Jordan", + "LastName": "Orange", + "abbrevName": "Orange JS", + "email": null, + "isCollectiveName": false, + "name": "Jordan S Orange" + }, + { + "ForeName": "Hellyeh", + "LastName": "Hamidi", + "abbrevName": "Hamidi H", + "email": null, + "isCollectiveName": false, + "name": "Hellyeh Hamidi" + }, + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "abbrevName": "Ivaska J", + "email": "johanna.ivaska@utu.fi", + "isCollectiveName": false, + "name": "Johanna Ivaska" + } + ], + "contacts": [ + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "email": [ + "guillaume.jacquemet@utu.fi" + ], + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "email": [ + "johanna.ivaska@utu.fi" + ], + "name": "Johanna Ivaska" + } + ] + }, + "doi": "10.1083/jcb.201704045", + "pmid": "28765364", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Biol 216 2017", + "title": "FiloQuant reveals increased filopodia density during breast cancer progression." + } + }, + { + "pmid": "27881003", + "pubmed": { + "ISODate": null, + "abstract": "Hepatocellular carcinoma (HCC) is the third leading cause of cancer associated mortality. Accumulating evidence has shown that microRNAs (miRNAs) act as critical factors for tumor recurrence and metastasis. MiR-508-5p has been reported as a down-regulated miRNA in the primary gastric cancer tissues. However, the role of miR-508-5p on HCC has not been well elucidated. In this study, we observed that miR-508-5p was downregulated in HCC tissues when compared to the non-tumorous tissues. We then demonstrated that overexpression of miR-508-5p attenuated HepG2 cells proliferation and invasion and induced cell apoptosis in vitro. Furthermore, our further investigations revealed that mesoderm development candidate 1 (MESDC1) is a potential target of miR-508-5p, as well as miR-508-5p overexpression downregulated MESDC1 expression. Overexpression of MESDC1 promoted HepG2 cells migration, invasion and proliferation in vitro. In addition, miR-508-5p markedly suppressed the tumor growth in xenograft model, while MESDC1 promoted the tumor growth in xenograft model. This study provides new insight into molecular mechanisms that miR-508-5p acts as a tumor suppressor by targeting MESDC1 in HCC progression.", + "authors": { + "abbreviation": "S G Wu, Y J Huang, B Bao, ..., W Chen", + "authorList": [ + { + "ForeName": "S", + "LastName": "Wu", + "abbrevName": "Wu SG", + "email": null, + "isCollectiveName": false, + "name": "S G Wu" + }, + { + "ForeName": "Y", + "LastName": "Huang", + "abbrevName": "Huang YJ", + "email": null, + "isCollectiveName": false, + "name": "Y J Huang" + }, + { + "ForeName": "B", + "LastName": "Bao", + "abbrevName": "Bao B", + "email": null, + "isCollectiveName": false, + "name": "B Bao" + }, + { + "ForeName": "L", + "LastName": "Wu", + "abbrevName": "Wu LM", + "email": null, + "isCollectiveName": false, + "name": "L M Wu" + }, + { + "ForeName": "J", + "LastName": "Dong", + "abbrevName": "Dong J", + "email": null, + "isCollectiveName": false, + "name": "J Dong" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XH", + "email": null, + "isCollectiveName": false, + "name": "X H Liu" + }, + { + "ForeName": "Z", + "LastName": "Li", + "abbrevName": "Li ZH", + "email": null, + "isCollectiveName": false, + "name": "Z H Li" + }, + { + "ForeName": "X", + "LastName": "Wang", + "abbrevName": "Wang XY", + "email": null, + "isCollectiveName": false, + "name": "X Y Wang" + }, + { + "ForeName": "L", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "L Wang" + }, + { + "ForeName": "B", + "LastName": "Chen", + "abbrevName": "Chen BJ", + "email": null, + "isCollectiveName": false, + "name": "B J Chen" + }, + { + "ForeName": "W", + "LastName": "Chen", + "abbrevName": "Chen W", + "email": null, + "isCollectiveName": false, + "name": "W Chen" + } + ], + "contacts": [] + }, + "doi": "10.4149/neo_2017_105", + "pmid": "27881003", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Neoplasma 64", + "title": "miR-508-5p acts as an anti-oncogene by targeting MESDC1 in hepatocellular carcinoma." + } + }, + { + "pmid": "27799471", + "pubmed": { + "ISODate": "2017-01-04T00:00:00.000Z", + "abstract": "The HUGO Gene Nomenclature Committee (HGNC) based at the European Bioinformatics Institute (EMBL-EBI) assigns unique symbols and names to human genes. Currently the HGNC database contains almost 40 000 approved gene symbols, over 19 000 of which represent protein-coding genes. In addition to naming genomic loci we manually curate genes into family sets based on shared characteristics such as homology, function or phenotype. We have recently updated our gene family resources and introduced new improved visualizations which can be seen alongside our gene symbol reports on our primary website http://www.genenames.org In 2016 we expanded our remit and formed the Vertebrate Gene Nomenclature Committee (VGNC) which is responsible for assigning names to vertebrate species lacking a dedicated nomenclature group. Using the chimpanzee genome as a pilot project we have approved symbols and names for over 14 500 protein-coding genes in chimpanzee, and have developed a new website http://vertebrate.genenames.org to distribute these data. Here, we review our online data and resources, focusing particularly on the improvements and new developments made during the last two years.", + "authors": { + "abbreviation": "Bethan Yates, Bryony Braschi, Kristian A Gray, ..., Elspeth A Bruford", + "authorList": [ + { + "ForeName": "Bethan", + "LastName": "Yates", + "abbrevName": "Yates B", + "email": "byates@ebi.ac.uk", + "isCollectiveName": false, + "name": "Bethan Yates" + }, + { + "ForeName": "Bryony", + "LastName": "Braschi", + "abbrevName": "Braschi B", + "email": null, + "isCollectiveName": false, + "name": "Bryony Braschi" + }, + { + "ForeName": "Kristian", + "LastName": "Gray", + "abbrevName": "Gray KA", + "email": null, + "isCollectiveName": false, + "name": "Kristian A Gray" + }, + { + "ForeName": "Ruth", + "LastName": "Seal", + "abbrevName": "Seal RL", + "email": null, + "isCollectiveName": false, + "name": "Ruth L Seal" + }, + { + "ForeName": "Susan", + "LastName": "Tweedie", + "abbrevName": "Tweedie S", + "email": null, + "isCollectiveName": false, + "name": "Susan Tweedie" + }, + { + "ForeName": "Elspeth", + "LastName": "Bruford", + "abbrevName": "Bruford EA", + "email": null, + "isCollectiveName": false, + "name": "Elspeth A Bruford" + } + ], + "contacts": [ + { + "ForeName": "Bethan", + "LastName": "Yates", + "email": [ + "byates@ebi.ac.uk" + ], + "name": "Bethan Yates" + } + ] + }, + "doi": "10.1093/nar/gkw1033", + "pmid": "27799471", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nucleic Acids Res 45 2017", + "title": "Genenames.org: the HGNC and VGNC resources in 2017." + } + }, + { + "pmid": "27548916", + "pubmed": { + "ISODate": "2016-09-01T00:00:00.000Z", + "abstract": "Integrin-based adhesions play critical roles in cell migration. Talin activates integrins and flexibly connects integrins to the actomyosin cytoskeleton, thereby serving as a 'molecular clutch' that transmits forces to the extracellular matrix to drive cell migration. Here we identify the evolutionarily conserved Kank protein family as novel components of focal adhesions (FAs). Kank proteins accumulate at the lateral border of FAs, which we term the FA belt, and in central sliding adhesions, where they directly bind the talin rod domain through the Kank amino-terminal (KN) motif and induce talin and integrin activation. In addition, Kank proteins diminish the talin-actomyosin linkage, which curbs force transmission across integrins, leading to reduced integrin-ligand bond strength, slippage between integrin and ligand, central adhesion formation and sliding, and reduced cell migration speed. Our data identify Kank proteins as talin activators that decrease the grip between the integrin-talin complex and actomyosin to regulate cell migration velocity.", + "authors": { + "abbreviation": "Zhiqi Sun, Hui-Yuan Tseng, Steven Tan, ..., Reinhard Fässler", + "authorList": [ + { + "ForeName": "Zhiqi", + "LastName": "Sun", + "abbrevName": "Sun Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqi Sun" + }, + { + "ForeName": "Hui-Yuan", + "LastName": "Tseng", + "abbrevName": "Tseng HY", + "email": null, + "isCollectiveName": false, + "name": "Hui-Yuan Tseng" + }, + { + "ForeName": "Steven", + "LastName": "Tan", + "abbrevName": "Tan S", + "email": null, + "isCollectiveName": false, + "name": "Steven Tan" + }, + { + "ForeName": "Fabrice", + "LastName": "Senger", + "abbrevName": "Senger F", + "email": null, + "isCollectiveName": false, + "name": "Fabrice Senger" + }, + { + "ForeName": "Laetitia", + "LastName": "Kurzawa", + "abbrevName": "Kurzawa L", + "email": null, + "isCollectiveName": false, + "name": "Laetitia Kurzawa" + }, + { + "ForeName": "Dirk", + "LastName": "Dedden", + "abbrevName": "Dedden D", + "email": null, + "isCollectiveName": false, + "name": "Dirk Dedden" + }, + { + "ForeName": "Naoko", + "LastName": "Mizuno", + "abbrevName": "Mizuno N", + "email": null, + "isCollectiveName": false, + "name": "Naoko Mizuno" + }, + { + "ForeName": "Anita", + "LastName": "Wasik", + "abbrevName": "Wasik AA", + "email": null, + "isCollectiveName": false, + "name": "Anita A Wasik" + }, + { + "ForeName": "Manuel", + "LastName": "Thery", + "abbrevName": "Thery M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Thery" + }, + { + "ForeName": "Alexander", + "LastName": "Dunn", + "abbrevName": "Dunn AR", + "email": null, + "isCollectiveName": false, + "name": "Alexander R Dunn" + }, + { + "ForeName": "Reinhard", + "LastName": "Fässler", + "abbrevName": "Fässler R", + "email": null, + "isCollectiveName": false, + "name": "Reinhard Fässler" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncb3402", + "pmid": "27548916", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nat Cell Biol 18 2016", + "title": "Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation." + } + }, + { + "pmid": "27410476", + "pubmed": { + "ISODate": "2016-07-13T00:00:00.000Z", + "abstract": "The cross-talk between dynamic microtubules and integrin-based adhesions to the extracellular matrix plays a crucial role in cell polarity and migration. Microtubules regulate the turnover of adhesion sites, and, in turn, focal adhesions promote the cortical microtubule capture and stabilization in their vicinity, but the underlying mechanism is unknown. Here, we show that cortical microtubule stabilization sites containing CLASPs, KIF21A, LL5β and liprins are recruited to focal adhesions by the adaptor protein KANK1, which directly interacts with the major adhesion component, talin. Structural studies showed that the conserved KN domain in KANK1 binds to the talin rod domain R7. Perturbation of this interaction, including a single point mutation in talin, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of microtubule-stabilizing complexes with focal adhesions. We propose that the talin-KANK1 interaction links the two macromolecular assemblies that control cortical attachment of actin fibers and microtubules.", + "authors": { + "abbreviation": "Benjamin P Bouchet, Rosemarie E Gough, York-Christoph Ammon, ..., Anna Akhmanova", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Bouchet", + "abbrevName": "Bouchet BP", + "email": null, + "isCollectiveName": false, + "name": "Benjamin P Bouchet" + }, + { + "ForeName": "Rosemarie", + "LastName": "Gough", + "abbrevName": "Gough RE", + "email": null, + "isCollectiveName": false, + "name": "Rosemarie E Gough" + }, + { + "ForeName": "York-Christoph", + "LastName": "Ammon", + "abbrevName": "Ammon YC", + "email": null, + "isCollectiveName": false, + "name": "York-Christoph Ammon" + }, + { + "ForeName": "Dieudonnée", + "LastName": "van de Willige", + "abbrevName": "van de Willige D", + "email": null, + "isCollectiveName": false, + "name": "Dieudonnée van de Willige" + }, + { + "ForeName": "Harm", + "LastName": "Post", + "abbrevName": "Post H", + "email": null, + "isCollectiveName": false, + "name": "Harm Post" + }, + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Af", + "LastName": "Altelaar", + "abbrevName": "Altelaar AM", + "email": null, + "isCollectiveName": false, + "name": "Af Maarten Altelaar" + }, + { + "ForeName": "Albert", + "LastName": "Heck", + "abbrevName": "Heck AJ", + "email": null, + "isCollectiveName": false, + "name": "Albert Jr Heck" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Anna", + "LastName": "Akhmanova", + "abbrevName": "Akhmanova A", + "email": null, + "isCollectiveName": false, + "name": "Anna Akhmanova" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.18124", + "pmid": "27410476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Elife 5 2016", + "title": "Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions." + } + }, + { + "pmid": "27384267", + "pubmed": { + "ISODate": "2016-07-07T00:00:00.000Z", + "abstract": "Talin, a force-bearing cytoplasmic adapter essential for integrin-mediated cell adhesion, links the actin cytoskeleton to integrin-based cell-extracellular matrix adhesions at the plasma membrane. Its C-terminal rod domain, which contains 13 helical bundles, plays important roles in mechanosensing during cell adhesion and spreading. However, how the structural stability and transition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly understood. Here we report the force-dependent unfolding and refolding kinetics of all talin rod domains. Using experimentally determined kinetics parameters, we determined the dynamics of force fluctuation during stretching of talin under physiologically relevant pulling speeds and experimentally measured extension fluctuation trajectories. Our results reveal that force-dependent stochastic unfolding and refolding of talin rod domains make talin a very effective force buffer that sets a physiological force range of only a few pNs in the talin-mediated force transmission pathway.", + "authors": { + "abbreviation": "Mingxi Yao, Benjamin T Goult, Benjamin Klapholz, ..., Jie Yan", + "authorList": [ + { + "ForeName": "Mingxi", + "LastName": "Yao", + "abbrevName": "Yao M", + "email": null, + "isCollectiveName": false, + "name": "Mingxi Yao" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Benjamin", + "LastName": "Klapholz", + "abbrevName": "Klapholz B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Klapholz" + }, + { + "ForeName": "Xian", + "LastName": "Hu", + "abbrevName": "Hu X", + "email": null, + "isCollectiveName": false, + "name": "Xian Hu" + }, + { + "ForeName": "Christopher", + "LastName": "Toseland", + "abbrevName": "Toseland CP", + "email": null, + "isCollectiveName": false, + "name": "Christopher P Toseland" + }, + { + "ForeName": "Yingjian", + "LastName": "Guo", + "abbrevName": "Guo Y", + "email": null, + "isCollectiveName": false, + "name": "Yingjian Guo" + }, + { + "ForeName": "Peiwen", + "LastName": "Cong", + "abbrevName": "Cong P", + "email": null, + "isCollectiveName": false, + "name": "Peiwen Cong" + }, + { + "ForeName": "Michael", + "LastName": "Sheetz", + "abbrevName": "Sheetz MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Sheetz" + }, + { + "ForeName": "Jie", + "LastName": "Yan", + "abbrevName": "Yan J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yan" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms11966", + "pmid": "27384267", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 7 2016", + "title": "The mechanical response of talin." + } + }, + { + "pmid": "27265849", + "pubmed": { + "ISODate": "2016-07-06T00:00:00.000Z", + "abstract": "Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.", + "authors": { + "abbreviation": "Thomas Zacharchenko, Xiaolan Qian, Benjamin T Goult, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Teresa", + "LastName": "Almeida", + "abbrevName": "Almeida TB", + "email": null, + "isCollectiveName": false, + "name": "Teresa B Almeida" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "igb2@liv.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "igb2@liv.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1016/j.str.2016.04.016", + "pmid": "27265849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 24 2016", + "title": "LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex." + } + }, + { + "pmid": "27166375", + "pubmed": { + "ISODate": "2016-07-08T00:00:00.000Z", + "abstract": "The degree of evolutionary conservation of an amino acid in a protein or a nucleic acid in DNA/RNA reflects a balance between its natural tendency to mutate and the overall need to retain the structural integrity and function of the macromolecule. The ConSurf web server (http://consurf.tau.ac.il), established over 15 years ago, analyses the evolutionary pattern of the amino/nucleic acids of the macromolecule to reveal regions that are important for structure and/or function. Starting from a query sequence or structure, the server automatically collects homologues, infers their multiple sequence alignment and reconstructs a phylogenetic tree that reflects their evolutionary relations. These data are then used, within a probabilistic framework, to estimate the evolutionary rates of each sequence position. Here we introduce several new features into ConSurf, including automatic selection of the best evolutionary model used to infer the rates, the ability to homology-model query proteins, prediction of the secondary structure of query RNA molecules from sequence, the ability to view the biological assembly of a query (in addition to the single chain), mapping of the conservation grades onto 2D RNA models and an advanced view of the phylogenetic tree that enables interactively rerunning ConSurf with the taxa of a sub-tree.", + "authors": { + "abbreviation": "Haim Ashkenazy, Shiran Abadi, Eric Martz, ..., Nir Ben-Tal", + "authorList": [ + { + "ForeName": "Haim", + "LastName": "Ashkenazy", + "abbrevName": "Ashkenazy H", + "email": null, + "isCollectiveName": false, + "name": "Haim Ashkenazy" + }, + { + "ForeName": "Shiran", + "LastName": "Abadi", + "abbrevName": "Abadi S", + "email": null, + "isCollectiveName": false, + "name": "Shiran Abadi" + }, + { + "ForeName": "Eric", + "LastName": "Martz", + "abbrevName": "Martz E", + "email": null, + "isCollectiveName": false, + "name": "Eric Martz" + }, + { + "ForeName": "Ofer", + "LastName": "Chay", + "abbrevName": "Chay O", + "email": null, + "isCollectiveName": false, + "name": "Ofer Chay" + }, + { + "ForeName": "Itay", + "LastName": "Mayrose", + "abbrevName": "Mayrose I", + "email": "itaymay@post.tau.ac.il", + "isCollectiveName": false, + "name": "Itay Mayrose" + }, + { + "ForeName": "Tal", + "LastName": "Pupko", + "abbrevName": "Pupko T", + "email": "talp@post.tau.ac.il", + "isCollectiveName": false, + "name": "Tal Pupko" + }, + { + "ForeName": "Nir", + "LastName": "Ben-Tal", + "abbrevName": "Ben-Tal N", + "email": "bental@tauex.tau.ac.il", + "isCollectiveName": false, + "name": "Nir Ben-Tal" + } + ], + "contacts": [ + { + "ForeName": "Itay", + "LastName": "Mayrose", + "email": [ + "itaymay@post.tau.ac.il" + ], + "name": "Itay Mayrose" + }, + { + "ForeName": "Tal", + "LastName": "Pupko", + "email": [ + "talp@post.tau.ac.il" + ], + "name": "Tal Pupko" + }, + { + "ForeName": "Nir", + "LastName": "Ben-Tal", + "email": [ + "bental@tauex.tau.ac.il" + ], + "name": "Nir Ben-Tal" + } + ] + }, + "doi": "10.1093/nar/gkw408", + "pmid": "27166375", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Nucleic Acids Res 44 2016", + "title": "ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules." + } + }, + { + "pmid": "27161398", + "pubmed": { + "ISODate": "2016-05-09T00:00:00.000Z", + "abstract": "Integrin-dependent adhesions are mechanosensitive structures in which talin mediates a linkage to actin filaments either directly or indirectly by recruiting vinculin. Here, we report the development and validation of a talin tension sensor. We find that talin in focal adhesions is under tension, which is higher in peripheral than central adhesions. Tension on talin is increased by vinculin and depends mainly on actin-binding site 2 (ABS2) within the middle of the rod domain, rather than ABS3 at the far C terminus. Unlike vinculin, talin is under lower tension on soft substrates. The difference between central and peripheral adhesions requires ABS3 but not vinculin or ABS2. However, differential stiffness sensing by talin requires ABS2 but not vinculin or ABS3. These results indicate that central versus peripheral adhesions must be organized and regulated differently, and that ABS2 and ABS3 have distinct functions in spatial variations and stiffness sensing. Overall, these results shed new light on talin function and constrain models for cellular mechanosensing.", + "authors": { + "abbreviation": "Abhishek Kumar, Mingxing Ouyang, Koen Van den Dries, ..., Martin A Schwartz", + "authorList": [ + { + "ForeName": "Abhishek", + "LastName": "Kumar", + "abbrevName": "Kumar A", + "email": null, + "isCollectiveName": false, + "name": "Abhishek Kumar" + }, + { + "ForeName": "Mingxing", + "LastName": "Ouyang", + "abbrevName": "Ouyang M", + "email": null, + "isCollectiveName": false, + "name": "Mingxing Ouyang" + }, + { + "ForeName": "Koen", + "LastName": "Van den Dries", + "abbrevName": "Van den Dries K", + "email": null, + "isCollectiveName": false, + "name": "Koen Van den Dries" + }, + { + "ForeName": "Ewan", + "LastName": "McGhee", + "abbrevName": "McGhee EJ", + "email": null, + "isCollectiveName": false, + "name": "Ewan James McGhee" + }, + { + "ForeName": "Keiichiro", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Keiichiro Tanaka" + }, + { + "ForeName": "Marie", + "LastName": "Anderson", + "abbrevName": "Anderson MD", + "email": null, + "isCollectiveName": false, + "name": "Marie D Anderson" + }, + { + "ForeName": "Alexander", + "LastName": "Groisman", + "abbrevName": "Groisman A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Groisman" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Kurt", + "LastName": "Anderson", + "abbrevName": "Anderson KI", + "email": null, + "isCollectiveName": false, + "name": "Kurt I Anderson" + }, + { + "ForeName": "Martin", + "LastName": "Schwartz", + "abbrevName": "Schwartz MA", + "email": "martin.schwartz@yale.edu", + "isCollectiveName": false, + "name": "Martin A Schwartz" + } + ], + "contacts": [ + { + "ForeName": "Martin", + "LastName": "Schwartz", + "email": [ + "martin.schwartz@yale.edu" + ], + "name": "Martin A Schwartz" + } + ] + }, + "doi": "10.1083/jcb.201510012", + "pmid": "27161398", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 213 2016", + "title": "Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity." + } + }, + { + "pmid": "26634421", + "pubmed": { + "ISODate": "2015-12-04T00:00:00.000Z", + "abstract": "The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs. ", + "authors": { + "abbreviation": "Paul Atherton, Ben Stutchbury, De-Yao Wang, ..., Christoph Ballestrem", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Atherton", + "abbrevName": "Atherton P", + "email": null, + "isCollectiveName": false, + "name": "Paul Atherton" + }, + { + "ForeName": "Ben", + "LastName": "Stutchbury", + "abbrevName": "Stutchbury B", + "email": null, + "isCollectiveName": false, + "name": "Ben Stutchbury" + }, + { + "ForeName": "De-Yao", + "LastName": "Wang", + "abbrevName": "Wang DY", + "email": null, + "isCollectiveName": false, + "name": "De-Yao Wang" + }, + { + "ForeName": "Devina", + "LastName": "Jethwa", + "abbrevName": "Jethwa D", + "email": null, + "isCollectiveName": false, + "name": "Devina Jethwa" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Eugenia", + "LastName": "Meiler-Rodriguez", + "abbrevName": "Meiler-Rodriguez E", + "email": null, + "isCollectiveName": false, + "name": "Eugenia Meiler-Rodriguez" + }, + { + "ForeName": "Pengbo", + "LastName": "Wang", + "abbrevName": "Wang P", + "email": null, + "isCollectiveName": false, + "name": "Pengbo Wang" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Roy", + "LastName": "Zent", + "abbrevName": "Zent R", + "email": null, + "isCollectiveName": false, + "name": "Roy Zent" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms10038", + "pmid": "26634421", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "Vinculin controls talin engagement with the actomyosin machinery." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "26186729", + "pubmed": { + "ISODate": "2015-10-01T00:00:00.000Z", + "abstract": "This review discusses recent advances in our understanding of the role filopodia and filopodia-like structures in cell adhesion and three dimensional (3D) cell migration both in vitro and in vivo. In particular, we focus on recent advances demonstrating that filopodia are involved in substrate tethering and environment sensing in vivo. We further discuss the emerging role of filopodia and filopodial proteins in tumor dissemination as mounting in vitro, in vivo and clinical evidence suggest that filopodia drive cancer cell invasion and highlight filopodia proteins as attractive therapeutic targets. Finally, we outline outstanding questions that remain to be addressed to elucidate the role of filopodia during 3D cell migration. ", + "authors": { + "abbreviation": "Guillaume Jacquemet, Hellyeh Hamidi, Johanna Ivaska", + "authorList": [ + { + "ForeName": "Guillaume", + "LastName": "Jacquemet", + "abbrevName": "Jacquemet G", + "email": null, + "isCollectiveName": false, + "name": "Guillaume Jacquemet" + }, + { + "ForeName": "Hellyeh", + "LastName": "Hamidi", + "abbrevName": "Hamidi H", + "email": null, + "isCollectiveName": false, + "name": "Hellyeh Hamidi" + }, + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "abbrevName": "Ivaska J", + "email": "joivaska@utu.fi", + "isCollectiveName": false, + "name": "Johanna Ivaska" + } + ], + "contacts": [ + { + "ForeName": "Johanna", + "LastName": "Ivaska", + "email": [ + "joivaska@utu.fi" + ], + "name": "Johanna Ivaska" + } + ] + }, + "doi": "10.1016/j.ceb.2015.06.007", + "pmid": "26186729", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Curr Opin Cell Biol 36 2015", + "title": "Filopodia in cell adhesion, 3D migration and cancer cell invasion." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "24870021", + "pubmed": { + "ISODate": "2014-06-15T00:00:00.000Z", + "abstract": "LD motifs (leucine-aspartic acid motifs) are short helical protein-protein interaction motifs that have emerged as key players in connecting cell adhesion with cell motility and survival. LD motifs are required for embryogenesis, wound healing and the evolution of multicellularity. LD motifs also play roles in disease, such as in cancer metastasis or viral infection. First described in the paxillin family of scaffolding proteins, LD motifs and similar acidic LXXLL interaction motifs have been discovered in several other proteins, whereas 16 proteins have been reported to contain LDBDs (LD motif-binding domains). Collectively, structural and functional analyses have revealed a surprising multivalency in LD motif interactions and a wide diversity in LDBD architectures. In the present review, we summarize the molecular basis for function, regulation and selectivity of LD motif interactions that has emerged from more than a decade of research. This overview highlights the intricate multi-level regulation and the inherently noisy and heterogeneous nature of signalling through short protein-protein interaction motifs.", + "authors": { + "abbreviation": "Tanvir Alam, Meshari Alazmi, Xin Gao, Stefan T Arold", + "authorList": [ + { + "ForeName": "Tanvir", + "LastName": "Alam", + "abbrevName": "Alam T", + "email": null, + "isCollectiveName": false, + "name": "Tanvir Alam" + }, + { + "ForeName": "Meshari", + "LastName": "Alazmi", + "abbrevName": "Alazmi M", + "email": null, + "isCollectiveName": false, + "name": "Meshari Alazmi" + }, + { + "ForeName": "Xin", + "LastName": "Gao", + "abbrevName": "Gao X", + "email": null, + "isCollectiveName": false, + "name": "Xin Gao" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + } + ], + "contacts": [] + }, + "doi": "10.1042/BJ20140298", + "pmid": "24870021", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochem J 460 2014", + "title": "How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs." + } + }, + { + "pmid": "23860236", + "pubmed": { + "ISODate": "2013-08-01T00:00:00.000Z", + "abstract": "Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling. ", + "authors": { + "abbreviation": "David A Calderwood, Iain D Campbell, David R Critchley", + "authorList": [ + { + "ForeName": "David", + "LastName": "Calderwood", + "abbrevName": "Calderwood DA", + "email": null, + "isCollectiveName": false, + "name": "David A Calderwood" + }, + { + "ForeName": "Iain", + "LastName": "Campbell", + "abbrevName": "Campbell ID", + "email": null, + "isCollectiveName": false, + "name": "Iain D Campbell" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/nrm3624", + "pmid": "23860236", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Nat Rev Mol Cell Biol 14 2013", + "title": "Talins and kindlins: partners in integrin-mediated adhesion." + } + }, + { + "pmid": "23793146", + "pubmed": { + "ISODate": "2013-07-01T00:00:00.000Z", + "abstract": "Following integration of the observed diffraction spots, the process of `data reduction' initially aims to determine the point-group symmetry of the data and the likely space group. This can be performed with the program POINTLESS. The scaling program then puts all the measurements on a common scale, averages measurements of symmetry-related reflections (using the symmetry determined previously) and produces many statistics that provide the first important measures of data quality. A new scaling program, AIMLESS, implements scaling models similar to those in SCALA but adds some additional analyses. From the analyses, a number of decisions can be made about the quality of the data and whether some measurements should be discarded. The effective `resolution' of a data set is a difficult and possibly contentious question (particularly with referees of papers) and this is discussed in the light of tests comparing the data-processing statistics with trials of refinement against observed and simulated data, and automated model-building and comparison of maps calculated with different resolution limits. These trials show that adding weak high-resolution data beyond the commonly used limits may make some improvement and does no harm. ", + "authors": { + "abbreviation": "Philip R Evans, Garib N Murshudov", + "authorList": [ + { + "ForeName": "Philip", + "LastName": "Evans", + "abbrevName": "Evans PR", + "email": "pre@mrc-lmb.cam.ac.uk", + "isCollectiveName": false, + "name": "Philip R Evans" + }, + { + "ForeName": "Garib", + "LastName": "Murshudov", + "abbrevName": "Murshudov GN", + "email": null, + "isCollectiveName": false, + "name": "Garib N Murshudov" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Evans", + "email": [ + "pre@mrc-lmb.cam.ac.uk" + ], + "name": "Philip R Evans" + } + ] + }, + "doi": "10.1107/S0907444913000061", + "pmid": "23793146", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 69 2013", + "title": "How good are my data and what is the resolution?" + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "23270813", + "pubmed": { + "ISODate": "2013-03-01T00:00:00.000Z", + "abstract": "Microscale thermophoresis (MST) allows for quantitative analysis of protein interactions in free solution and with low sample consumption. The technique is based on thermophoresis, the directed motion of molecules in temperature gradients. Thermophoresis is highly sensitive to all types of binding-induced changes of molecular properties, be it in size, charge, hydration shell or conformation. In an all-optical approach, an infrared laser is used for local heating, and molecule mobility in the temperature gradient is analyzed via fluorescence. In standard MST one binding partner is fluorescently labeled. However, MST can also be performed label-free by exploiting intrinsic protein UV-fluorescence. Despite the high molecular weight ratio, the interaction of small molecules and peptides with proteins is readily accessible by MST. Furthermore, MST assays are highly adaptable to fit to the diverse requirements of different biomolecules, such as membrane proteins to be stabilized in solution. The type of buffer and additives can be chosen freely. Measuring is even possible in complex bioliquids like cell lysate allowing close to in vivo conditions without sample purification. Binding modes that are quantifiable via MST include dimerization, cooperativity and competition. Thus, its flexibility in assay design qualifies MST for analysis of biomolecular interactions in complex experimental settings, which we herein demonstrate by addressing typically challenging types of binding events from various fields of life science.", + "authors": { + "abbreviation": "Susanne A I Seidel, Patricia M Dijkman, Wendy A Lea, ..., Stefan Duhr", + "authorList": [ + { + "ForeName": "Susanne", + "LastName": "Seidel", + "abbrevName": "Seidel SA", + "email": null, + "isCollectiveName": false, + "name": "Susanne A I Seidel" + }, + { + "ForeName": "Patricia", + "LastName": "Dijkman", + "abbrevName": "Dijkman PM", + "email": null, + "isCollectiveName": false, + "name": "Patricia M Dijkman" + }, + { + "ForeName": "Wendy", + "LastName": "Lea", + "abbrevName": "Lea WA", + "email": null, + "isCollectiveName": false, + "name": "Wendy A Lea" + }, + { + "ForeName": "Geert", + "LastName": "van den Bogaart", + "abbrevName": "van den Bogaart G", + "email": null, + "isCollectiveName": false, + "name": "Geert van den Bogaart" + }, + { + "ForeName": "Moran", + "LastName": "Jerabek-Willemsen", + "abbrevName": "Jerabek-Willemsen M", + "email": null, + "isCollectiveName": false, + "name": "Moran Jerabek-Willemsen" + }, + { + "ForeName": "Ana", + "LastName": "Lazic", + "abbrevName": "Lazic A", + "email": null, + "isCollectiveName": false, + "name": "Ana Lazic" + }, + { + "ForeName": "Jeremiah", + "LastName": "Joseph", + "abbrevName": "Joseph JS", + "email": null, + "isCollectiveName": false, + "name": "Jeremiah S Joseph" + }, + { + "ForeName": "Prakash", + "LastName": "Srinivasan", + "abbrevName": "Srinivasan P", + "email": null, + "isCollectiveName": false, + "name": "Prakash Srinivasan" + }, + { + "ForeName": "Philipp", + "LastName": "Baaske", + "abbrevName": "Baaske P", + "email": null, + "isCollectiveName": false, + "name": "Philipp Baaske" + }, + { + "ForeName": "Anton", + "LastName": "Simeonov", + "abbrevName": "Simeonov A", + "email": null, + "isCollectiveName": false, + "name": "Anton Simeonov" + }, + { + "ForeName": "Ilia", + "LastName": "Katritch", + "abbrevName": "Katritch I", + "email": null, + "isCollectiveName": false, + "name": "Ilia Katritch" + }, + { + "ForeName": "Fernando", + "LastName": "Melo", + "abbrevName": "Melo FA", + "email": null, + "isCollectiveName": false, + "name": "Fernando A Melo" + }, + { + "ForeName": "John", + "LastName": "Ladbury", + "abbrevName": "Ladbury JE", + "email": null, + "isCollectiveName": false, + "name": "John E Ladbury" + }, + { + "ForeName": "Gideon", + "LastName": "Schreiber", + "abbrevName": "Schreiber G", + "email": null, + "isCollectiveName": false, + "name": "Gideon Schreiber" + }, + { + "ForeName": "Anthony", + "LastName": "Watts", + "abbrevName": "Watts A", + "email": null, + "isCollectiveName": false, + "name": "Anthony Watts" + }, + { + "ForeName": "Dieter", + "LastName": "Braun", + "abbrevName": "Braun D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Braun" + }, + { + "ForeName": "Stefan", + "LastName": "Duhr", + "abbrevName": "Duhr S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Duhr" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.ymeth.2012.12.005", + "pmid": "23270813", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Methods 59 2013", + "title": "Microscale thermophoresis quantifies biomolecular interactions under previously challenging conditions." + } + }, + { + "pmid": "22930834", + "pubmed": { + "ISODate": "2012-07-01T00:00:00.000Z", + "abstract": "For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.", + "authors": { + "abbreviation": "Caroline A Schneider, Wayne S Rasband, Kevin W Eliceiri", + "authorList": [ + { + "ForeName": "Caroline", + "LastName": "Schneider", + "abbrevName": "Schneider CA", + "email": null, + "isCollectiveName": false, + "name": "Caroline A Schneider" + }, + { + "ForeName": "Wayne", + "LastName": "Rasband", + "abbrevName": "Rasband WS", + "email": null, + "isCollectiveName": false, + "name": "Wayne S Rasband" + }, + { + "ForeName": "Kevin", + "LastName": "Eliceiri", + "abbrevName": "Eliceiri KW", + "email": null, + "isCollectiveName": false, + "name": "Kevin W Eliceiri" + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth.2089", + "pmid": "22930834", + "pubTypes": [ + { + "UI": "D016456", + "value": "Historical Article" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Methods 9 2012", + "title": "NIH Image to ImageJ: 25 years of image analysis." + } + }, + { + "pmid": "22743772", + "pubmed": { + "ISODate": "2012-06-28T00:00:00.000Z", + "abstract": "Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.", + "authors": { + "abbreviation": "Johannes Schindelin, Ignacio Arganda-Carreras, Erwin Frise, ..., Albert Cardona", + "authorList": [ + { + "ForeName": "Johannes", + "LastName": "Schindelin", + "abbrevName": "Schindelin J", + "email": null, + "isCollectiveName": false, + "name": "Johannes Schindelin" + }, + { + "ForeName": "Ignacio", + "LastName": "Arganda-Carreras", + "abbrevName": "Arganda-Carreras I", + "email": null, + "isCollectiveName": false, + "name": "Ignacio Arganda-Carreras" + }, + { + "ForeName": "Erwin", + "LastName": "Frise", + "abbrevName": "Frise E", + "email": null, + "isCollectiveName": false, + "name": "Erwin Frise" + }, + { + "ForeName": "Verena", + "LastName": "Kaynig", + "abbrevName": "Kaynig V", + "email": null, + "isCollectiveName": false, + "name": "Verena Kaynig" + }, + { + "ForeName": "Mark", + "LastName": "Longair", + "abbrevName": "Longair M", + "email": null, + "isCollectiveName": false, + "name": "Mark Longair" + }, + { + "ForeName": "Tobias", + "LastName": "Pietzsch", + "abbrevName": "Pietzsch T", + "email": null, + "isCollectiveName": false, + "name": "Tobias Pietzsch" + }, + { + "ForeName": "Stephan", + "LastName": "Preibisch", + "abbrevName": "Preibisch S", + "email": null, + "isCollectiveName": false, + "name": "Stephan Preibisch" + }, + { + "ForeName": "Curtis", + "LastName": "Rueden", + "abbrevName": "Rueden C", + "email": null, + "isCollectiveName": false, + "name": "Curtis Rueden" + }, + { + "ForeName": "Stephan", + "LastName": "Saalfeld", + "abbrevName": "Saalfeld S", + "email": null, + "isCollectiveName": false, + "name": "Stephan Saalfeld" + }, + { + "ForeName": "Benjamin", + "LastName": "Schmid", + "abbrevName": "Schmid B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Schmid" + }, + { + "ForeName": "Jean-Yves", + "LastName": "Tinevez", + "abbrevName": "Tinevez JY", + "email": null, + "isCollectiveName": false, + "name": "Jean-Yves Tinevez" + }, + { + "ForeName": "Daniel", + "LastName": "White", + "abbrevName": "White DJ", + "email": null, + "isCollectiveName": false, + "name": "Daniel James White" + }, + { + "ForeName": "Volker", + "LastName": "Hartenstein", + "abbrevName": "Hartenstein V", + "email": null, + "isCollectiveName": false, + "name": "Volker Hartenstein" + }, + { + "ForeName": "Kevin", + "LastName": "Eliceiri", + "abbrevName": "Eliceiri K", + "email": null, + "isCollectiveName": false, + "name": "Kevin Eliceiri" + }, + { + "ForeName": "Pavel", + "LastName": "Tomancak", + "abbrevName": "Tomancak P", + "email": null, + "isCollectiveName": false, + "name": "Pavel Tomancak" + }, + { + "ForeName": "Albert", + "LastName": "Cardona", + "abbrevName": "Cardona A", + "email": null, + "isCollectiveName": false, + "name": "Albert Cardona" + } + ], + "contacts": [] + }, + "doi": "10.1038/nmeth.2019", + "pmid": "22743772", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Methods 9 2012", + "title": "Fiji: an open-source platform for biological-image analysis." + } + }, + { + "pmid": "22726438", + "pubmed": { + "ISODate": "2012-06-22T00:00:00.000Z", + "abstract": "Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this \"background\" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.", + "authors": { + "abbreviation": "Chi-Chuan Lin, Fernando A Melo, Ragini Ghosh, ..., John E Ladbury", + "authorList": [ + { + "ForeName": "Chi-Chuan", + "LastName": "Lin", + "abbrevName": "Lin CC", + "email": null, + "isCollectiveName": false, + "name": "Chi-Chuan Lin" + }, + { + "ForeName": "Fernando", + "LastName": "Melo", + "abbrevName": "Melo FA", + "email": null, + "isCollectiveName": false, + "name": "Fernando A Melo" + }, + { + "ForeName": "Ragini", + "LastName": "Ghosh", + "abbrevName": "Ghosh R", + "email": null, + "isCollectiveName": false, + "name": "Ragini Ghosh" + }, + { + "ForeName": "Kin", + "LastName": "Suen", + "abbrevName": "Suen KM", + "email": null, + "isCollectiveName": false, + "name": "Kin M Suen" + }, + { + "ForeName": "Loren", + "LastName": "Stagg", + "abbrevName": "Stagg LJ", + "email": null, + "isCollectiveName": false, + "name": "Loren J Stagg" + }, + { + "ForeName": "John", + "LastName": "Kirkpatrick", + "abbrevName": "Kirkpatrick J", + "email": null, + "isCollectiveName": false, + "name": "John Kirkpatrick" + }, + { + "ForeName": "Stefan", + "LastName": "Arold", + "abbrevName": "Arold ST", + "email": null, + "isCollectiveName": false, + "name": "Stefan T Arold" + }, + { + "ForeName": "Zamal", + "LastName": "Ahmed", + "abbrevName": "Ahmed Z", + "email": null, + "isCollectiveName": false, + "name": "Zamal Ahmed" + }, + { + "ForeName": "John", + "LastName": "Ladbury", + "abbrevName": "Ladbury JE", + "email": null, + "isCollectiveName": false, + "name": "John E Ladbury" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cell.2012.04.033", + "pmid": "22726438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell 149 2012", + "title": "Inhibition of basal FGF receptor signaling by dimeric Grb2." + } + }, + { + "pmid": "22505256", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "phenix.refine is a program within the PHENIX package that supports crystallographic structure refinement against experimental data with a wide range of upper resolution limits using a large repertoire of model parameterizations. It has several automation features and is also highly flexible. Several hundred parameters enable extensive customizations for complex use cases. Multiple user-defined refinement strategies can be applied to specific parts of the model in a single refinement run. An intuitive graphical user interface is available to guide novice users and to assist advanced users in managing refinement projects. X-ray or neutron diffraction data can be used separately or jointly in refinement. phenix.refine is tightly integrated into the PHENIX suite, where it serves as a critical component in automated model building, final structure refinement, structure validation and deposition to the wwPDB. This paper presents an overview of the major phenix.refine features, with extensive literature references for readers interested in more detailed discussions of the methods.", + "authors": { + "abbreviation": "Pavel V Afonine, Ralf W Grosse-Kunstleve, Nathaniel Echols, ..., Paul D Adams", + "authorList": [ + { + "ForeName": "Pavel", + "LastName": "Afonine", + "abbrevName": "Afonine PV", + "email": "pafonine@lbl.gov", + "isCollectiveName": false, + "name": "Pavel V Afonine" + }, + { + "ForeName": "Ralf", + "LastName": "Grosse-Kunstleve", + "abbrevName": "Grosse-Kunstleve RW", + "email": null, + "isCollectiveName": false, + "name": "Ralf W Grosse-Kunstleve" + }, + { + "ForeName": "Nathaniel", + "LastName": "Echols", + "abbrevName": "Echols N", + "email": null, + "isCollectiveName": false, + "name": "Nathaniel Echols" + }, + { + "ForeName": "Jeffrey", + "LastName": "Headd", + "abbrevName": "Headd JJ", + "email": null, + "isCollectiveName": false, + "name": "Jeffrey J Headd" + }, + { + "ForeName": "Nigel", + "LastName": "Moriarty", + "abbrevName": "Moriarty NW", + "email": null, + "isCollectiveName": false, + "name": "Nigel W Moriarty" + }, + { + "ForeName": "Marat", + "LastName": "Mustyakimov", + "abbrevName": "Mustyakimov M", + "email": null, + "isCollectiveName": false, + "name": "Marat Mustyakimov" + }, + { + "ForeName": "Thomas", + "LastName": "Terwilliger", + "abbrevName": "Terwilliger TC", + "email": null, + "isCollectiveName": false, + "name": "Thomas C Terwilliger" + }, + { + "ForeName": "Alexandre", + "LastName": "Urzhumtsev", + "abbrevName": "Urzhumtsev A", + "email": null, + "isCollectiveName": false, + "name": "Alexandre Urzhumtsev" + }, + { + "ForeName": "Peter", + "LastName": "Zwart", + "abbrevName": "Zwart PH", + "email": null, + "isCollectiveName": false, + "name": "Peter H Zwart" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + } + ], + "contacts": [ + { + "ForeName": "Pavel", + "LastName": "Afonine", + "email": [ + "pafonine@lbl.gov" + ], + "name": "Pavel V Afonine" + } + ] + }, + "doi": "10.1107/S0907444912001308", + "pmid": "22505256", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D057666", + "value": "Research Support, American Recovery and Reinvestment Act" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 68 2012", + "title": "Towards automated crystallographic structure refinement with phenix.refine." + } + }, + { + "pmid": "22179486", + "pubmed": { + "ISODate": "2012-04-01T00:00:00.000Z", + "abstract": "Our previous studies suggested that microRNA (miR)-574-3p is a candidate tumor suppressor microRNA (miRNA) in human bladder cancer (BC). Among 17 down-regulated miRNAs, miR-574-3p is located on chromosome 4p14 where we had identified a chromosomal loss region by array-CGH in BC cell lines. MiR-574-3p expression was down-regulated in BC cell lines. Gain-of-function analysis revealed that cell proliferation, migration and invasion were significantly inhibited in miR‑574‑3p-transfected BC cell lines. Flow cytometry analysis showed that cell apoptosis was induced in miR-574-3p transfectants. Oligo microarray analysis suggested that the mesoderm development candidate 1 (MESDC1) gene was a target gene in miR-574-3p transfectants. Luciferase assays revealed that miR‑574‑3p was directly bound to MESDC1 mRNA. MESDC1 is predicted to be a novel actin-binding protein located on chromosome 15q13. Although the gene is conserved among many species, its functional role is still unknown in both human malignancies and normal tissues. Loss-of-function studies demonstrated that cell proliferation, migration and invasion were significantly inhibited in si-MESDC1-transfected BC cell lines. Flow cytometry analysis showed that apoptosis was induced in si-MESDC1 transfectants. We are the first to demonstrate that miR-574-3p is a miRNA with tumor suppressor function and that MESDC1 (which has a potential oncogenic function in BC) may be targeted by miR-574-3p.", + "authors": { + "abbreviation": "Shuichi Tatarano, Takeshi Chiyomaru, Kazumori Kawakami, ..., Masayuki Nakagawa", + "authorList": [ + { + "ForeName": "Shuichi", + "LastName": "Tatarano", + "abbrevName": "Tatarano S", + "email": null, + "isCollectiveName": false, + "name": "Shuichi Tatarano" + }, + { + "ForeName": "Takeshi", + "LastName": "Chiyomaru", + "abbrevName": "Chiyomaru T", + "email": null, + "isCollectiveName": false, + "name": "Takeshi Chiyomaru" + }, + { + "ForeName": "Kazumori", + "LastName": "Kawakami", + "abbrevName": "Kawakami K", + "email": null, + "isCollectiveName": false, + "name": "Kazumori Kawakami" + }, + { + "ForeName": "Hideki", + "LastName": "Enokida", + "abbrevName": "Enokida H", + "email": null, + "isCollectiveName": false, + "name": "Hideki Enokida" + }, + { + "ForeName": "Hirofumi", + "LastName": "Yoshino", + "abbrevName": "Yoshino H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Yoshino" + }, + { + "ForeName": "Hideo", + "LastName": "Hidaka", + "abbrevName": "Hidaka H", + "email": null, + "isCollectiveName": false, + "name": "Hideo Hidaka" + }, + { + "ForeName": "Nijiro", + "LastName": "Nohata", + "abbrevName": "Nohata N", + "email": null, + "isCollectiveName": false, + "name": "Nijiro Nohata" + }, + { + "ForeName": "Takeshi", + "LastName": "Yamasaki", + "abbrevName": "Yamasaki T", + "email": null, + "isCollectiveName": false, + "name": "Takeshi Yamasaki" + }, + { + "ForeName": "Takenari", + "LastName": "Gotanda", + "abbrevName": "Gotanda T", + "email": null, + "isCollectiveName": false, + "name": "Takenari Gotanda" + }, + { + "ForeName": "Tokushi", + "LastName": "Tachiwada", + "abbrevName": "Tachiwada T", + "email": null, + "isCollectiveName": false, + "name": "Tokushi Tachiwada" + }, + { + "ForeName": "Naohiko", + "LastName": "Seki", + "abbrevName": "Seki N", + "email": null, + "isCollectiveName": false, + "name": "Naohiko Seki" + }, + { + "ForeName": "Masayuki", + "LastName": "Nakagawa", + "abbrevName": "Nakagawa M", + "email": null, + "isCollectiveName": false, + "name": "Masayuki Nakagawa" + } + ], + "contacts": [] + }, + "doi": "10.3892/ijo.2011.1294", + "pmid": "22179486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Oncol 40 2012", + "title": "Novel oncogenic function of mesoderm development candidate 1 and its regulation by MiR-574-3p in bladder cancer cell lines." + } + }, + { + "pmid": "21975550", + "pubmed": { + "ISODate": null, + "abstract": "The goal of this review is to highlight how emerging new models of filopodia assembly, which include tissue specific actin-bundling proteins, could provide more comprehensive representations of filopodia assembly that would describe more adequately and effectively the complexity and plasticity of epithelial cells.  This review also describes how the true diversity of actin bundling proteins must be considered to predict the far-reaching significance and versatile functions of filopodia in epithelial cells.", + "authors": { + "abbreviation": "Seema Khurana, Sudeep P George", + "authorList": [ + { + "ForeName": "Seema", + "LastName": "Khurana", + "abbrevName": "Khurana S", + "email": "skhurana@uh.edu", + "isCollectiveName": false, + "name": "Seema Khurana" + }, + { + "ForeName": "Sudeep", + "LastName": "George", + "abbrevName": "George SP", + "email": null, + "isCollectiveName": false, + "name": "Sudeep P George" + } + ], + "contacts": [ + { + "ForeName": "Seema", + "LastName": "Khurana", + "email": [ + "skhurana@uh.edu" + ], + "name": "Seema Khurana" + } + ] + }, + "doi": "10.4161/cam.5.5.17644", + "pmid": "21975550", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Cell Adh Migr 5", + "title": "The role of actin bundling proteins in the assembly of filopodia in epithelial cells." + } + }, + { + "pmid": "21969587", + "pubmed": { + "ISODate": "2011-10-11T00:00:00.000Z", + "abstract": "The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.", + "authors": { + "abbreviation": "Guorong Li, Xiaoli Du, William C Vass, ..., Xiaolan Qian", + "authorList": [ + { + "ForeName": "Guorong", + "LastName": "Li", + "abbrevName": "Li G", + "email": null, + "isCollectiveName": false, + "name": "Guorong Li" + }, + { + "ForeName": "Xiaoli", + "LastName": "Du", + "abbrevName": "Du X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoli Du" + }, + { + "ForeName": "William", + "LastName": "Vass", + "abbrevName": "Vass WC", + "email": null, + "isCollectiveName": false, + "name": "William C Vass" + }, + { + "ForeName": "Alex", + "LastName": "Papageorge", + "abbrevName": "Papageorge AG", + "email": null, + "isCollectiveName": false, + "name": "Alex G Papageorge" + }, + { + "ForeName": "Douglas", + "LastName": "Lowy", + "abbrevName": "Lowy DR", + "email": null, + "isCollectiveName": false, + "name": "Douglas R Lowy" + }, + { + "ForeName": "Xiaolan", + "LastName": "Qian", + "abbrevName": "Qian X", + "email": null, + "isCollectiveName": false, + "name": "Xiaolan Qian" + } + ], + "contacts": [] + }, + "doi": "10.1073/pnas.1112122108", + "pmid": "21969587", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052060", + "value": "Research Support, N.I.H., Intramural" + } + ], + "reference": "Proc Natl Acad Sci U S A 108 2011", + "title": "Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK)." + } + }, + { + "pmid": "21460447", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "A typical diffraction experiment will generate many images and data sets from different crystals in a very short time. This creates a challenge for the high-throughput operation of modern synchrotron beamlines as well as for the subsequent data processing. Novice users in particular may feel overwhelmed by the tables, plots and numbers that the different data-processing programs and software packages present to them. Here, some of the more common problems that a user has to deal with when processing a set of images that will finally make up a processed data set are shown, concentrating on difficulties that may often show up during the first steps along the path of turning the experiment (i.e. data collection) into a model (i.e. interpreted electron density). Difficulties such as unexpected crystal forms, issues in crystal handling and suboptimal choices of data-collection strategies can often be dealt with, or at least diagnosed, by analysing specific data characteristics during processing. In the end, one wants to distinguish problems over which one has no immediate control once the experiment is finished from problems that can be remedied a posteriori. A new software package, autoPROC, is also presented that combines third-party processing programs with new tools and an automated workflow script that is intended to provide users with both guidance and insight into the offline processing of data affected by the difficulties mentioned above, with particular emphasis on the automated treatment of multi-sweep data sets collected on multi-axis goniostats.", + "authors": { + "abbreviation": "Clemens Vonrhein, Claus Flensburg, Peter Keller, ..., Gérard Bricogne", + "authorList": [ + { + "ForeName": "Clemens", + "LastName": "Vonrhein", + "abbrevName": "Vonrhein C", + "email": "vonrhein@globalphasing.com", + "isCollectiveName": false, + "name": "Clemens Vonrhein" + }, + { + "ForeName": "Claus", + "LastName": "Flensburg", + "abbrevName": "Flensburg C", + "email": null, + "isCollectiveName": false, + "name": "Claus Flensburg" + }, + { + "ForeName": "Peter", + "LastName": "Keller", + "abbrevName": "Keller P", + "email": null, + "isCollectiveName": false, + "name": "Peter Keller" + }, + { + "ForeName": "Andrew", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "Andrew Sharff" + }, + { + "ForeName": "Oliver", + "LastName": "Smart", + "abbrevName": "Smart O", + "email": null, + "isCollectiveName": false, + "name": "Oliver Smart" + }, + { + "ForeName": "Wlodek", + "LastName": "Paciorek", + "abbrevName": "Paciorek W", + "email": null, + "isCollectiveName": false, + "name": "Wlodek Paciorek" + }, + { + "ForeName": "Thomas", + "LastName": "Womack", + "abbrevName": "Womack T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Womack" + }, + { + "ForeName": "Gérard", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "Gérard Bricogne" + } + ], + "contacts": [ + { + "ForeName": "Clemens", + "LastName": "Vonrhein", + "email": [ + "vonrhein@globalphasing.com" + ], + "name": "Clemens Vonrhein" + } + ] + }, + "doi": "10.1107/S0907444911007773", + "pmid": "21460447", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 67 2011", + "title": "Data processing and analysis with the autoPROC toolbox." + } + }, + { + "pmid": "21460446", + "pubmed": { + "ISODate": "2011-04-01T00:00:00.000Z", + "abstract": "This paper presents an overview of how to run the CCP4 programs for data reduction (SCALA, POINTLESS and CTRUNCATE) through the CCP4 graphical interface ccp4i and points out some issues that need to be considered, together with a few examples. It covers determination of the point-group symmetry of the diffraction data (the Laue group), which is required for the subsequent scaling step, examination of systematic absences, which in many cases will allow inference of the space group, putting multiple data sets on a common indexing system when there are alternatives, the scaling step itself, which produces a large set of data-quality indicators, estimation of |F| from intensity and finally examination of intensity statistics to detect crystal pathologies such as twinning. An appendix outlines the scoring schemes used by the program POINTLESS to assign probabilities to possible Laue and space groups.", + "authors": { + "abbreviation": "Philip R Evans", + "authorList": [ + { + "ForeName": "Philip", + "LastName": "Evans", + "abbrevName": "Evans PR", + "email": "pre@mrc-lmb.cam.ac.uk", + "isCollectiveName": false, + "name": "Philip R Evans" + } + ], + "contacts": [ + { + "ForeName": "Philip", + "LastName": "Evans", + "email": [ + "pre@mrc-lmb.cam.ac.uk" + ], + "name": "Philip R Evans" + } + ] + }, + "doi": "10.1107/S090744491003982X", + "pmid": "21460446", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 67 2011", + "title": "An introduction to data reduction: space-group determination, scaling and intensity statistics." + } + }, + { + "pmid": "20947018", + "pubmed": { + "ISODate": "2010-10-13T00:00:00.000Z", + "abstract": "FERM domains are found in a diverse superfamily of signaling and adaptor proteins at membrane interfaces. They typically consist of three separately folded domains (F1, F2, F3) in a compact cloverleaf structure. The crystal structure of the N-terminal head of the integrin-associated cytoskeletal protein talin reported here reveals a novel FERM domain with a linear domain arrangement, plus an additional domain F0 packed against F1. While F3 binds β-integrin tails, basic residues in F1 and F2 are required for membrane association and for integrin activation. We show that these same residues are also required for cell spreading and focal adhesion assembly in cells. We suggest that the extended conformation of the talin head allows simultaneous binding to integrins via F3 and to PtdIns(4,5)P2-enriched microdomains via basic residues distributed along one surface of the talin head, and that these multiple interactions are required to stabilize integrins in the activated state.", + "authors": { + "abbreviation": "Paul R Elliott, Benjamin T Goult, Petra M Kopp, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2010.07.011", + "pmid": "20947018", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 18 2010", + "title": "The Structure of the talin head reveals a novel extended conformation of the FERM domain." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "20383002", + "pubmed": { + "ISODate": "2010-04-01T00:00:00.000Z", + "abstract": "Coot is a molecular-graphics application for model building and validation of biological macromolecules. The program displays electron-density maps and atomic models and allows model manipulations such as idealization, real-space refinement, manual rotation/translation, rigid-body fitting, ligand search, solvation, mutations, rotamers and Ramachandran idealization. Furthermore, tools are provided for model validation as well as interfaces to external programs for refinement, validation and graphics. The software is designed to be easy to learn for novice users, which is achieved by ensuring that tools for common tasks are 'discoverable' through familiar user-interface elements (menus and toolbars) or by intuitive behaviour (mouse controls). Recent developments have focused on providing tools for expert users, with customisable key bindings, extensions and an extensive scripting interface. The software is under rapid development, but has already achieved very widespread use within the crystallographic community. The current state of the software is presented, with a description of the facilities available and of some of the underlying methods employed.", + "authors": { + "abbreviation": "P Emsley, B Lohkamp, W G Scott, K Cowtan", + "authorList": [ + { + "ForeName": "P", + "LastName": "Emsley", + "abbrevName": "Emsley P", + "email": "paul.emsley@bioch.ox.ac.uk", + "isCollectiveName": false, + "name": "P Emsley" + }, + { + "ForeName": "B", + "LastName": "Lohkamp", + "abbrevName": "Lohkamp B", + "email": null, + "isCollectiveName": false, + "name": "B Lohkamp" + }, + { + "ForeName": "W", + "LastName": "Scott", + "abbrevName": "Scott WG", + "email": null, + "isCollectiveName": false, + "name": "W G Scott" + }, + { + "ForeName": "K", + "LastName": "Cowtan", + "abbrevName": "Cowtan K", + "email": null, + "isCollectiveName": false, + "name": "K Cowtan" + } + ], + "contacts": [ + { + "ForeName": "P", + "LastName": "Emsley", + "email": [ + "paul.emsley@bioch.ox.ac.uk" + ], + "name": "P Emsley" + } + ] + }, + "doi": "10.1107/S0907444910007493", + "pmid": "20383002", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 66 2010", + "title": "Features and development of Coot." + } + }, + { + "pmid": "20124692", + "pubmed": { + "ISODate": "2010-02-01T00:00:00.000Z", + "abstract": "The usage and control of recent modifications of the program package XDS for the processing of rotation images are described in the context of previous versions. New features include automatic determination of spot size and reflecting range and recognition and assignment of crystal symmetry. Moreover, the limitations of earlier package versions on the number of correction/scaling factors and the representation of pixel contents have been removed. Large program parts have been restructured for parallel processing so that the quality and completeness of collected data can be assessed soon after measurement.", + "authors": { + "abbreviation": "Wolfgang Kabsch", + "authorList": [ + { + "ForeName": "Wolfgang", + "LastName": "Kabsch", + "abbrevName": "Kabsch W", + "email": "wolfgang.kabsch@mpimf-heidelberg.mpg.de", + "isCollectiveName": false, + "name": "Wolfgang Kabsch" + } + ], + "contacts": [ + { + "ForeName": "Wolfgang", + "LastName": "Kabsch", + "email": [ + "wolfgang.kabsch@mpimf-heidelberg.mpg.de" + ], + "name": "Wolfgang Kabsch" + } + ] + }, + "doi": "10.1107/S0907444909047337", + "pmid": "20124692", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 66 2010", + "title": "XDS." + } + }, + { + "pmid": "20057044", + "pubmed": { + "ISODate": "2010-01-01T00:00:00.000Z", + "abstract": "MolProbity is a structure-validation web service that provides broad-spectrum solidly based evaluation of model quality at both the global and local levels for both proteins and nucleic acids. It relies heavily on the power and sensitivity provided by optimized hydrogen placement and all-atom contact analysis, complemented by updated versions of covalent-geometry and torsion-angle criteria. Some of the local corrections can be performed automatically in MolProbity and all of the diagnostics are presented in chart and graphical forms that help guide manual rebuilding. X-ray crystallography provides a wealth of biologically important molecular data in the form of atomic three-dimensional structures of proteins, nucleic acids and increasingly large complexes in multiple forms and states. Advances in automation, in everything from crystallization to data collection to phasing to model building to refinement, have made solving a structure using crystallography easier than ever. However, despite these improvements, local errors that can affect biological interpretation are widespread at low resolution and even high-resolution structures nearly all contain at least a few local errors such as Ramachandran outliers, flipped branched protein side chains and incorrect sugar puckers. It is critical both for the crystallographer and for the end user that there are easy and reliable methods to diagnose and correct these sorts of errors in structures. MolProbity is the authors' contribution to helping solve this problem and this article reviews its general capabilities, reports on recent enhancements and usage, and presents evidence that the resulting improvements are now beneficially affecting the global database.", + "authors": { + "abbreviation": "Vincent B Chen, W Bryan Arendall, Jeffrey J Headd, ..., David C Richardson", + "authorList": [ + { + "ForeName": "Vincent", + "LastName": "Chen", + "abbrevName": "Chen VB", + "email": null, + "isCollectiveName": false, + "name": "Vincent B Chen" + }, + { + "ForeName": "W", + "LastName": "Arendall", + "abbrevName": "Arendall WB", + "email": null, + "isCollectiveName": false, + "name": "W Bryan Arendall" + }, + { + "ForeName": "Jeffrey", + "LastName": "Headd", + "abbrevName": "Headd JJ", + "email": null, + "isCollectiveName": false, + "name": "Jeffrey J Headd" + }, + { + "ForeName": "Daniel", + "LastName": "Keedy", + "abbrevName": "Keedy DA", + "email": null, + "isCollectiveName": false, + "name": "Daniel A Keedy" + }, + { + "ForeName": "Robert", + "LastName": "Immormino", + "abbrevName": "Immormino RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Immormino" + }, + { + "ForeName": "Gary", + "LastName": "Kapral", + "abbrevName": "Kapral GJ", + "email": null, + "isCollectiveName": false, + "name": "Gary J Kapral" + }, + { + "ForeName": "Laura", + "LastName": "Murray", + "abbrevName": "Murray LW", + "email": null, + "isCollectiveName": false, + "name": "Laura W Murray" + }, + { + "ForeName": "Jane", + "LastName": "Richardson", + "abbrevName": "Richardson JS", + "email": null, + "isCollectiveName": false, + "name": "Jane S Richardson" + }, + { + "ForeName": "David", + "LastName": "Richardson", + "abbrevName": "Richardson DC", + "email": null, + "isCollectiveName": false, + "name": "David C Richardson" + } + ], + "contacts": [] + }, + "doi": "10.1107/S0907444909042073", + "pmid": "20057044", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 66 2010", + "title": "MolProbity: all-atom structure validation for macromolecular crystallography." + } + }, + { + "pmid": "19461840", + "pubmed": { + "ISODate": "2007-08-01T00:00:00.000Z", + "abstract": "Phaser is a program for phasing macromolecular crystal structures by both molecular replacement and experimental phasing methods. The novel phasing algorithms implemented in Phaser have been developed using maximum likelihood and multivariate statistics. For molecular replacement, the new algorithms have proved to be significantly better than traditional methods in discriminating correct solutions from noise, and for single-wavelength anomalous dispersion experimental phasing, the new algorithms, which account for correlations between F(+) and F(-), give better phases (lower mean phase error with respect to the phases given by the refined structure) than those that use mean F and anomalous differences DeltaF. One of the design concepts of Phaser was that it be capable of a high degree of automation. To this end, Phaser (written in C++) can be called directly from Python, although it can also be called using traditional CCP4 keyword-style input. Phaser is a platform for future development of improved phasing methods and their release, including source code, to the crystallographic community.", + "authors": { + "abbreviation": "Airlie J McCoy, Ralf W Grosse-Kunstleve, Paul D Adams, ..., Randy J Read", + "authorList": [ + { + "ForeName": "Airlie", + "LastName": "McCoy", + "abbrevName": "McCoy AJ", + "email": null, + "isCollectiveName": false, + "name": "Airlie J McCoy" + }, + { + "ForeName": "Ralf", + "LastName": "Grosse-Kunstleve", + "abbrevName": "Grosse-Kunstleve RW", + "email": null, + "isCollectiveName": false, + "name": "Ralf W Grosse-Kunstleve" + }, + { + "ForeName": "Paul", + "LastName": "Adams", + "abbrevName": "Adams PD", + "email": null, + "isCollectiveName": false, + "name": "Paul D Adams" + }, + { + "ForeName": "Martyn", + "LastName": "Winn", + "abbrevName": "Winn MD", + "email": null, + "isCollectiveName": false, + "name": "Martyn D Winn" + }, + { + "ForeName": "Laurent", + "LastName": "Storoni", + "abbrevName": "Storoni LC", + "email": null, + "isCollectiveName": false, + "name": "Laurent C Storoni" + }, + { + "ForeName": "Randy", + "LastName": "Read", + "abbrevName": "Read RJ", + "email": null, + "isCollectiveName": false, + "name": "Randy J Read" + } + ], + "contacts": [] + }, + "doi": "10.1107/S0021889807021206", + "pmid": "19461840", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Appl Crystallogr 40 2007", + "title": "Phaser crystallographic software." + } + }, + { + "pmid": "18342854", + "pubmed": { + "ISODate": "2008-05-01T00:00:00.000Z", + "abstract": "The type VI intermediate filament (IF) protein synemin is a unique member of the IF protein superfamily. Synemin associates with the major type III IF protein desmin forming heteropolymeric intermediate filaments (IFs) within developed mammalian striated muscle cells. These IFs encircle and link all adjacent myofibrils together at their Z-lines, as well as link the Z-lines of the peripheral layer of cellular myofibrils to the costameres located periodically along and subjacent to the sarcolemma. Costameres are multi-protein assemblies enriched in the cytoskeletal proteins vinculin, alpha-actinin, and talin. We report herein a direct interaction of human alpha-synemin with the cytoskeletal protein talin by protein-protein interaction assays. The 312 amino acid insert (SNTIII) present only within alpha-synemin binds to the rod domain of talin in vitro and co-localizes with talin at focal adhesion sites within mammalian muscle cells. Confocal microscopy studies showed that synemin co-localizes with talin within the costameres of human skeletal muscle cells. Analysis of the primary sequences of human alpha- and beta-synemins revealed that SNTIII is composed of seven tandem repeats, each containing a specific Ser/Thr-X-Arg-His/Gln (S/T-X-R-H/Q) motif. Our results suggest human alpha-synemin plays an essential role in linking the heteropolymeric IFs to adherens-type junctions, such as the costameres within mammalian striated muscle cells, via its interaction with talin, thereby helping provide mechanical integration for the muscle cell cytoskeleton.", + "authors": { + "abbreviation": "Ning Sun, David R Critchley, Denise Paulin, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ning", + "LastName": "Sun", + "abbrevName": "Sun N", + "email": null, + "isCollectiveName": false, + "name": "Ning Sun" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Denise", + "LastName": "Paulin", + "abbrevName": "Paulin D", + "email": null, + "isCollectiveName": false, + "name": "Denise Paulin" + }, + { + "ForeName": "Zhenlin", + "LastName": "Li", + "abbrevName": "Li Z", + "email": null, + "isCollectiveName": false, + "name": "Zhenlin Li" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.yexcr.2008.01.034", + "pmid": "18342854", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Exp Cell Res 314 2008", + "title": "Identification of a repeated domain within mammalian alpha-synemin that interacts directly with talin." + } + }, + { + "pmid": "18094476", + "pubmed": { + "ISODate": "2008-01-01T00:00:00.000Z", + "abstract": "The number of macromolecular structures solved and deposited in the Protein Data Bank (PDB) is higher than 40 000. Using this information in macromolecular crystallography (MX) should in principle increase the efficiency of MX structure solution. This paper describes a molecular-replacement pipeline, BALBES, that makes extensive use of this repository. It uses a reorganized database taken from the PDB with multimeric as well as domain organization. A system manager written in Python controls the workflow of the process. Testing the current version of the pipeline using entries from the PDB has shown that this approach has huge potential and that around 75% of structures can be solved automatically without user intervention.", + "authors": { + "abbreviation": "Fei Long, Alexei A Vagin, Paul Young, Garib N Murshudov", + "authorList": [ + { + "ForeName": "Fei", + "LastName": "Long", + "abbrevName": "Long F", + "email": null, + "isCollectiveName": false, + "name": "Fei Long" + }, + { + "ForeName": "Alexei", + "LastName": "Vagin", + "abbrevName": "Vagin AA", + "email": null, + "isCollectiveName": false, + "name": "Alexei A Vagin" + }, + { + "ForeName": "Paul", + "LastName": "Young", + "abbrevName": "Young P", + "email": null, + "isCollectiveName": false, + "name": "Paul Young" + }, + { + "ForeName": "Garib", + "LastName": "Murshudov", + "abbrevName": "Murshudov GN", + "email": null, + "isCollectiveName": false, + "name": "Garib N Murshudov" + } + ], + "contacts": [] + }, + "doi": "10.1107/S0907444907050172", + "pmid": "18094476", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Acta Crystallogr D Biol Crystallogr 64 2008", + "title": "BALBES: a molecular-replacement pipeline." + } + }, + { + "pmid": "17712139", + "pubmed": { + "ISODate": "2007-08-21T00:00:00.000Z", + "abstract": "Filopodia are actin-based structures composed of parallel bundles of actin filaments and various actin-associated proteins, and they play important roles in cell-cell signaling, guidance toward chemoattractants, and adhesion to the extracellular matrix. Two mechanisms for the formation of filopodia have been suggested, each using different sets of actin-regulating proteins, creating some controversy in the field. New molecules, some of unknown functions, have also been implicated in filopodium formation, suggesting that other possible mechanisms of filopodium formation exist. We discuss established and novel proteins that mediate the formation and dynamics of filopodia, different mechanisms of filopodium formation, and the various functions that distinct filopodia perform.", + "authors": { + "abbreviation": "Stephanie L Gupton, Frank B Gertler", + "authorList": [ + { + "ForeName": "Stephanie", + "LastName": "Gupton", + "abbrevName": "Gupton SL", + "email": "gupton@mit.edu", + "isCollectiveName": false, + "name": "Stephanie L Gupton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + } + ], + "contacts": [ + { + "ForeName": "Stephanie", + "LastName": "Gupton", + "email": [ + "gupton@mit.edu" + ], + "name": "Stephanie L Gupton" + } + ] + }, + "doi": "10.1126/stke.4002007re5", + "pmid": "17712139", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Sci STKE 2007 2007", + "title": "Filopodia: the fingers that do the walking." + } + }, + { + "pmid": "17681537", + "pubmed": { + "ISODate": "2007-09-21T00:00:00.000Z", + "abstract": "We discuss basic physical-chemical principles underlying the formation of stable macromolecular complexes, which in many cases are likely to be the biological units performing a certain physiological function. We also consider available theoretical approaches to the calculation of macromolecular affinity and entropy of complexation. The latter is shown to play an important role and make a major effect on complex size and symmetry. We develop a new method, based on chemical thermodynamics, for automatic detection of macromolecular assemblies in the Protein Data Bank (PDB) entries that are the results of X-ray diffraction experiments. As found, biological units may be recovered at 80-90% success rate, which makes X-ray crystallography an important source of experimental data on macromolecular complexes and protein-protein interactions. The method is implemented as a public WWW service.", + "authors": { + "abbreviation": "Evgeny Krissinel, Kim Henrick", + "authorList": [ + { + "ForeName": "Evgeny", + "LastName": "Krissinel", + "abbrevName": "Krissinel E", + "email": null, + "isCollectiveName": false, + "name": "Evgeny Krissinel" + }, + { + "ForeName": "Kim", + "LastName": "Henrick", + "abbrevName": "Henrick K", + "email": null, + "isCollectiveName": false, + "name": "Kim Henrick" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2007.05.022", + "pmid": "17681537", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 372 2007", + "title": "Inference of macromolecular assemblies from crystalline state." + } + }, + { + "pmid": "12581525", + "pubmed": { + "ISODate": "2003-02-07T00:00:00.000Z", + "abstract": "Specification of embryonic polarity and pattern formation in multicellular organisms requires inductive signals from neighboring cells. One approach toward understanding these interactions is to study mutations that disrupt development. Here, we demonstrate that mesd, a gene identified in the mesoderm development (mesd) deletion interval on mouse chromosome 7, is essential for specification of embryonic polarity and mesoderm induction. MESD functions in the endoplasmic reticulum as a specific chaperone for LRP5 and LRP6, which in conjunction with Frizzled, are coreceptors for canonical WNT signal transduction. Disruption of embryonic polarity and mesoderm differentiation in mesd-deficient embryos likely results from a primary defect in WNT signaling. However, phenotypic differences between mesd-deficient and wnt3(-)(/)(-) embryos suggest that MESD may function on related members of the low-density lipoprotein receptor (LDLR) family, whose members mediate diverse cellular processes ranging from cargo transport to signaling.", + "authors": { + "abbreviation": "Jen-Chih Hsieh, Lance Lee, Liqun Zhang, ..., Bernadette C Holdener", + "authorList": [ + { + "ForeName": "Jen-Chih", + "LastName": "Hsieh", + "abbrevName": "Hsieh JC", + "email": null, + "isCollectiveName": false, + "name": "Jen-Chih Hsieh" + }, + { + "ForeName": "Lance", + "LastName": "Lee", + "abbrevName": "Lee L", + "email": null, + "isCollectiveName": false, + "name": "Lance Lee" + }, + { + "ForeName": "Liqun", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "Liqun Zhang" + }, + { + "ForeName": "Stephen", + "LastName": "Wefer", + "abbrevName": "Wefer S", + "email": null, + "isCollectiveName": false, + "name": "Stephen Wefer" + }, + { + "ForeName": "Kristen", + "LastName": "Brown", + "abbrevName": "Brown K", + "email": null, + "isCollectiveName": false, + "name": "Kristen Brown" + }, + { + "ForeName": "Charles", + "LastName": "DeRossi", + "abbrevName": "DeRossi C", + "email": null, + "isCollectiveName": false, + "name": "Charles DeRossi" + }, + { + "ForeName": "Mary", + "LastName": "Wines", + "abbrevName": "Wines ME", + "email": null, + "isCollectiveName": false, + "name": "Mary E Wines" + }, + { + "ForeName": "Thomas", + "LastName": "Rosenquist", + "abbrevName": "Rosenquist T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Rosenquist" + }, + { + "ForeName": "Bernadette", + "LastName": "Holdener", + "abbrevName": "Holdener BC", + "email": null, + "isCollectiveName": false, + "name": "Bernadette C Holdener" + } + ], + "contacts": [] + }, + "doi": "10.1016/s0092-8674(03)00045-x", + "pmid": "12581525", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Cell 112 2003", + "title": "Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity." + } + }, + { + "pmid": "11247670", + "pubmed": { + "ISODate": "2001-02-15T00:00:00.000Z", + "abstract": "The proximal albino deletions identify several functional regions on mouse Chromosome 7 critical for differentiation of mesoderm (mesd), development of the hypothalamus neuroendocrine lineage (nelg), and function of the liver (hsdr1). Using comparative mapping and genomic sequence analysis, we have identified four novel genes and Il16 in the mesd deletion interval. Two of the novel genes, mesdc1 and mesdc2, are located within the mesd critical region defined by BAC transgenic rescue. We have investigated the fetal role of genes located outside the mesd critical region using BAC transgenic complementation of the mesd early embryonic lethality. Using human radiation hybrid mapping and BAC contig construction, we have identified a conserved region of human chromosome 15 homologous to the mesd, nelg, and hsdr1 functional regions. Three human diseases cosegregate with microsatellite markers used in construction of the human BAC/YAC physical map, including autosomal dominant nocturnal frontal lobe epilepsy (ENFL2; also known as ADNFLE), a syndrome of mental retardation, spasticity, and tapetoretinal degeneration (MRST); and a pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA).", + "authors": { + "abbreviation": "M E Wines, L Lee, M S Katari, ..., B C Holdener", + "authorList": [ + { + "ForeName": "M", + "LastName": "Wines", + "abbrevName": "Wines ME", + "email": null, + "isCollectiveName": false, + "name": "M E Wines" + }, + { + "ForeName": "L", + "LastName": "Lee", + "abbrevName": "Lee L", + "email": null, + "isCollectiveName": false, + "name": "L Lee" + }, + { + "ForeName": "M", + "LastName": "Katari", + "abbrevName": "Katari MS", + "email": null, + "isCollectiveName": false, + "name": "M S Katari" + }, + { + "ForeName": "L", + "LastName": "Zhang", + "abbrevName": "Zhang L", + "email": null, + "isCollectiveName": false, + "name": "L Zhang" + }, + { + "ForeName": "C", + "LastName": "DeRossi", + "abbrevName": "DeRossi C", + "email": null, + "isCollectiveName": false, + "name": "C DeRossi" + }, + { + "ForeName": "Y", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Y Shi" + }, + { + "ForeName": "S", + "LastName": "Perkins", + "abbrevName": "Perkins S", + "email": null, + "isCollectiveName": false, + "name": "S Perkins" + }, + { + "ForeName": "M", + "LastName": "Feldman", + "abbrevName": "Feldman M", + "email": null, + "isCollectiveName": false, + "name": "M Feldman" + }, + { + "ForeName": "W", + "LastName": "McCombie", + "abbrevName": "McCombie WR", + "email": null, + "isCollectiveName": false, + "name": "W R McCombie" + }, + { + "ForeName": "B", + "LastName": "Holdener", + "abbrevName": "Holdener BC", + "email": null, + "isCollectiveName": false, + "name": "B C Holdener" + } + ], + "contacts": [] + }, + "doi": "10.1006/geno.2000.6466", + "pmid": "11247670", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Genomics 72 2001", + "title": "Identification of mesoderm development (mesd) candidate genes by comparative mapping and genome sequence analysis." + } + }, + { + "pmid": "8937989", + "pubmed": { + "ISODate": "1996-11-01T00:00:00.000Z", + "abstract": "We have determined the sequence of chicken talin (2,541 amino acids, M(r) 271,881) which is very similar (89% identity) to that of the mouse protein. Alignments with the Caenorhabditis elegans and Dictyostelium discoideum talin sequences show that the N- and C-terminal regions of the protein are conserved whereas the central part of the molecule is more divergent. By expressing overlapping talin polypeptides as fusion proteins, we have identified at least three regions of the protein which can bind F-actin: residues 102-497, 951-1,327 and 2,269-2,541. The N-terminal binding site contains a region with homology to the ERM family of actin-binding proteins, and the C-terminal site is homologous to the yeast actin-binding protein Sla2p. Each of the actin-binding sites is close to, but distinct from a binding site for vinculin, a protein which also binds actin. The Pro1176 to Thr substitution found in talin from Wistar-Furth rats does not destroy the capacity of this region of the protein to bind actin or vinculin. Microinjection studies showed that a fusion protein containing the N-terminal actin-binding site localised weakly to stress fibres, whereas one containing the C-terminal site initially localised predominantly to focal adhesions. The former was readily solubilised, and the latter was resistant to Triton extraction. The N-terminal talin polypeptide eventually disrupted actin stress fibres whereas the C-terminal polypeptide was without effect. However, a larger C-terminal fusion protein also containing a vinculin-binding site did disrupt stress fibres and focal adhesions. The results suggest that, although both the N- and C-terminal regions of talin bind actin, the properties of these two regions of the protein are distinct.", + "authors": { + "abbreviation": "L Hemmings, D J Rees, V Ohanian, ..., D R Critchley", + "authorList": [ + { + "ForeName": "L", + "LastName": "Hemmings", + "abbrevName": "Hemmings L", + "email": null, + "isCollectiveName": false, + "name": "L Hemmings" + }, + { + "ForeName": "D", + "LastName": "Rees", + "abbrevName": "Rees DJ", + "email": null, + "isCollectiveName": false, + "name": "D J Rees" + }, + { + "ForeName": "V", + "LastName": "Ohanian", + "abbrevName": "Ohanian V", + "email": null, + "isCollectiveName": false, + "name": "V Ohanian" + }, + { + "ForeName": "S", + "LastName": "Bolton", + "abbrevName": "Bolton SJ", + "email": null, + "isCollectiveName": false, + "name": "S J Bolton" + }, + { + "ForeName": "A", + "LastName": "Gilmore", + "abbrevName": "Gilmore AP", + "email": null, + "isCollectiveName": false, + "name": "A P Gilmore" + }, + { + "ForeName": "B", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "B Patel" + }, + { + "ForeName": "H", + "LastName": "Priddle", + "abbrevName": "Priddle H", + "email": null, + "isCollectiveName": false, + "name": "H Priddle" + }, + { + "ForeName": "J", + "LastName": "Trevithick", + "abbrevName": "Trevithick JE", + "email": null, + "isCollectiveName": false, + "name": "J E Trevithick" + }, + { + "ForeName": "R", + "LastName": "Hynes", + "abbrevName": "Hynes RO", + "email": null, + "isCollectiveName": false, + "name": "R O Hynes" + }, + { + "ForeName": "D", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "D R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1242/jcs.109.11.2715", + "pmid": "8937989", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Cell Sci 109 ( Pt 11) 1996", + "title": "Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site." + } + }, + { + "pmid": "8026341", + "pubmed": { + "ISODate": "1994-05-01T00:00:00.000Z", + "abstract": "Mesoderm induction is fundamental for establishing the basic body plan of the vertebrate embryo and mutations are critical for dissecting this process. Mouse embryos lacking msd (mesoderm deficiency) do not produce mesoderm but have well-defined extraembryonic and thickened embryonic ectoderm. Distribution of transcripts indicate that temporal regulation of gene expression relevant to gastrulation has begun but primitive-streak formation and mesoderm induction are blocked. Both msd-deficient embryos and embryonic stem (ES) cells fail to form highly differentiated structures of mesoderm origin, but are capable of ectodermal differentiation. Thus, the effects of the msd mutation are restricted to mesoderm formation and could result from the inability to respond to an inducing signal.", + "authors": { + "abbreviation": "B C Holdener, C Faust, N S Rosenthal, T Magnuson", + "authorList": [ + { + "ForeName": "B", + "LastName": "Holdener", + "abbrevName": "Holdener BC", + "email": null, + "isCollectiveName": false, + "name": "B C Holdener" + }, + { + "ForeName": "C", + "LastName": "Faust", + "abbrevName": "Faust C", + "email": null, + "isCollectiveName": false, + "name": "C Faust" + }, + { + "ForeName": "N", + "LastName": "Rosenthal", + "abbrevName": "Rosenthal NS", + "email": null, + "isCollectiveName": false, + "name": "N S Rosenthal" + }, + { + "ForeName": "T", + "LastName": "Magnuson", + "abbrevName": "Magnuson T", + "email": null, + "isCollectiveName": false, + "name": "T Magnuson" + } + ], + "contacts": [] + }, + "doi": "10.1242/dev.120.5.1335", + "pmid": "8026341", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Development 120 1994", + "title": "msd is required for mesoderm induction in mice." + } + }, + { + "pmid": "4254541", + "pubmed": { + "ISODate": "1971-08-10T00:00:00.000Z", + "abstract": null, + "authors": { + "abbreviation": "J A Spudich, S Watt", + "authorList": [ + { + "ForeName": "J", + "LastName": "Spudich", + "abbrevName": "Spudich JA", + "email": null, + "isCollectiveName": false, + "name": "J A Spudich" + }, + { + "ForeName": "S", + "LastName": "Watt", + "abbrevName": "Watt S", + "email": null, + "isCollectiveName": false, + "name": "S Watt" + } + ], + "contacts": [] + }, + "doi": null, + "pmid": "4254541", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Biol Chem 246 1971", + "title": "The regulation of rabbit skeletal muscle contraction. I. Biochemical studies of the interaction of the tropomyosin-troponin complex with actin and the proteolytic fragments of myosin." + } + } + ], + "relatedPapers": [ + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + } + ], + "relatedPapersNotified": true, + "secret": "read-only", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": "2022-02-02T16:01:31.836Z", + "_newestOpId": "ec9ee9d5-9bec-49a8-b10b-fac79b54f795", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "609036" + }, + { + "db": "HGNC", + "id": "HGNC:17379" + }, + { + "db": "Ensembl", + "id": "ENSG00000077420" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.754701, + "id": "54518", + "name": "APBB1IP", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100, + "shortSynonyms": [ + "APBB1IP", + "INAG1", + "PREL1", + "RARP1", + "RIAM", + "amyloid beta A4 precursor protein-binding family B member 1-interacting protein", + "proline-rich protein 73", + "proline rich EVH1 ligand 1", + "retinoic acid-responsive proline-rich protein 1", + "amyloid beta precursor protein binding family B member 1 interacting protein", + "RARP-1" + ], + "synonyms": [ + "INAG1", + "PREL1", + "RARP1", + "RIAM", + "amyloid beta A4 precursor protein-binding family B member 1-interacting protein", + "APBB1-interacting protein 1", + "PREL-1", + "RARP-1", + "Rap1-GTP-interacting adaptor molecule", + "Rap1-interacting adaptor molecule", + "proline rich EVH1 ligand 1", + "proline-rich protein 73", + "rap1-GTP-interacting adapter molecule", + "retinoic acid-responsive proline-rich protein 1", + "amyloid beta precursor protein binding family B member 1 interacting protein" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "5e0f15cf-4601-4f69-bbe4-72c13d745cd0", + "liveId": "9ad3b888-3cf1-4e9f-b024-cb3678e4e293", + "lock": null, + "locked": false, + "name": "RIAM", + "position": { + "x": 177.7215189873418, + "y": 174.68354430379745 + }, + "relatedPapers": [ + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T16:03:49.791Z", + "_newestOpId": "05dc5ecd-ddd9-4c3d-b256-2a178e489930", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "93986510-92f8-45bd-a3f3-0eab34305361" + }, + { + "group": "unsigned", + "id": "401d53b5-520c-419c-84c4-b44829b8c259" + } + ], + "id": "e59c16c4-11e8-4755-8e2f-f88fe4a73b30", + "liveId": "1d5a96d8-edb6-468f-ac94-a82df9ed3010", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T16:02:27.426Z", + "_newestOpId": "68c0bcd2-97c8-4e51-af08-6b4fbc2d7332", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "d38e87a9-a2ad-43f2-a026-63803cdd8120" + }, + { + "group": "unsigned", + "id": "93986510-92f8-45bd-a3f3-0eab34305361" + } + ], + "id": "13ab91d1-ee5f-46ca-a1ea-82ce72a938f4", + "liveId": "4e38eba5-da40-44b2-b21e-e2db469a1414", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T16:01:50.310Z", + "_newestOpId": "9392c9cb-55db-4574-bd3e-e537753ae1d8", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "607704" + }, + { + "db": "HGNC", + "id": "HGNC:19309" + }, + { + "db": "Ensembl", + "id": "ENSG00000107104" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.754701, + "id": "23189", + "name": "KANK1", + "nameDistance": 0.1428571428571429, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 14, + "shortSynonyms": [ + "KANK1", + "ANKRD15", + "CPSQ2", + "KANK", + "KN motif and ankyrin repeat domain-containing protein 1", + "ankyrin repeat domain-containing protein 15", + "kidney ankyrin repeat-containing protein", + "KN motif and ankyrin repeat domains 1" + ], + "synonyms": [ + "ANKRD15", + "CPSQ2", + "KANK", + "KN motif and ankyrin repeat domain-containing protein 1", + "ankyrin repeat domain-containing protein 15", + "kidney ankyrin repeat-containing protein", + "KN motif and ankyrin repeat domains 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "0ce40cac-ced5-4b88-ba29-cd754a61937e", + "liveId": "c493b4bc-204a-432c-be65-414233d4551a", + "lock": null, + "locked": false, + "name": "KANK", + "position": { + "x": 92.15189873417721, + "y": 162.53164556962025 + }, + "relatedPapers": [ + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T16:03:13.218Z", + "_newestOpId": "902efbb3-0c65-4e15-8633-0bd60495359d", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "609035" + }, + { + "db": "HGNC", + "id": "HGNC:14436" + }, + { + "db": "Ensembl", + "id": "ENSG00000173166" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.754701, + "formulae": null, + "id": "65059", + "mass": null, + "monoisotopicMass": null, + "name": "RAPH1", + "nameDistance": 1, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 100, + "shortSynonyms": [ + "RAPH1", + "ALS2CR18", + "ALS2CR9", + "LPD", + "PREL-2", + "PREL2", + "lamellipodin", + "proline-rich EVH1 ligand 2", + "amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 9", + "amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 18", + "Ras association (RalGDS/AF-6) and pleckstrin homology domains 1" + ], + "summary": null, + "synonyms": [ + "ALS2CR18", + "ALS2CR9", + "LPD", + "PREL-2", + "PREL2", + "RMO1", + "RalGDS/AF-6", + "ras-associated and pleckstrin homology domains-containing protein 1", + "amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 18", + "amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 9", + "lamellipodin", + "proline-rich EVH1 ligand 2", + "Ras association (RalGDS/AF-6) and pleckstrin homology domains 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "401d53b5-520c-419c-84c4-b44829b8c259", + "liveId": "a0a3d8d3-e6fd-451e-8b2d-07e04c6161f9", + "lock": null, + "locked": false, + "name": "Lamellipodin", + "position": { + "x": 265.82278481012656, + "y": 184.30379746835442 + }, + "relatedPapers": [ + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T16:00:22.462Z", + "_newestOpId": "a6f87406-9b7a-4ec5-9916-55624d169685", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "615466" + }, + { + "db": "HGNC", + "id": "HGNC:13519" + }, + { + "db": "Ensembl", + "id": "ENSG00000140406" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.863279, + "id": "59274", + "name": "TLNRD1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "MESDC1", + "talin rod domain-containing protein 1", + "mesoderm development candidate 1", + "talin rod domain containing 1" + ], + "synonyms": [ + "MESDC1", + "talin rod domain-containing protein 1", + "mesoderm development candidate 1", + "talin rod domain containing 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "93986510-92f8-45bd-a3f3-0eab34305361", + "liveId": "ca22c58f-b0c7-4d73-a3b3-5de8200f686a", + "lock": null, + "locked": false, + "name": "TLNRD1", + "position": { + "x": 174.68354430379748, + "y": 91.13924050632912 + }, + "relatedPapers": [ + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T16:00:38.198Z", + "_newestOpId": "38f1babd-2233-4534-b7b1-f6cbf2213b37", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "102630" + }, + { + "db": "HGNC", + "id": "HGNC:132" + }, + { + "db": "Ensembl", + "id": "ENSG00000075624" + } + ], + "defaultOrganismIndex": 2, + "distance": 0.11111111111111116, + "esScore": 8.835306, + "formulae": null, + "id": "60", + "inchi": null, + "inchiKey": null, + "mass": null, + "monoisotopicMass": null, + "name": "ACTB", + "nameDistance": 0.4285714285714286, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 1100000043, + "shortSynonyms": [ + "ACTB", + "BRWS1", + "PS1TP5BP1", + "actin, cytoplasmic 1", + "I(2)-actin", + "PS1TP5-binding protein 1", + "beta cytoskeletal actin", + "actin beta" + ], + "summary": null, + "synonyms": [ + "BRWS1", + "PS1TP5BP1", + "actin, cytoplasmic 1", + "I(2)-actin", + "PS1TP5-binding protein 1", + "beta cytoskeletal actin", + "actin beta" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "d4a6eb78-7ac4-44eb-8257-c553e82b4ca3", + "liveId": "b450be99-9a93-491a-9f36-2828762de954", + "lock": null, + "locked": false, + "name": "Actin", + "position": { + "x": 254.68354430379742, + "y": 98.73417721518987 + }, + "relatedPapers": [ + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T16:01:22.161Z", + "_newestOpId": "e63bdafb-74fc-4b04-9ac3-15d3ed23a6e8", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "93986510-92f8-45bd-a3f3-0eab34305361" + }, + { + "group": "unsigned", + "id": "d4a6eb78-7ac4-44eb-8257-c553e82b4ca3" + } + ], + "id": "d5d9fbcc-a1d9-4026-b1d3-d4a97faff36b", + "liveId": "26b8df2a-2222-4e5c-a502-e51a861c8aaa", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T16:03:40.868Z", + "_newestOpId": "536ea4c5-b48f-48d8-86f8-54ed639d9dcb", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "93986510-92f8-45bd-a3f3-0eab34305361" + }, + { + "group": "unsigned", + "id": "5e0f15cf-4601-4f69-bbe4-72c13d745cd0" + } + ], + "id": "eec84ebe-eece-4143-b406-cd99cdbe2e43", + "liveId": "a0b66709-b5f4-462f-959b-94d028ca424f", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 60.75949367088607, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + } + ], + "secret": "read-only", + "type": "binding" + }, + { + "_creationTimestamp": "2022-02-02T16:02:13.920Z", + "_newestOpId": "2ac35ba3-07cd-458b-8aa8-141818bcae04", + "_ops": [], + "association": { + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "615466" + }, + { + "db": "HGNC", + "id": "HGNC:13519" + }, + { + "db": "Ensembl", + "id": "ENSG00000140406" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.863279, + "id": "59274", + "name": "TLNRD1", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 0, + "shortSynonyms": [ + "MESDC1", + "talin rod domain-containing protein 1", + "mesoderm development candidate 1", + "talin rod domain containing 1" + ], + "synonyms": [ + "MESDC1", + "talin rod domain-containing protein 1", + "mesoderm development candidate 1", + "talin rod domain containing 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "d38e87a9-a2ad-43f2-a026-63803cdd8120", + "liveId": "9196b8e5-8a22-4057-8d35-f41ab500c0a9", + "lock": null, + "locked": false, + "name": "TLNRD1", + "position": { + "x": 81.01265822784809, + "y": 82.02531645569618 + }, + "relatedPapers": [ + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + } + ], + "secret": "read-only", + "type": "protein" + }, + { + "_creationTimestamp": "2022-02-02T16:03:34.548Z", + "_newestOpId": "8cbfb11b-bfe3-44c1-8929-f43171c9f372", + "_ops": [], + "association": "binding", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "93986510-92f8-45bd-a3f3-0eab34305361" + }, + { + "group": "unsigned", + "id": "0ce40cac-ced5-4b88-ba29-cd754a61937e" + } + ], + "id": "d7b2a15d-43bf-4494-815b-a77e08cea59c", + "liveId": "7756d3e0-d98f-42bb-a508-368e3c322d3b", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": 55.69620253164557, + "y": 60.75949367088607 + }, + "relatedPapers": [ + { + "pmid": "29760438", + "pubmed": { + "ISODate": "2018-05-14T00:00:00.000Z", + "abstract": "Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on \"re-charging\" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers.", + "authors": { + "abbreviation": "Tommi Kotila, Konstantin Kogan, Giray Enkavi, ..., Pekka Lappalainen", + "authorList": [ + { + "ForeName": "Tommi", + "LastName": "Kotila", + "abbrevName": "Kotila T", + "email": null, + "isCollectiveName": false, + "name": "Tommi Kotila" + }, + { + "ForeName": "Konstantin", + "LastName": "Kogan", + "abbrevName": "Kogan K", + "email": null, + "isCollectiveName": false, + "name": "Konstantin Kogan" + }, + { + "ForeName": "Giray", + "LastName": "Enkavi", + "abbrevName": "Enkavi G", + "email": null, + "isCollectiveName": false, + "name": "Giray Enkavi" + }, + { + "ForeName": "Siyang", + "LastName": "Guo", + "abbrevName": "Guo S", + "email": null, + "isCollectiveName": false, + "name": "Siyang Guo" + }, + { + "ForeName": "Ilpo", + "LastName": "Vattulainen", + "abbrevName": "Vattulainen I", + "email": null, + "isCollectiveName": false, + "name": "Ilpo Vattulainen" + }, + { + "ForeName": "Bruce", + "LastName": "Goode", + "abbrevName": "Goode BL", + "email": null, + "isCollectiveName": false, + "name": "Bruce L Goode" + }, + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "abbrevName": "Lappalainen P", + "email": "pekka.lappalainen@helsinki.fi", + "isCollectiveName": false, + "name": "Pekka Lappalainen" + } + ], + "contacts": [ + { + "ForeName": "Pekka", + "LastName": "Lappalainen", + "email": [ + "pekka.lappalainen@helsinki.fi" + ], + "name": "Pekka Lappalainen" + } + ] + }, + "doi": "10.1038/s41467-018-04231-7", + "pmid": "29760438", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 9 2018", + "title": "Structural basis of actin monomer re-charging by cyclase-associated protein." + } + }, + { + "pmid": "33453188", + "pubmed": { + "ISODate": "2021-03-05T00:00:00.000Z", + "abstract": "The folding of disulfide bond containing proteins in the endoplasmic reticulum (ER) is a complex process that requires protein folding factors, some of which are protein-specific. The ER resident saposin-like protein pERp1 (MZB1, CNPY5) is crucial for the correct folding of IgA, IgM and integrins. pERp1 also plays a role in ER calcium homeostasis and plasma cell mobility. As an important factor for proper IgM maturation and hence immune function, pERp1 is upregulated in many auto-immune diseases. This makes it a potential therapeutic target. pERp1 belongs to the CNPY family of ER resident saposin-like proteins. To date, five of these proteins have been identified. All are implicated in protein folding and all contain a saposin-like domain. All previously structurally characterized saposins are involved in lipid binding. However, there are no reports of CNPY family members interacting with lipids, suggesting a novel function for the saposin fold. However, the molecular mechanisms of their function remain elusive. To date, no structure of any CNPY protein has been reported. Here, we present the high-resolution (1.4 Å) crystal structure of human pERp1 and confirm that it has a saposin-fold with unique structural elements not present in other saposin-fold structures. The implications for the role of CNPY proteins in protein folding in the ER are discussed.", + "authors": { + "abbreviation": "Sven T Sowa, Antti Moilanen, Ekaterina Biterova, ..., Lloyd W Ruddock", + "authorList": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "abbrevName": "Sowa ST", + "email": "sven.sowa@oulu.fi", + "isCollectiveName": false, + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "abbrevName": "Moilanen A", + "email": "antti.moilanen@oulu.fi", + "isCollectiveName": false, + "name": "Antti Moilanen" + }, + { + "ForeName": "Ekaterina", + "LastName": "Biterova", + "abbrevName": "Biterova E", + "email": null, + "isCollectiveName": false, + "name": "Ekaterina Biterova" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "abbrevName": "Saaranen MJ", + "email": "mirva.saaranen@oulu.fi", + "isCollectiveName": false, + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "abbrevName": "Lehtiö L", + "email": "lari.lehtio@oulu.fi", + "isCollectiveName": false, + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "abbrevName": "Ruddock LW", + "email": "lloyd.ruddock@oulu.fi", + "isCollectiveName": false, + "name": "Lloyd W Ruddock" + } + ], + "contacts": [ + { + "ForeName": "Sven", + "LastName": "Sowa", + "email": [ + "sven.sowa@oulu.fi" + ], + "name": "Sven T Sowa" + }, + { + "ForeName": "Antti", + "LastName": "Moilanen", + "email": [ + "antti.moilanen@oulu.fi" + ], + "name": "Antti Moilanen" + }, + { + "ForeName": "Mirva", + "LastName": "Saaranen", + "email": [ + "mirva.saaranen@oulu.fi" + ], + "name": "Mirva J Saaranen" + }, + { + "ForeName": "Lari", + "LastName": "Lehtiö", + "email": [ + "lari.lehtio@oulu.fi" + ], + "name": "Lari Lehtiö" + }, + { + "ForeName": "Lloyd", + "LastName": "Ruddock", + "email": [ + "lloyd.ruddock@oulu.fi" + ], + "name": "Lloyd W Ruddock" + } + ] + }, + "doi": "10.1016/j.jmb.2021.166826", + "pmid": "33453188", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Mol Biol 433 2021", + "title": "High-resolution Crystal Structure of Human pERp1, A Saposin-like Protein Involved in IgA, IgM and Integrin Maturation in the Endoplasmic Reticulum." + } + }, + { + "pmid": "20404115", + "pubmed": { + "ISODate": "2010-04-19T00:00:00.000Z", + "abstract": "Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.", + "authors": { + "abbreviation": "Daniel C Worth, Kairbaan Hodivala-Dilke, Stephen D Robinson, ..., Maddy Parsons", + "authorList": [ + { + "ForeName": "Daniel", + "LastName": "Worth", + "abbrevName": "Worth DC", + "email": null, + "isCollectiveName": false, + "name": "Daniel C Worth" + }, + { + "ForeName": "Kairbaan", + "LastName": "Hodivala-Dilke", + "abbrevName": "Hodivala-Dilke K", + "email": null, + "isCollectiveName": false, + "name": "Kairbaan Hodivala-Dilke" + }, + { + "ForeName": "Stephen", + "LastName": "Robinson", + "abbrevName": "Robinson SD", + "email": null, + "isCollectiveName": false, + "name": "Stephen D Robinson" + }, + { + "ForeName": "Samantha", + "LastName": "King", + "abbrevName": "King SJ", + "email": null, + "isCollectiveName": false, + "name": "Samantha J King" + }, + { + "ForeName": "Penny", + "LastName": "Morton", + "abbrevName": "Morton PE", + "email": null, + "isCollectiveName": false, + "name": "Penny E Morton" + }, + { + "ForeName": "Frank", + "LastName": "Gertler", + "abbrevName": "Gertler FB", + "email": null, + "isCollectiveName": false, + "name": "Frank B Gertler" + }, + { + "ForeName": "Martin", + "LastName": "Humphries", + "abbrevName": "Humphries MJ", + "email": null, + "isCollectiveName": false, + "name": "Martin J Humphries" + }, + { + "ForeName": "Maddy", + "LastName": "Parsons", + "abbrevName": "Parsons M", + "email": null, + "isCollectiveName": false, + "name": "Maddy Parsons" + } + ], + "contacts": [] + }, + "doi": "10.1083/jcb.200912014", + "pmid": "20404115", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 189 2010", + "title": "Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration." + } + }, + { + "pmid": "29276177", + "pubmed": { + "ISODate": "2018-02-16T00:00:00.000Z", + "abstract": "Focal adhesions (FAs) mechanically couple the extracellular matrix to the dynamic actin cytoskeleton, via transmembrane integrins and actin-binding proteins. The molecular mechanisms by which protein machineries control force transmission along this molecular axis (i.e. modulating integrin activation and controlling actin polymerization) remain largely unknown. Talin is a major actin-binding protein that controls both the inside-out activation of integrins and actin filament anchoring and thus plays a major role in the establishment of the actin-extracellular matrix mechanical coupling. Talin contains three actin-binding domains (ABDs). The N-terminal head domain contains both the F3 integrin-activating domain and ABD1, whereas the C-terminal rod contains the actin-anchoring ABD2 and ABD3. Integrin binding is regulated by an intramolecular interaction between the N-terminal head and a C-terminal five-helix bundle (R9). Whether talin ABDs regulate actin polymerization in a constitutive or regulated manner has not been fully explored. Here, we combine kinetics assays using fluorescence spectroscopy and single actin filament observation in total internal reflection fluorescence microscopy, to examine relevant functions of the three ABDs of talin. We find that the N-terminal ABD1 blocks actin filament barbed-end elongation, whereas ABD2 and ABD3 do not show any activity. By mutating residues in ABD1, we find that this activity is mediated by a positively charged surface that is partially masked by its intramolecular interaction with R9. Our results also demonstrate that, once this intramolecular interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly.", + "authors": { + "abbreviation": "Corina Ciobanasu, Hong Wang, Véronique Henriot, ..., Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Corina", + "LastName": "Ciobanasu", + "abbrevName": "Ciobanasu C", + "email": null, + "isCollectiveName": false, + "name": "Corina Ciobanasu" + }, + { + "ForeName": "Hong", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hong Wang" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Cécile", + "LastName": "Mathieu", + "abbrevName": "Mathieu C", + "email": null, + "isCollectiveName": false, + "name": "Cécile Mathieu" + }, + { + "ForeName": "Annabelle", + "LastName": "Fente", + "abbrevName": "Fente A", + "email": null, + "isCollectiveName": false, + "name": "Annabelle Fente" + }, + { + "ForeName": "Sandrine", + "LastName": "Csillag", + "abbrevName": "Csillag S", + "email": null, + "isCollectiveName": false, + "name": "Sandrine Csillag" + }, + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Bruno", + "LastName": "Faivre", + "abbrevName": "Faivre B", + "email": null, + "isCollectiveName": false, + "name": "Bruno Faivre" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1074/jbc.M117.808204", + "pmid": "29276177", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 293 2018", + "title": "Integrin-bound talin head inhibits actin filament barbed-end elongation." + } + }, + { + "pmid": "23389036", + "pubmed": { + "ISODate": "2013-03-22T00:00:00.000Z", + "abstract": "Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1-R13) organized into a compact cluster of four-helix bundles (R2-R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.", + "authors": { + "abbreviation": "Benjamin T Goult, Thomas Zacharchenko, Neil Bate, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Thomas", + "LastName": "Zacharchenko", + "abbrevName": "Zacharchenko T", + "email": null, + "isCollectiveName": false, + "name": "Thomas Zacharchenko" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Ricky", + "LastName": "Tsang", + "abbrevName": "Tsang R", + "email": null, + "isCollectiveName": false, + "name": "Ricky Tsang" + }, + { + "ForeName": "Fiona", + "LastName": "Hey", + "abbrevName": "Hey F", + "email": null, + "isCollectiveName": false, + "name": "Fiona Hey" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Paul", + "LastName": "Elliott", + "abbrevName": "Elliott PR", + "email": null, + "isCollectiveName": false, + "name": "Paul R Elliott" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GCK", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Christoph", + "LastName": "Ballestrem", + "abbrevName": "Ballestrem C", + "email": null, + "isCollectiveName": false, + "name": "Christoph Ballestrem" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": "drc@le.ac.uk", + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": "i.barsukov@liverpool.ac.uk", + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [ + { + "ForeName": "David", + "LastName": "Critchley", + "email": [ + "drc@le.ac.uk" + ], + "name": "David R Critchley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "email": [ + "i.barsukov@liverpool.ac.uk" + ], + "name": "Igor L Barsukov" + } + ] + }, + "doi": "10.1074/jbc.M112.438119", + "pmid": "23389036", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 288 2013", + "title": "RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover." + } + }, + { + "pmid": "25520155", + "pubmed": { + "ISODate": "2014-12-18T00:00:00.000Z", + "abstract": "The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. ", + "authors": { + "abbreviation": "Jun Yang, Liang Zhu, Hao Zhang, ..., Jun Qin", + "authorList": [ + { + "ForeName": "Jun", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jun Yang" + }, + { + "ForeName": "Liang", + "LastName": "Zhu", + "abbrevName": "Zhu L", + "email": null, + "isCollectiveName": false, + "name": "Liang Zhu" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Jamila", + "LastName": "Hirbawi", + "abbrevName": "Hirbawi J", + "email": null, + "isCollectiveName": false, + "name": "Jamila Hirbawi" + }, + { + "ForeName": "Koichi", + "LastName": "Fukuda", + "abbrevName": "Fukuda K", + "email": null, + "isCollectiveName": false, + "name": "Koichi Fukuda" + }, + { + "ForeName": "Pallavi", + "LastName": "Dwivedi", + "abbrevName": "Dwivedi P", + "email": null, + "isCollectiveName": false, + "name": "Pallavi Dwivedi" + }, + { + "ForeName": "Jianmin", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jianmin Liu" + }, + { + "ForeName": "Tatiana", + "LastName": "Byzova", + "abbrevName": "Byzova T", + "email": null, + "isCollectiveName": false, + "name": "Tatiana Byzova" + }, + { + "ForeName": "Edward", + "LastName": "Plow", + "abbrevName": "Plow EF", + "email": null, + "isCollectiveName": false, + "name": "Edward F Plow" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jinhua Wu" + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms6880", + "pmid": "25520155", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Commun 5 2014", + "title": "Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion." + } + }, + { + "pmid": "14752106", + "pubmed": { + "ISODate": "2004-04-09T00:00:00.000Z", + "abstract": "Insulin receptor tyrosine kinase substrate p53 (IRSp53) has been identified as an SH3 domain-containing adaptor that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia. The recruitment of these SH3-binding partners by IRSp53 is thought to be crucial for F-actin rearrangements. Here, we show that the N-terminal predicted helical stretch of 250 amino acids of IRSp53 is an evolutionarily conserved F-actin bundling domain involved in filopodium formation. Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates. We named the conserved domain IRSp53/MIM homology domain (IMD). The IMD has domain relatives in invertebrates but does not show obvious homology to any known actin interacting proteins. The IMD alone, derived from either IRSp53 or MIM, induced filopodia in HeLa cells and the formation of tightly packed parallel F-actin bundles in vitro. These results suggest that IRSp53 and MIM belong to a novel actin bundling protein family. Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1. The SH3 domain was not necessary for IMD-induced filopodium formation. Our results indicate that IRSp53, when activated by small GTPases, participates in F-actin reorganization not only in an SH3-dependent manner but also in a manner dependent on the activity of the IMD.", + "authors": { + "abbreviation": "Akiko Yamagishi, Michitaka Masuda, Takashi Ohki, ..., Naoki Mochizuki", + "authorList": [ + { + "ForeName": "Akiko", + "LastName": "Yamagishi", + "abbrevName": "Yamagishi A", + "email": null, + "isCollectiveName": false, + "name": "Akiko Yamagishi" + }, + { + "ForeName": "Michitaka", + "LastName": "Masuda", + "abbrevName": "Masuda M", + "email": null, + "isCollectiveName": false, + "name": "Michitaka Masuda" + }, + { + "ForeName": "Takashi", + "LastName": "Ohki", + "abbrevName": "Ohki T", + "email": null, + "isCollectiveName": false, + "name": "Takashi Ohki" + }, + { + "ForeName": "Hirofumi", + "LastName": "Onishi", + "abbrevName": "Onishi H", + "email": null, + "isCollectiveName": false, + "name": "Hirofumi Onishi" + }, + { + "ForeName": "Naoki", + "LastName": "Mochizuki", + "abbrevName": "Mochizuki N", + "email": null, + "isCollectiveName": false, + "name": "Naoki Mochizuki" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M309408200", + "pmid": "14752106", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 279 2004", + "title": "A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein." + } + }, + { + "pmid": "25359136", + "pubmed": { + "ISODate": "2015-02-01T00:00:00.000Z", + "abstract": "Noncatalytic region of tyrosine kinase (Nck) is an adapter protein that comprises one SH2 (Src homology) domain and three SH3 domains. Nck links receptors and receptor-associated tyrosine kinases or adapter proteins to proteins that regulate the actin cytoskeleton. Whereas the SH2 domain binds to phosphorylated receptors or associated phosphoproteins, individual interactions of the SH3 domains with proline-based recognition motifs result in the formation of larger protein complexes. In T cells, changes in cell polarity and morphology during T-cell activation and effector function require the T-cell receptor-mediated recruitment and activation of actin-regulatory proteins to initiate cytoskeletal reorganization at the immunological synapse. We previously identified the adapter protein HS1 as a putative Nck-interacting protein. We now demonstrate that the SH2 domain of Nck specifically interacts with HS1 upon phosphorylation of its tyrosine residue 378. We report that in human T cells, ligation of the chemokine receptor CXCR4 by stromal cell-derived factor 1α (SDF1α) induces a rapid and transient phosphorylation of tyrosine 378 of HS1 resulting in an increased association with Nck. Consequently, siRNA-mediated downregulation of HS1 and/or Nck impairs SDF1α-induced actin polymerization and T-cell migration. ", + "authors": { + "abbreviation": "Marcus Lettau, Dieter Kabelitz, Ottmar Janssen", + "authorList": [ + { + "ForeName": "Marcus", + "LastName": "Lettau", + "abbrevName": "Lettau M", + "email": null, + "isCollectiveName": false, + "name": "Marcus Lettau" + }, + { + "ForeName": "Dieter", + "LastName": "Kabelitz", + "abbrevName": "Kabelitz D", + "email": null, + "isCollectiveName": false, + "name": "Dieter Kabelitz" + }, + { + "ForeName": "Ottmar", + "LastName": "Janssen", + "abbrevName": "Janssen O", + "email": null, + "isCollectiveName": false, + "name": "Ottmar Janssen" + } + ], + "contacts": [] + }, + "doi": "10.1002/eji.201444473", + "pmid": "25359136", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Eur J Immunol 45 2015", + "title": "SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells." + } + }, + { + "pmid": "25062413", + "pubmed": { + "ISODate": "2014-07-02T00:00:00.000Z", + "abstract": "The cytoskeleton mediates various cellular processes such as differentiation and fusion, including in the filopodia and podosomes. However, apart from cell migration and formation of the sealing zone, little is known regarding the changes and related regulatory mechanisms of the cytoskeleton and additional roles of the filopodia and podosomes during the differentiation and fusion of osteoclasts. The cytomorphology and cytoskeleton of osteoclasts in the differentiation process were evaluated using tartrate-resistant acid phosphatase staining and immunofluorescence staining. Moreover, the expression levels of Rho GTPases and enzymes related to osteoclast differentiation and bone resorption were detected by quantitative reverse transcription-polymerase chain reaction. We detected 3 types of filopodia in osteoclast precursors and only 1 type of filopodia in undifferentiated cells. Mature osteoclasts were completely devoid of filopodia. Interestingly, cell fusion was highly specific, and the fusion initially occurred to the filopodia. Confocal images revealed that F-actin and microtubules significantly differed among fused cells. These results suggest that filopodia and podosomes not only play important roles in cell migration and the formation of sealing zones but also in the pre-fusion selectivity of 2 cells and the movement direction of the cell nucleus and cytoplasm during the fusion process. In addition, cdc42v1, RhoU, and RhoF regulate the formation of 3 types of filopodia during various stages of differentiation, while Rac1, Rac2, and filament A may be associated with cell selectivity during the fusion process. ", + "authors": { + "abbreviation": "R L Song, X Z Liu, J Q Zhu, ..., Z P Liu", + "authorList": [ + { + "ForeName": "R", + "LastName": "Song", + "abbrevName": "Song RL", + "email": null, + "isCollectiveName": false, + "name": "R L Song" + }, + { + "ForeName": "X", + "LastName": "Liu", + "abbrevName": "Liu XZ", + "email": null, + "isCollectiveName": false, + "name": "X Z Liu" + }, + { + "ForeName": "J", + "LastName": "Zhu", + "abbrevName": "Zhu JQ", + "email": null, + "isCollectiveName": false, + "name": "J Q Zhu" + }, + { + "ForeName": "J", + "LastName": "Zhang", + "abbrevName": "Zhang JM", + "email": null, + "isCollectiveName": false, + "name": "J M Zhang" + }, + { + "ForeName": "Q", + "LastName": "Gao", + "abbrevName": "Gao Q", + "email": null, + "isCollectiveName": false, + "name": "Q Gao" + }, + { + "ForeName": "H", + "LastName": "Zhao", + "abbrevName": "Zhao HY", + "email": null, + "isCollectiveName": false, + "name": "H Y Zhao" + }, + { + "ForeName": "A", + "LastName": "Sheng", + "abbrevName": "Sheng AZ", + "email": null, + "isCollectiveName": false, + "name": "A Z Sheng" + }, + { + "ForeName": "Y", + "LastName": "Yuan", + "abbrevName": "Yuan Y", + "email": null, + "isCollectiveName": false, + "name": "Y Yuan" + }, + { + "ForeName": "J", + "LastName": "Gu", + "abbrevName": "Gu JH", + "email": null, + "isCollectiveName": false, + "name": "J H Gu" + }, + { + "ForeName": "H", + "LastName": "Zou", + "abbrevName": "Zou H", + "email": null, + "isCollectiveName": false, + "name": "H Zou" + }, + { + "ForeName": "Q", + "LastName": "Wang", + "abbrevName": "Wang QC", + "email": null, + "isCollectiveName": false, + "name": "Q C Wang" + }, + { + "ForeName": "Z", + "LastName": "Liu", + "abbrevName": "Liu ZP", + "email": "liuzongping@yzu.edu.cn", + "isCollectiveName": false, + "name": "Z P Liu" + } + ], + "contacts": [ + { + "ForeName": "Z", + "LastName": "Liu", + "email": [ + "liuzongping@yzu.edu.cn" + ], + "name": "Z P Liu" + } + ] + }, + "doi": "10.4238/2014.July.2.7", + "pmid": "25062413", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Genet Mol Res 13 2014", + "title": "New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts." + } + }, + { + "pmid": "24891603", + "pubmed": { + "ISODate": "2014-06-09T00:00:00.000Z", + "abstract": "Invadopodia are actin-rich protrusions that degrade the extracellular matrix and are required for stromal invasion, intravasation, and metastasis. The role of the focal adhesion protein talin in regulating these structures is not known. Here, we demonstrate that talin is required for invadopodial matrix degradation and three-dimensional extracellular matrix invasion in metastatic breast cancer cells. The sodium/hydrogen exchanger 1 (NHE-1) is linked to the cytoskeleton by ezrin/radixin/moesin family proteins and is known to regulate invadopodium-mediated matrix degradation. We show that the talin C terminus binds directly to the moesin band 4.1 ERM (FERM) domain to recruit a moesin-NHE-1 complex to invadopodia. Silencing talin resulted in a decrease in cytosolic pH at invadopodia and blocked cofilin-dependent actin polymerization, leading to impaired invadopodium stability and matrix degradation. Furthermore, talin is required for mammary tumor cell motility, intravasation, and spontaneous lung metastasis in vivo. Thus, our findings provide a novel understanding of how intracellular pH is regulated and a molecular mechanism by which talin enhances tumor cell invasion and metastasis.", + "authors": { + "abbreviation": "Brian T Beaty, Yarong Wang, Jose Javier Bravo-Cordero, ..., John Condeelis", + "authorList": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "abbrevName": "Beaty BT", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "Brian T Beaty" + }, + { + "ForeName": "Yarong", + "LastName": "Wang", + "abbrevName": "Wang Y", + "email": null, + "isCollectiveName": false, + "name": "Yarong Wang" + }, + { + "ForeName": "Jose", + "LastName": "Bravo-Cordero", + "abbrevName": "Bravo-Cordero JJ", + "email": null, + "isCollectiveName": false, + "name": "Jose Javier Bravo-Cordero" + }, + { + "ForeName": "Ved", + "LastName": "Sharma", + "abbrevName": "Sharma VP", + "email": null, + "isCollectiveName": false, + "name": "Ved P Sharma" + }, + { + "ForeName": "Veronika", + "LastName": "Miskolci", + "abbrevName": "Miskolci V", + "email": null, + "isCollectiveName": false, + "name": "Veronika Miskolci" + }, + { + "ForeName": "Louis", + "LastName": "Hodgson", + "abbrevName": "Hodgson L", + "email": null, + "isCollectiveName": false, + "name": "Louis Hodgson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": "brian.beaty@med.einstein.yu.edu", + "isCollectiveName": false, + "name": "John Condeelis" + } + ], + "contacts": [ + { + "ForeName": "Brian", + "LastName": "Beaty", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "Brian T Beaty" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "email": [ + "brian.beaty@med.einstein.yu.edu", + "john.condeelis@einstein.yu.edu" + ], + "name": "John Condeelis" + } + ] + }, + "doi": "10.1083/jcb.201312046", + "pmid": "24891603", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Cell Biol 205 2014", + "title": "Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis." + } + }, + { + "pmid": "33862101", + "pubmed": { + "ISODate": "2021-06-15T00:00:00.000Z", + "abstract": "The mechanism that mediates the interaction between the contractile ring and the plasma membrane during cytokinesis remains elusive. We previously found that ERM (Ezrin/Radixin/Moesin) proteins, which usually mediate cellular pole contraction, become over-accumulated at the cell equator and support furrow ingression upon the loss of other actin-membrane associated proteins, anillin and supervillin. In this study, we addressed the molecular basis of the exchangeability between ezrin and other actin-membrane associated proteins in mediating cortical contraction during cytokinesis. We found that depletion of anillin and supervillin caused over-accumulation of the membrane-associated FERM domain and actin-binding C-terminal domain (C-term) of ezrin at the cleavage furrow, respectively. This finding suggests that ezrin differentially shares its binding sites with these proteins on the actin cytoskeleton or inner membrane surface. Using chimeric mutants, we found that ezrin C-term, but not the FERM domain, can substitute for the corresponding anillin domains in cytokinesis and cell proliferation. On the other hand, either the membrane-associated or the actin/myosin-binding domains of anillin could not substitute for the corresponding ezrin domains in controlling cortical blebbing at the cell poles. Our results highlight specific designs of actin- or membrane-associated moieties of different actin-membrane associated proteins with limited exchangeability, which enables them to support diverse cortical activities on the shared actin-membrane interface during cytokinesis.", + "authors": { + "abbreviation": "Guang Yang, Shota Hiruma, Akira Kitamura, ..., Ryota Uehara", + "authorList": [ + { + "ForeName": "Guang", + "LastName": "Yang", + "abbrevName": "Yang G", + "email": null, + "isCollectiveName": false, + "name": "Guang Yang" + }, + { + "ForeName": "Shota", + "LastName": "Hiruma", + "abbrevName": "Hiruma S", + "email": null, + "isCollectiveName": false, + "name": "Shota Hiruma" + }, + { + "ForeName": "Akira", + "LastName": "Kitamura", + "abbrevName": "Kitamura A", + "email": null, + "isCollectiveName": false, + "name": "Akira Kitamura" + }, + { + "ForeName": "Masataka", + "LastName": "Kinjo", + "abbrevName": "Kinjo M", + "email": null, + "isCollectiveName": false, + "name": "Masataka Kinjo" + }, + { + "ForeName": "Mithilesh", + "LastName": "Mishra", + "abbrevName": "Mishra M", + "email": null, + "isCollectiveName": false, + "name": "Mithilesh Mishra" + }, + { + "ForeName": "Ryota", + "LastName": "Uehara", + "abbrevName": "Uehara R", + "email": "ruehara@sci.hokudai.ac.jp", + "isCollectiveName": false, + "name": "Ryota Uehara" + } + ], + "contacts": [ + { + "ForeName": "Ryota", + "LastName": "Uehara", + "email": [ + "ruehara@sci.hokudai.ac.jp" + ], + "name": "Ryota Uehara" + } + ] + }, + "doi": "10.1016/j.yexcr.2021.112600", + "pmid": "33862101", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Exp Cell Res 403 2021", + "title": "Molecular basis of functional exchangeability between ezrin and other actin-membrane associated proteins during cytokinesis." + } + }, + { + "pmid": "23726984", + "pubmed": { + "ISODate": "2013-10-01T00:00:00.000Z", + "abstract": "Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full-length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut-shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. ", + "authors": { + "abbreviation": "Benjamin T Goult, Xiao-Ping Xu, Alexandre R Gingras, ..., Dorit Hanein", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Xiao-Ping", + "LastName": "Xu", + "abbrevName": "Xu XP", + "email": null, + "isCollectiveName": false, + "name": "Xiao-Ping Xu" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Mark", + "LastName": "Swift", + "abbrevName": "Swift M", + "email": null, + "isCollectiveName": false, + "name": "Mark Swift" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jsb.2013.05.014", + "pmid": "23726984", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Struct Biol 184 2013", + "title": "Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation." + } + }, + { + "pmid": "21648001", + "pubmed": { + "ISODate": "2011-08-01T00:00:00.000Z", + "abstract": "The cytoskeletal proteins talin and vinculin are localized at cell-matrix junctions and are key regulators of cell signaling, adhesion, and migration. Talin couples integrins via its FERM domain to F-actin and is an important regulator of integrin activation and clustering. The 220 kDa talin rod domain comprises several four- and five-helix bundles that harbor amphipathic α-helical vinculin binding sites (VBSs). In its inactive state, the hydrophobic VBS residues involved in binding to vinculin are buried within these helix bundles, and the mechanical force emanating from bound integrin receptors is thought necessary for their release and binding to vinculin. The crystal structure of a four-helix bundle of talin that harbors one of these VBSs, coined VBS33, was recently determined. Here we report the crystal structure of VBS33 in complex with vinculin at 2 Å resolution. Notably, comparison of the apo and vinculin bound structures shows that intermolecular interactions of the VBS33 α-helix with vinculin are more extensive than the intramolecular interactions of the VBS33 within the talin four-helix bundle.", + "authors": { + "abbreviation": "S D Yogesha, A Sharff, G Bricogne, T Izard", + "authorList": [ + { + "ForeName": "S", + "LastName": "Yogesha", + "abbrevName": "Yogesha SD", + "email": null, + "isCollectiveName": false, + "name": "S D Yogesha" + }, + { + "ForeName": "A", + "LastName": "Sharff", + "abbrevName": "Sharff A", + "email": null, + "isCollectiveName": false, + "name": "A Sharff" + }, + { + "ForeName": "G", + "LastName": "Bricogne", + "abbrevName": "Bricogne G", + "email": null, + "isCollectiveName": false, + "name": "G Bricogne" + }, + { + "ForeName": "T", + "LastName": "Izard", + "abbrevName": "Izard T", + "email": null, + "isCollectiveName": false, + "name": "T Izard" + } + ], + "contacts": [] + }, + "doi": "10.1002/pro.671", + "pmid": "21648001", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Protein Sci 20 2011", + "title": "Intermolecular versus intramolecular interactions of the vinculin binding site 33 of talin." + } + }, + { + "pmid": "32561773", + "pubmed": { + "ISODate": "2020-06-19T00:00:00.000Z", + "abstract": "Cells reinforce adhesion strength and cytoskeleton anchoring in response to the actomyosin force. The mechanical stretching of talin, which exposes cryptic vinculin-binding sites, triggers this process. The binding of RIAM to talin could regulate this mechanism. However, the mechanosensitivity of the talin-RIAM complex has never been tested. It is also not known whether RIAM controls the mechanosensitivity of the talin-vinculin complex. To address these issues, we designed an in vitro microscopy assay with purified proteins in which the actomyosin force controls RIAM and vinculin-binding to talin. We demonstrate that actomyosin triggers RIAM dissociation from several talin domains. Actomyosin also provokes the sequential exchange of RIAM for vinculin on talin. The effect of RIAM on this force-dependent binding of vinculin to talin varies from one talin domain to another. This mechanism could allow talin to biochemically code a wide range of forces by selecting different combinations of partners.", + "authors": { + "abbreviation": "Clémence Vigouroux, Véronique Henriot, Christophe Le Clainche", + "authorList": [ + { + "ForeName": "Clémence", + "LastName": "Vigouroux", + "abbrevName": "Vigouroux C", + "email": null, + "isCollectiveName": false, + "name": "Clémence Vigouroux" + }, + { + "ForeName": "Véronique", + "LastName": "Henriot", + "abbrevName": "Henriot V", + "email": null, + "isCollectiveName": false, + "name": "Véronique Henriot" + }, + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "abbrevName": "Le Clainche C", + "email": "christophe.leclainche@i2bc.paris-saclay.fr", + "isCollectiveName": false, + "name": "Christophe Le Clainche" + } + ], + "contacts": [ + { + "ForeName": "Christophe", + "LastName": "Le Clainche", + "email": [ + "christophe.leclainche@i2bc.paris-saclay.fr" + ], + "name": "Christophe Le Clainche" + } + ] + }, + "doi": "10.1038/s41467-020-16922-1", + "pmid": "32561773", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D059040", + "value": "Video-Audio Media" + } + ], + "reference": "Nat Commun 11 2020", + "title": "Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force." + } + }, + { + "pmid": "18044991", + "pubmed": { + "ISODate": "2007-11-01T00:00:00.000Z", + "abstract": "Actin polymerization-driven protrusion of the leading edge is a key element of cell motility. The important actin nucleators formins and the Arp2/3 complex are believed to have nonoverlapping functions in inducing actin filament bundles in filopodia and dendritic networks in lamellipodia, respectively. We tested this idea by investigating the role of mDia2 formin in leading-edge protrusion by loss-of-function and gain-of-function approaches. Unexpectedly, mDia2 depletion by short interfering RNA (siRNA) severely inhibited lamellipodia. Structural analysis of the actin network in the few remaining lamellipodia suggested an mDia2 role in generation of long filaments. Consistently, constitutively active mDia2 (DeltaGBD-mDia2) induced accumulation of long actin filaments in lamellipodia and increased persistence of lamellipodial protrusion. Depletion of mDia2 also inhibited filopodia, whereas expression of DeltaGBD-mDia2 promoted their formation. Correlative light and electron microscopy showed that DeltaGBD-mDia2-induced filopodia were formed from lamellipodial network through gradual convergence of long lamellipodial filaments into bundles. Efficient filopodia induction required mDia2 targeting to the membrane, likely through a scaffolding protein Abi1. Furthermore, mDia2 and Abi1 interacted through the N-terminal regulatory sequences of mDia2 and the SH3-containing Abi1 sequences. We propose that mDia2 plays an important role in formation of lamellipodia by nucleating and/or protecting from capping lamellipodial actin filaments, which subsequently exhibit high tendency to converge into filopodia.", + "authors": { + "abbreviation": "Changsong Yang, Lubov Czech, Silke Gerboth, ..., Tatyana Svitkina", + "authorList": [ + { + "ForeName": "Changsong", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Changsong Yang" + }, + { + "ForeName": "Lubov", + "LastName": "Czech", + "abbrevName": "Czech L", + "email": null, + "isCollectiveName": false, + "name": "Lubov Czech" + }, + { + "ForeName": "Silke", + "LastName": "Gerboth", + "abbrevName": "Gerboth S", + "email": null, + "isCollectiveName": false, + "name": "Silke Gerboth" + }, + { + "ForeName": "Shin-ichiro", + "LastName": "Kojima", + "abbrevName": "Kojima S", + "email": null, + "isCollectiveName": false, + "name": "Shin-ichiro Kojima" + }, + { + "ForeName": "Giorgio", + "LastName": "Scita", + "abbrevName": "Scita G", + "email": null, + "isCollectiveName": false, + "name": "Giorgio Scita" + }, + { + "ForeName": "Tatyana", + "LastName": "Svitkina", + "abbrevName": "Svitkina T", + "email": null, + "isCollectiveName": false, + "name": "Tatyana Svitkina" + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.0050317", + "pmid": "18044991", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS Biol 5 2007", + "title": "Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells." + } + }, + { + "pmid": "19098287", + "pubmed": { + "ISODate": "2009-02-20T00:00:00.000Z", + "abstract": "Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.", + "authors": { + "abbreviation": "Ho-Sup Lee, Chinten James Lim, Wilma Puzon-McLaughlin, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Chinten", + "LastName": "Lim", + "abbrevName": "Lim CJ", + "email": null, + "isCollectiveName": false, + "name": "Chinten James Lim" + }, + { + "ForeName": "Wilma", + "LastName": "Puzon-McLaughlin", + "abbrevName": "Puzon-McLaughlin W", + "email": null, + "isCollectiveName": false, + "name": "Wilma Puzon-McLaughlin" + }, + { + "ForeName": "Sanford", + "LastName": "Shattil", + "abbrevName": "Shattil SJ", + "email": null, + "isCollectiveName": false, + "name": "Sanford J Shattil" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M807117200", + "pmid": "19098287", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 284 2009", + "title": "RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences." + } + }, + { + "pmid": "15642262", + "pubmed": { + "ISODate": "2005-01-01T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin plays a key role in activating integrins and in coupling them to the actin cytoskeleton. Its N-terminal globular head, which binds beta integrins, is linked to an extended rod having a C-terminal actin binding site and several vinculin binding sites (VBSs). The NMR structure of residues 755-889 of the rod (containing a VBS) is shown to be an amphipathic four-helix bundle with a left-handed topology. A talin peptide corresponding to the VBS binds the vinculin head; the X-ray crystallographic structure of this complex shows that the residues which interact with vinculin are buried in the hydrophobic core of the talin fragment. NMR shows that the interaction involves a major structural change in the talin fragment, including unfolding of one of its helices, making the VBS accessible to vinculin. Interestingly, the talin 755-889 fragment binds more than one vinculin head molecule, suggesting that the talin rod may contain additional as yet unrecognized VBSs.", + "authors": { + "abbreviation": "Ian Fillingham, Alexandre R Gingras, Evangelos Papagrigoriou, ..., Igor L Barsukov", + "authorList": [ + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham I", + "email": null, + "isCollectiveName": false, + "name": "Ian Fillingham" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Evangelos", + "LastName": "Papagrigoriou", + "abbrevName": "Papagrigoriou E", + "email": null, + "isCollectiveName": false, + "name": "Evangelos Papagrigoriou" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.str.2004.11.006", + "pmid": "15642262", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Structure 13 2005", + "title": "A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head." + } + }, + { + "pmid": "20399778", + "pubmed": { + "ISODate": "2010-06-03T00:00:00.000Z", + "abstract": "Talin is a large flexible rod-shaped protein that activates the integrin family of cell adhesion molecules and couples them to cytoskeletal actin. Its rod region consists of a series of helical bundles. Here we show that residues 1815-1973 form a 5-helix bundle, with a topology unique to talin which is optimally suited for formation of a long rod such as talin. This is much more stable than the 4-helix (1843-1973) domain described earlier and as a result its vinculin binding sequence is inaccessible to vinculin at room temperature, with implications for the overall mechanism of the talin-vinculin interaction.", + "authors": { + "abbreviation": "Benjamin T Goult, Alexandre R Gingras, Neil Bate, ..., Gordon C K Roberts", + "authorList": [ + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.febslet.2010.04.028", + "pmid": "20399778", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "FEBS Lett 584 2010", + "title": "The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site." + } + }, + { + "pmid": "20610383", + "pubmed": { + "ISODate": "2010-09-17T00:00:00.000Z", + "abstract": "Talin is an adaptor protein that couples integrins to F-actin. Structural studies show that the N-terminal talin head contains an atypical FERM domain, whereas the N- and C-terminal parts of the talin rod include a series of α-helical bundles. However, determining the structure of the central part of the rod has proved problematic. Residues 1359-1659 are homologous to the MESDc1 gene product, and we therefore expressed this region of talin in Escherichia coli. The crystal structure shows a unique fold comprised of a 5- and 4-helix bundle. The 5-helix bundle is composed of nonsequential helices due to insertion of the 4-helix bundle into the loop at the C terminus of helix α3. The linker connecting the bundles forms a two-stranded anti-parallel β-sheet likely limiting the relative movement of the two bundles. Because the 5-helix bundle contains the N and C termini of this module, we propose that it is linked by short loops to adjacent bundles, whereas the 4-helix bundle protrudes from the rod. This suggests the 4-helix bundle has a unique role, and its pI (7.8) is higher than other rod domains. Both helical bundles contain vinculin-binding sites but that in the isolated 5-helix bundle is cryptic, whereas that in the isolated 4-helix bundle is constitutively active. In contrast, both bundles are required for actin binding. Finally, we show that the MESDc1 protein, which is predicted to have a similar fold, is a novel actin-binding protein.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Petra", + "LastName": "Kopp", + "abbrevName": "Kopp PM", + "email": null, + "isCollectiveName": false, + "name": "Petra M Kopp" + }, + { + "ForeName": "Jonas", + "LastName": "Emsley", + "abbrevName": "Emsley J", + "email": null, + "isCollectiveName": false, + "name": "Jonas Emsley" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M109.095455", + "pmid": "20610383", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 285 2010", + "title": "Central region of talin has a unique fold that binds vinculin and actin." + } + }, + { + "pmid": "27169557", + "pubmed": { + "ISODate": "2016-06-01T00:00:00.000Z", + "abstract": "Filopodia are finger-like protrusions at the leading edge of migrating cells that play a crucial antennal function during cell motility. It is known that actin filaments are bundled hexagonally and provide rigidity to filopodia by virtue of fascin, which plays a central role in actin filament bundling. However, the molecular mechanisms underlying their formation remain unclear. Here, we observed the filopodia of intact whole cells fixed by rapid freezing and revealed their three-dimensional structure by cryo-electron tomography and image processing; the actin filament bundling structure by fascin was clarified at high resolution under physiological conditions. It was found that actin filaments in vivo were more numerous than in bundles reconstructed in vitro, and each filopodial actin filament had limited variability in helical twisting. In addition, statistical analysis of actin filament bundles unveiled their detailed architecture. In filopodia, actin filaments had highly ordered structures, and the shift between cross-links of each adjacent actin filament was approximately 2.7 nm, similar to the monomer repeat of actin filaments. We then proposed a plausible actin-fascin cross-link model at the amino acid level and identified three fascin binding sites on two adjacent actin filaments: one filament bound fascin at two discrete, widely separated regions and the other bound fascin in a single small region. We propose that these two different binding modalities should confer rigid bundles that retain flexibility and dynamic performance. © 2016 Wiley Periodicals, Inc. ", + "authors": { + "abbreviation": "Shinji Aramaki, Kouta Mayanagi, Mingyue Jin, ..., Takuo Yasunaga", + "authorList": [ + { + "ForeName": "Shinji", + "LastName": "Aramaki", + "abbrevName": "Aramaki S", + "email": null, + "isCollectiveName": false, + "name": "Shinji Aramaki" + }, + { + "ForeName": "Kouta", + "LastName": "Mayanagi", + "abbrevName": "Mayanagi K", + "email": null, + "isCollectiveName": false, + "name": "Kouta Mayanagi" + }, + { + "ForeName": "Mingyue", + "LastName": "Jin", + "abbrevName": "Jin M", + "email": null, + "isCollectiveName": false, + "name": "Mingyue Jin" + }, + { + "ForeName": "Kazuhiro", + "LastName": "Aoyama", + "abbrevName": "Aoyama K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Aoyama" + }, + { + "ForeName": "Takuo", + "LastName": "Yasunaga", + "abbrevName": "Yasunaga T", + "email": null, + "isCollectiveName": false, + "name": "Takuo Yasunaga" + } + ], + "contacts": [] + }, + "doi": "10.1002/cm.21309", + "pmid": "27169557", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cytoskeleton (Hoboken) 73 2016", + "title": "Filopodia formation by crosslinking of F-actin with fascin in two different binding manners." + } + }, + { + "pmid": "26419705", + "pubmed": { + "ISODate": "2015-09-30T00:00:00.000Z", + "abstract": "The leading edge of migrating cells contains rapidly translocating activated integrins associated with growing actin filaments that form 'sticky fingers' to sense extracellular matrix and guide cell migration. Here we utilized indirect bimolecular fluorescence complementation to visualize a molecular complex containing a Mig-10/RIAM/lamellipodin (MRL) protein (Rap1-GTP-interacting adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells. This complex localizes at the tips of growing actin filaments in lamellipodial and filopodial protrusions, thus corresponding to the tips of the 'sticky fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the integrins. Moreover, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion. These data reveal the molecular basis of the formation of 'sticky fingers' at the leading edge of migrating cells and show that an MIT complex drives these protrusions. ", + "authors": { + "abbreviation": "Frederic Lagarrigue, Praju Vikas Anekal, Ho-Sup Lee, ..., Mark H Ginsberg", + "authorList": [ + { + "ForeName": "Frederic", + "LastName": "Lagarrigue", + "abbrevName": "Lagarrigue F", + "email": null, + "isCollectiveName": false, + "name": "Frederic Lagarrigue" + }, + { + "ForeName": "Praju", + "LastName": "Vikas Anekal", + "abbrevName": "Vikas Anekal P", + "email": null, + "isCollectiveName": false, + "name": "Praju Vikas Anekal" + }, + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Alexia", + "LastName": "Bachir", + "abbrevName": "Bachir AI", + "email": null, + "isCollectiveName": false, + "name": "Alexia I Bachir" + }, + { + "ForeName": "Jailal", + "LastName": "Ablack", + "abbrevName": "Ablack JN", + "email": null, + "isCollectiveName": false, + "name": "Jailal N Ablack" + }, + { + "ForeName": "Alan", + "LastName": "Horwitz", + "abbrevName": "Horwitz AF", + "email": null, + "isCollectiveName": false, + "name": "Alan F Horwitz" + }, + { + "ForeName": "Mark", + "LastName": "Ginsberg", + "abbrevName": "Ginsberg MH", + "email": null, + "isCollectiveName": false, + "name": "Mark H Ginsberg" + } + ], + "contacts": [] + }, + "doi": "10.1038/ncomms9492", + "pmid": "26419705", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Nat Commun 6 2015", + "title": "A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration." + } + }, + { + "pmid": "33288679", + "pubmed": { + "ISODate": null, + "abstract": "MinD is a cell division ATPase in Escherichia coli that oscillates from pole to pole and regulates the spatial position of the cell division machinery. Together with MinC and MinE, the Min system restricts assembly of the FtsZ-ring to midcell, oscillating between the opposite ends of the cell and preventing FtsZ-ring misassembly at the poles. Here, we show that the ATP-dependent bacterial proteasome complex ClpXP degrades MinD in reconstituted degradation reactions in vitro and in vivo through direct recognition of the MinD N-terminal region. MinD degradation is enhanced during stationary phase, suggesting that ClpXP regulates levels of MinD in cells that are not actively dividing. ClpXP is a major regulator of growth phase-dependent proteins, and these results suggest that MinD levels are also controlled during stationary phase. In vitro, MinC and MinD are known to coassemble into linear polymers; therefore, we monitored copolymers assembled in vitro after incubation with ClpXP and observed that ClpXP promotes rapid MinCD copolymer destabilization and direct MinD degradation by ClpXP. The N terminus of MinD, including residue Arg 3, which is near the ATP-binding site in sequence, is critical for degradation by ClpXP. Together, these results demonstrate that ClpXP degradation modifies conformational assemblies of MinD in vitro and depresses Min function in vivo during periods of reduced proliferation.", + "authors": { + "abbreviation": "Christopher J LaBreck, Catherine E Trebino, Colby N Ferreira, ..., Jodi L Camberg", + "authorList": [ + { + "ForeName": "Christopher", + "LastName": "LaBreck", + "abbrevName": "LaBreck CJ", + "email": null, + "isCollectiveName": false, + "name": "Christopher J LaBreck" + }, + { + "ForeName": "Catherine", + "LastName": "Trebino", + "abbrevName": "Trebino CE", + "email": null, + "isCollectiveName": false, + "name": "Catherine E Trebino" + }, + { + "ForeName": "Colby", + "LastName": "Ferreira", + "abbrevName": "Ferreira CN", + "email": null, + "isCollectiveName": false, + "name": "Colby N Ferreira" + }, + { + "ForeName": "Josiah", + "LastName": "Morrison", + "abbrevName": "Morrison JJ", + "email": null, + "isCollectiveName": false, + "name": "Josiah J Morrison" + }, + { + "ForeName": "Eric", + "LastName": "DiBiasio", + "abbrevName": "DiBiasio EC", + "email": null, + "isCollectiveName": false, + "name": "Eric C DiBiasio" + }, + { + "ForeName": "Joseph", + "LastName": "Conti", + "abbrevName": "Conti J", + "email": null, + "isCollectiveName": false, + "name": "Joseph Conti" + }, + { + "ForeName": "Jodi", + "LastName": "Camberg", + "abbrevName": "Camberg JL", + "email": "cambergj@uri.edu", + "isCollectiveName": false, + "name": "Jodi L Camberg" + } + ], + "contacts": [ + { + "ForeName": "Jodi", + "LastName": "Camberg", + "email": [ + "cambergj@uri.edu" + ], + "name": "Jodi L Camberg" + } + ] + }, + "doi": "10.1074/jbc.RA120.013866", + "pmid": "33288679", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Biol Chem 296", + "title": "Degradation of MinD oscillator complexes by Escherichia coli ClpXP." + } + }, + { + "pmid": "15788569", + "pubmed": { + "ISODate": "2005-06-01T00:00:00.000Z", + "abstract": "Macrophage actin-associated tyrosine phosphorylated protein (MAYP) belongs to the Pombe Cdc15 homology (PCH) family of proteins involved in the regulation of actin-based functions including cell adhesion and motility. In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration. Because MAYP associates with F-actin, we investigated the function of MAYP in regulating actin organization in macrophages. Overexpression of MAYP decreased CSF-1-induced membrane ruffling and increased filopodia formation, motility and CSF-1-mediated chemotaxis. The opposite phenotype was observed with reduced expression of MAYP, indicating that MAYP is a negative regulator of CSF-1-induced membrane ruffling and positively regulates formation of filopodia and directional migration. Overexpression of MAYP led to a reduction in total macrophage F-actin content but was associated with increased actin bundling. Consistent with this, purified MAYP bundled F-actin and regulated its turnover in vitro. In addition, MAYP colocalized with cortical and filopodial F-actin in vivo. Because filopodia are postulated to increase directional motility by acting as environmental sensors, the MAYP-stimulated increase in directional movement may be at least partly explained by enhancement of filopodia formation.", + "authors": { + "abbreviation": "Violeta Chitu, Fiona J Pixley, Frank Macaluso, ..., E Richard Stanley", + "authorList": [ + { + "ForeName": "Violeta", + "LastName": "Chitu", + "abbrevName": "Chitu V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Chitu" + }, + { + "ForeName": "Fiona", + "LastName": "Pixley", + "abbrevName": "Pixley FJ", + "email": null, + "isCollectiveName": false, + "name": "Fiona J Pixley" + }, + { + "ForeName": "Frank", + "LastName": "Macaluso", + "abbrevName": "Macaluso F", + "email": null, + "isCollectiveName": false, + "name": "Frank Macaluso" + }, + { + "ForeName": "Daniel", + "LastName": "Larson", + "abbrevName": "Larson DR", + "email": null, + "isCollectiveName": false, + "name": "Daniel R Larson" + }, + { + "ForeName": "John", + "LastName": "Condeelis", + "abbrevName": "Condeelis J", + "email": null, + "isCollectiveName": false, + "name": "John Condeelis" + }, + { + "ForeName": "Yee-Guide", + "LastName": "Yeung", + "abbrevName": "Yeung YG", + "email": null, + "isCollectiveName": false, + "name": "Yee-Guide Yeung" + }, + { + "ForeName": "E", + "LastName": "Stanley", + "abbrevName": "Stanley ER", + "email": null, + "isCollectiveName": false, + "name": "E Richard Stanley" + } + ], + "contacts": [] + }, + "doi": "10.1091/mbc.e04-10-0914", + "pmid": "15788569", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Biol Cell 16 2005", + "title": "The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages." + } + }, + { + "pmid": "17398099", + "pubmed": { + "ISODate": "2007-04-03T00:00:00.000Z", + "abstract": "BACKGROUND: Mammalian Diaphanous (mDia)-related formins and the N-WASP-activated Arp2/3 complex initiate the assembly of filamentous actin. Dia-interacting protein (DIP) binds via its amino-terminal SH3 domain to the proline-rich formin homology 1 (FH1) domain of mDia1 and mDia2 and to the N-WASp proline-rich region. RESULTS: Here, we investigated an interaction between a conserved leucine-rich region (LRR) in DIP and the mDia FH2 domain that nucleates, processively elongates, and bundles actin filaments. DIP binding to mDia2 was regulated by the same Rho-GTPase-controlled autoinhibitory mechanism modulating formin-mediated actin assembly. DIP was previously shown to interact with and stimulate N-WASp-dependent branched filament assembly via Arp2/3. Despite direct binding to both mDia1 and mDia2 FH2 domains, DIP LRR inhibited only mDia2-dependent filament assembly and bundling in vitro. DIP expression interfered with filopodia formation, consistent with a role for mDia2 in assembly of these structures. After filopodia retraction into the cell body, DIP expression induced excessive nonapoptotic membrane blebbing, a physiological process involved in both cytokinesis and amoeboid cell movement. DIP-induced blebbing was dependent on mDia2 but did not require the activities of either mDia1 or Arp2/3. CONCLUSIONS: These observations point to a pivotal role for DIP in the control of nonbranched and branched actin-filament assembly that is mediated by Diaphanous-related formins and activators of Arp2/3, respectively. The ability of DIP to trigger blebbing also suggests a role for mDia2 in the assembly of cortical actin necessary for maintaining plasma-membrane integrity.", + "authors": { + "abbreviation": "Kathryn M Eisenmann, Elizabeth S Harris, Susan M Kitchen, ..., Arthur S Alberts", + "authorList": [ + { + "ForeName": "Kathryn", + "LastName": "Eisenmann", + "abbrevName": "Eisenmann KM", + "email": null, + "isCollectiveName": false, + "name": "Kathryn M Eisenmann" + }, + { + "ForeName": "Elizabeth", + "LastName": "Harris", + "abbrevName": "Harris ES", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth S Harris" + }, + { + "ForeName": "Susan", + "LastName": "Kitchen", + "abbrevName": "Kitchen SM", + "email": null, + "isCollectiveName": false, + "name": "Susan M Kitchen" + }, + { + "ForeName": "Holly", + "LastName": "Holman", + "abbrevName": "Holman HA", + "email": null, + "isCollectiveName": false, + "name": "Holly A Holman" + }, + { + "ForeName": "Henry", + "LastName": "Higgs", + "abbrevName": "Higgs HN", + "email": null, + "isCollectiveName": false, + "name": "Henry N Higgs" + }, + { + "ForeName": "Arthur", + "LastName": "Alberts", + "abbrevName": "Alberts AS", + "email": null, + "isCollectiveName": false, + "name": "Arthur S Alberts" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.cub.2007.03.024", + "pmid": "17398099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Curr Biol 17 2007", + "title": "Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex." + } + }, + { + "pmid": "11879206", + "pubmed": { + "ISODate": "2002-03-15T00:00:00.000Z", + "abstract": "The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.", + "authors": { + "abbreviation": "Mark D Bass, Bipin Patel, Igor G Barsukov, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Mark", + "LastName": "Bass", + "abbrevName": "Bass MD", + "email": null, + "isCollectiveName": false, + "name": "Mark D Bass" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IG", + "email": null, + "isCollectiveName": false, + "name": "Igor G Barsukov" + }, + { + "ForeName": "Ian", + "LastName": "Fillingham", + "abbrevName": "Fillingham IJ", + "email": null, + "isCollectiveName": false, + "name": "Ian J Fillingham" + }, + { + "ForeName": "Robert", + "LastName": "Mason", + "abbrevName": "Mason R", + "email": null, + "isCollectiveName": false, + "name": "Robert Mason" + }, + { + "ForeName": "Beverley", + "LastName": "Smith", + "abbrevName": "Smith BJ", + "email": null, + "isCollectiveName": false, + "name": "Beverley J Smith" + }, + { + "ForeName": "Clive", + "LastName": "Bagshaw", + "abbrevName": "Bagshaw CR", + "email": null, + "isCollectiveName": false, + "name": "Clive R Bagshaw" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1042/0264-6021:3620761", + "pmid": "11879206", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochem J 362 2002", + "title": "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." + } + }, + { + "pmid": "18157087", + "pubmed": { + "ISODate": "2008-01-23T00:00:00.000Z", + "abstract": "Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.", + "authors": { + "abbreviation": "Alexandre R Gingras, Neil Bate, Benjamin T Goult, ..., David R Critchley", + "authorList": [ + { + "ForeName": "Alexandre", + "LastName": "Gingras", + "abbrevName": "Gingras AR", + "email": null, + "isCollectiveName": false, + "name": "Alexandre R Gingras" + }, + { + "ForeName": "Neil", + "LastName": "Bate", + "abbrevName": "Bate N", + "email": null, + "isCollectiveName": false, + "name": "Neil Bate" + }, + { + "ForeName": "Benjamin", + "LastName": "Goult", + "abbrevName": "Goult BT", + "email": null, + "isCollectiveName": false, + "name": "Benjamin T Goult" + }, + { + "ForeName": "Larnele", + "LastName": "Hazelwood", + "abbrevName": "Hazelwood L", + "email": null, + "isCollectiveName": false, + "name": "Larnele Hazelwood" + }, + { + "ForeName": "Ilona", + "LastName": "Canestrelli", + "abbrevName": "Canestrelli I", + "email": null, + "isCollectiveName": false, + "name": "Ilona Canestrelli" + }, + { + "ForeName": "J", + "LastName": "Grossmann", + "abbrevName": "Grossmann JG", + "email": null, + "isCollectiveName": false, + "name": "J Günter Grossmann" + }, + { + "ForeName": "HongJun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "HongJun Liu" + }, + { + "ForeName": "Nicholas", + "LastName": "Putz", + "abbrevName": "Putz NS", + "email": null, + "isCollectiveName": false, + "name": "Nicholas S M Putz" + }, + { + "ForeName": "Gordon", + "LastName": "Roberts", + "abbrevName": "Roberts GC", + "email": null, + "isCollectiveName": false, + "name": "Gordon C K Roberts" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "Igor", + "LastName": "Barsukov", + "abbrevName": "Barsukov IL", + "email": null, + "isCollectiveName": false, + "name": "Igor L Barsukov" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7601965", + "pmid": "18157087", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 27 2008", + "title": "The structure of the C-terminal actin-binding domain of talin." + } + }, + { + "pmid": "28893863", + "pubmed": { + "ISODate": "2017-11-01T00:00:00.000Z", + "abstract": "Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.", + "authors": { + "abbreviation": "Nina M Dräger, Eliana Nachman, Moritz Winterhoff, ..., Thomas R Jahn", + "authorList": [ + { + "ForeName": "Nina", + "LastName": "Dräger", + "abbrevName": "Dräger NM", + "email": null, + "isCollectiveName": false, + "name": "Nina M Dräger" + }, + { + "ForeName": "Eliana", + "LastName": "Nachman", + "abbrevName": "Nachman E", + "email": null, + "isCollectiveName": false, + "name": "Eliana Nachman" + }, + { + "ForeName": "Moritz", + "LastName": "Winterhoff", + "abbrevName": "Winterhoff M", + "email": null, + "isCollectiveName": false, + "name": "Moritz Winterhoff" + }, + { + "ForeName": "Stefan", + "LastName": "Brühmann", + "abbrevName": "Brühmann S", + "email": null, + "isCollectiveName": false, + "name": "Stefan Brühmann" + }, + { + "ForeName": "Pranav", + "LastName": "Shah", + "abbrevName": "Shah P", + "email": null, + "isCollectiveName": false, + "name": "Pranav Shah" + }, + { + "ForeName": "Taxiarchis", + "LastName": "Katsinelos", + "abbrevName": "Katsinelos T", + "email": null, + "isCollectiveName": false, + "name": "Taxiarchis Katsinelos" + }, + { + "ForeName": "Steeve", + "LastName": "Boulant", + "abbrevName": "Boulant S", + "email": null, + "isCollectiveName": false, + "name": "Steeve Boulant" + }, + { + "ForeName": "Aurelio", + "LastName": "Teleman", + "abbrevName": "Teleman AA", + "email": null, + "isCollectiveName": false, + "name": "Aurelio A Teleman" + }, + { + "ForeName": "Jan", + "LastName": "Faix", + "abbrevName": "Faix J", + "email": null, + "isCollectiveName": false, + "name": "Jan Faix" + }, + { + "ForeName": "Thomas", + "LastName": "Jahn", + "abbrevName": "Jahn TR", + "email": "thomas.r.jahn@abbvie.com", + "isCollectiveName": false, + "name": "Thomas R Jahn" + } + ], + "contacts": [ + { + "ForeName": "Thomas", + "LastName": "Jahn", + "email": [ + "thomas.r.jahn@abbvie.com" + ], + "name": "Thomas R Jahn" + } + ] + }, + "doi": "10.15252/embr.201744137", + "pmid": "28893863", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "EMBO Rep 18 2017", + "title": "Bin1 directly remodels actin dynamics through its BAR domain." + } + }, + { + "pmid": "15465061", + "pubmed": { + "ISODate": "2004-10-22T00:00:00.000Z", + "abstract": "Talin is a large cytoskeletal protein that couples integrins to F-actin. Three actin-binding sites (ABS1-3) have been reported: one in the N-terminal head, and two in the C-terminal rod domain. Although the C-terminal ABS3 has been partially characterized, the presence and properties of ABS1 within the talin head are less well defined. We show here that the talin head binds F-actin in vitro and in vivo at a specific site within the actin filament. Thus, purified talin head liberated from gizzard talin by calpain cleavage cosediments with F-actin in a low salt buffer at pH 6.4 (conditions that are optimal for binding intact talin), and using recombinant polypeptides, we have mapped ABS1 to the FERM domain within the talin head. Both the F2 and F3 FERM subdomains contribute to binding, and EGFP-tagged FERM subdomains colocalize with actin stress fibers when expressed in COS cells. High-resolution electron microscopy of actin filaments decorated with F2F3 localizes binding to a site that is distinct from that recognized by members of the calponin-homology superfamily. Finally, we show that the FERM domain can couple F-actin to PIPkin, and by inference to integrins, since they bind to the same pocket in the F3 subdomain. This suggests that the talin FERM domain functions as a linker between PIPkin or integrins and F-actin at sites of cell-matrix adhesions.", + "authors": { + "abbreviation": "Ho-Sup Lee, Robert M Bellin, Diane L Walker, ..., Richard M Robson", + "authorList": [ + { + "ForeName": "Ho-Sup", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Ho-Sup Lee" + }, + { + "ForeName": "Robert", + "LastName": "Bellin", + "abbrevName": "Bellin RM", + "email": null, + "isCollectiveName": false, + "name": "Robert M Bellin" + }, + { + "ForeName": "Diane", + "LastName": "Walker", + "abbrevName": "Walker DL", + "email": null, + "isCollectiveName": false, + "name": "Diane L Walker" + }, + { + "ForeName": "Bipin", + "LastName": "Patel", + "abbrevName": "Patel B", + "email": null, + "isCollectiveName": false, + "name": "Bipin Patel" + }, + { + "ForeName": "Pam", + "LastName": "Powers", + "abbrevName": "Powers P", + "email": null, + "isCollectiveName": false, + "name": "Pam Powers" + }, + { + "ForeName": "Hongjun", + "LastName": "Liu", + "abbrevName": "Liu H", + "email": null, + "isCollectiveName": false, + "name": "Hongjun Liu" + }, + { + "ForeName": "Begoña", + "LastName": "Garcia-Alvarez", + "abbrevName": "Garcia-Alvarez B", + "email": null, + "isCollectiveName": false, + "name": "Begoña Garcia-Alvarez" + }, + { + "ForeName": "José", + "LastName": "de Pereda", + "abbrevName": "de Pereda JM", + "email": null, + "isCollectiveName": false, + "name": "José M de Pereda" + }, + { + "ForeName": "Robert", + "LastName": "Liddington", + "abbrevName": "Liddington RC", + "email": null, + "isCollectiveName": false, + "name": "Robert C Liddington" + }, + { + "ForeName": "Niels", + "LastName": "Volkmann", + "abbrevName": "Volkmann N", + "email": null, + "isCollectiveName": false, + "name": "Niels Volkmann" + }, + { + "ForeName": "Dorit", + "LastName": "Hanein", + "abbrevName": "Hanein D", + "email": null, + "isCollectiveName": false, + "name": "Dorit Hanein" + }, + { + "ForeName": "David", + "LastName": "Critchley", + "abbrevName": "Critchley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Critchley" + }, + { + "ForeName": "Richard", + "LastName": "Robson", + "abbrevName": "Robson RM", + "email": null, + "isCollectiveName": false, + "name": "Richard M Robson" + } + ], + "contacts": [] + }, + "doi": "10.1016/j.jmb.2004.08.069", + "pmid": "15465061", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "J Mol Biol 343 2004", + "title": "Characterization of an actin-binding site within the talin FERM domain." + } + }, + { + "pmid": "25465129", + "pubmed": { + "ISODate": "2014-12-02T00:00:00.000Z", + "abstract": "Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.", + "authors": { + "abbreviation": "Yu-Chung Chang, Hao Zhang, Janusz Franco-Barraza, ..., Jinhua Wu", + "authorList": [ + { + "ForeName": "Yu-Chung", + "LastName": "Chang", + "abbrevName": "Chang YC", + "email": null, + "isCollectiveName": false, + "name": "Yu-Chung Chang" + }, + { + "ForeName": "Hao", + "LastName": "Zhang", + "abbrevName": "Zhang H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhang" + }, + { + "ForeName": "Janusz", + "LastName": "Franco-Barraza", + "abbrevName": "Franco-Barraza J", + "email": null, + "isCollectiveName": false, + "name": "Janusz Franco-Barraza" + }, + { + "ForeName": "Mark", + "LastName": "Brennan", + "abbrevName": "Brennan ML", + "email": null, + "isCollectiveName": false, + "name": "Mark L Brennan" + }, + { + "ForeName": "Tejash", + "LastName": "Patel", + "abbrevName": "Patel T", + "email": null, + "isCollectiveName": false, + "name": "Tejash Patel" + }, + { + "ForeName": "Edna", + "LastName": "Cukierman", + "abbrevName": "Cukierman E", + "email": null, + "isCollectiveName": false, + "name": "Edna Cukierman" + }, + { + "ForeName": "Jinhua", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": "jinhua.wu@fccc.edu", + "isCollectiveName": false, + "name": "Jinhua Wu" + } + ], + "contacts": [ + { + "ForeName": "Jinhua", + "LastName": "Wu", + "email": [ + "jinhua.wu@fccc.edu" + ], + "name": "Jinhua Wu" + } + ] + }, + "doi": "10.1016/j.str.2014.09.020", + "pmid": "25465129", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Structure 22 2014", + "title": "Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling." + } + }, + { + "pmid": "17722883", + "pubmed": { + "ISODate": "2007-09-25T00:00:00.000Z", + "abstract": "Focal adhesion complexes are plasma membrane-associated multicomponent complexes that are essential for integrin-linked signal transduction as well as cell adhesion and cell motility. The cytoskeletal protein Talin1 links integrin adhesion receptors with the actin cytoskeleton. Talin1 and the other animal and amoebozoan talins are members of the I/LWEQ module superfamily, which also includes fungal Sla2 and animal Hip1/Hip1R. The I/LWEQ module is a conserved C-terminal structural element that is critical for I/LWEQ module protein function. The I/LWEQ module of Talin1 binds to F-actin and targets the protein to focal adhesions in vivo. The I/LWEQ modules of Sla2 and Hip1 are required for the participation of these proteins in endocytosis. In addition to these roles in I/LWEQ module protein function, we have recently shown that the I/LWEQ module also contains a determinant for protein dimerization. Taken together, these results suggest that actin binding, subcellular targeting, and dimerization are associated in I/LWEQ module proteins. In this report we have used alanine-scanning mutagenesis of a putative coiled coil at the C-terminus of the Talin1 I/LWEQ module to show that the amino acids responsible for dimerization are necessary for F-actin binding, the stabilization of actin filaments, the cross-linking of actin filaments, and focal adhesion targeting. Our results suggest that this conserved dimerization motif in the I/LWEQ module plays an essential role in the function of Talin1 as a component of focal adhesions and, by extension, the other I/LWEQ module proteins in other multicomponent assemblies involved in cell adhesion and vesicle trafficking.", + "authors": { + "abbreviation": "Steven J Smith, Richard O McCann", + "authorList": [ + { + "ForeName": "Steven", + "LastName": "Smith", + "abbrevName": "Smith SJ", + "email": null, + "isCollectiveName": false, + "name": "Steven J Smith" + }, + { + "ForeName": "Richard", + "LastName": "McCann", + "abbrevName": "McCann RO", + "email": null, + "isCollectiveName": false, + "name": "Richard O McCann" + } + ], + "contacts": [] + }, + "doi": "10.1021/bi700637a", + "pmid": "17722883", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Biochemistry 46 2007", + "title": "A C-terminal dimerization motif is required for focal adhesion targeting of Talin1 and the interaction of the Talin1 I/LWEQ module with F-actin." + } + } + ], + "secret": "read-only", + "type": "binding" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/document/testDoc.json b/neo4j-test/document/testDoc.json new file mode 100644 index 000000000..21fa4da88 --- /dev/null +++ b/neo4j-test/document/testDoc.json @@ -0,0 +1,15548 @@ +{ + "document": [ + { + "_creationTimestamp": { + "$reql_type$": "TIME", + "epoch_time": 1671052617.559, + "timezone": "+00:00" + }, + "_newestOpId": "b2ac3309-1dc5-41f6-9cb0-512998c8f0ce", + "_ops": [], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer. MAPK6 expression also correlated with AKT phosphorylation at S473 in human cancer tissues. We conclude that MAPK6 can promote cancer by activating AKT independent of mTORC2 and targeting MAPK6, either alone or in combination with mTOR blockade, may be effective in cancers.", + "ArticleTitle": "MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + }, + { + "Affiliation": "Center of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Qinbo", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0001-5294-4319" + } + ], + "Initials": "Q", + "LastName": "Cai" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + }, + { + "Affiliation": "Department of Thoracic Surgery, Xiangya Hospital of Central South University, Changsha 410008, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Wolong", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0001-8784-6196" + } + ], + "Initials": "W", + "LastName": "Zhou" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Wei", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-0600-7276" + } + ], + "Initials": "W", + "LastName": "Wang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + }, + { + "Affiliation": "Department of Medicine, Baylor College of Medicine, Houston, TX 77070, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Bingning", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-4300-3928" + } + ], + "Initials": "B", + "LastName": "Dong" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Dong", + "Identifier": [], + "Initials": "D", + "LastName": "Han" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Tao", + "Identifier": [], + "Initials": "T", + "LastName": "Shen" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Medicine, Baylor College of Medicine, Houston, TX 77070, USA.", + "email": null + }, + { + "Affiliation": "Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Chad J", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-6090-703X" + } + ], + "Initials": "CJ", + "LastName": "Creighton" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + }, + { + "Affiliation": "Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "David D", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-5151-9748" + } + ], + "Initials": "DD", + "LastName": "Moore" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Feng", + "Identifier": [ + { + "Source": "ORCID", + "id": "0000-0002-3401-5783" + } + ], + "Initials": "F", + "LastName": "Yang" + } + ], + "Journal": { + "ISOAbbreviation": "Sci Adv", + "ISSN": { + "IssnType": "Electronic", + "value": "2375-2548" + }, + "JournalIssue": { + "Issue": "46", + "PubDate": { + "Day": "12", + "Month": "Nov", + "Year": "2021" + }, + "Volume": "7" + }, + "Title": "Science advances" + }, + "PublicationTypeList": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ] + }, + "ChemicalList": [], + "InvestigatorList": [], + "KeywordList": [], + "MeshheadingList": [] + }, + "PubmedData": { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "34767444" + }, + { + "IdType": "pmc", + "id": "PMC8589317" + }, + { + "IdType": "doi", + "id": "10.1126/sciadv.abi6439" + } + ], + "History": [ + { + "PubMedPubDate": { + "Day": "12", + "Month": "11", + "Year": "2021" + }, + "PubStatus": "entrez" + }, + { + "PubMedPubDate": { + "Day": "13", + "Month": "11", + "Year": "2021" + }, + "PubStatus": "pubmed" + }, + { + "PubMedPubDate": { + "Day": "13", + "Month": "11", + "Year": "2021" + }, + "PubStatus": "medline" + } + ], + "ReferenceList": [ + { + "Reference": [ + { + "ArticleIdList": [ + { + "IdType": "pubmed", + "id": "17161475" + } + ], + "Citation": "Coulombe P., Meloche S., Atypical mitogen-activated protein kinases: Structure, regulation and functions. 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Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by MAPK4 promoted PCa cell proliferation, anchorage-independent growth, xenograft growth, and castration resistance. Conversely, knockdown of MAPK4 decreased activation of both AR and AKT and inhibited PCa cell and xenograft growth, including castration-resistant growth. Both GATA2/AR and AKT activation were necessary for MAPK4 tumor-promoting activity. Interestingly, combined overexpression of GATA2 plus a constitutively activated AKT was sufficient to drive PCa growth and castration resistance, shedding light on an alternative, MAPK4-independent tumor-promoting pathway in human PCa. We concluded that MAPK4 promotes PCa growth and castration resistance by cooperating parallel pathways of activating GATA2/AR and AKT and that MAPK4 is a novel therapeutic target in PCa, especially CRPC.", + "authors": { + "abbreviation": "Tao Shen, Wei Wang, Wolong Zhou, ..., Feng Yang", + "authorList": [ + { + "ForeName": "Tao", + "LastName": "Shen", + "abbrevName": "Shen T", + "email": null, + "isCollectiveName": false, + "name": "Tao Shen", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Wolong", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wolong Zhou", + "orcid": null + }, + { + "ForeName": "Ilsa", + "LastName": "Coleman", + "abbrevName": "Coleman I", + "email": null, + "isCollectiveName": false, + "name": "Ilsa Coleman", + "orcid": null + }, + { + "ForeName": "Qinbo", + "LastName": "Cai", + "abbrevName": "Cai Q", + "email": null, + "isCollectiveName": false, + "name": "Qinbo Cai", + "orcid": null + }, + { + "ForeName": "Bingning", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bingning Dong", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Ittmann", + "abbrevName": "Ittmann MM", + "email": null, + "isCollectiveName": false, + "name": "Michael M Ittmann", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Yingnan", + "LastName": "Bian", + "abbrevName": "Bian Y", + "email": null, + "isCollectiveName": false, + "name": "Yingnan Bian", + "orcid": null + }, + { + "ForeName": "Yanling", + "LastName": "Meng", + "abbrevName": "Meng Y", + "email": null, + "isCollectiveName": false, + "name": "Yanling Meng", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Rowley", + "abbrevName": "Rowley DR", + "email": null, + "isCollectiveName": false, + "name": "David R Rowley", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Nelson", + "abbrevName": "Nelson PS", + "email": null, + "isCollectiveName": false, + "name": "Peter S Nelson", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moore", + "abbrevName": "Moore DD", + "email": null, + "isCollectiveName": false, + "name": "David D Moore", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI135465", + "pmid": "33586682", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Clin Invest 131 2021", + "title": "MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT." + } + }, + { + "pmid": "32314963", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1587427200, + "timezone": "+00:00" + }, + "abstract": "ERK3 is a ubiquitously expressed member of the atypical mitogen activated protein kinases (MAPKs) and the physiological significance of its short half-life remains unclear. By employing gastrointestinal 3D organoids, we detect that ERK3 protein levels steadily decrease during epithelial differentiation. ERK3 is not required for 3D growth of human gastric epithelium. However, ERK3 is stabilized and activated in tumorigenic cells, but deteriorates over time in primary cells in response to lipopolysaccharide (LPS). ERK3 is necessary for production of several cellular factors including interleukin-8 (IL-8), in both, normal and tumorigenic cells. Particularly, ERK3 is critical for AP-1 signaling through its interaction and regulation of c-Jun protein. The secretome of ERK3-deficient cells is defective in chemotaxis of neutrophils and monocytes both in vitro and in vivo. Further, knockdown of ERK3 reduces metastatic potential of invasive breast cancer cells. We unveil an ERK3-mediated regulation of IL-8 and epithelial secretome for chemotaxis.", + "authors": { + "abbreviation": "Katarzyna Bogucka, Malvika Pompaiah, Federico Marini, ..., Krishnaraj Rajalingam", + "authorList": [ + { + "ForeName": "Katarzyna", + "LastName": "Bogucka", + "abbrevName": "Bogucka K", + "email": null, + "isCollectiveName": false, + "name": "Katarzyna Bogucka", + "orcid": null + }, + { + "ForeName": "Malvika", + "LastName": "Pompaiah", + "abbrevName": "Pompaiah M", + "email": null, + "isCollectiveName": false, + "name": "Malvika Pompaiah", + "orcid": null + }, + { + "ForeName": "Federico", + "LastName": "Marini", + "abbrevName": "Marini F", + "email": null, + "isCollectiveName": false, + "name": "Federico Marini", + "orcid": "0000-0003-3252-7758" + }, + { + "ForeName": "Harald", + "LastName": "Binder", + "abbrevName": "Binder H", + "email": null, + "isCollectiveName": false, + "name": "Harald Binder", + "orcid": null + }, + { + "ForeName": "Gregory", + "LastName": "Harms", + "abbrevName": "Harms G", + "email": null, + "isCollectiveName": false, + "name": "Gregory Harms", + "orcid": null + }, + { + "ForeName": "Manuel", + "LastName": "Kaulich", + "abbrevName": "Kaulich M", + "email": null, + "isCollectiveName": false, + "name": "Manuel Kaulich", + "orcid": "0000-0002-9528-8822" + }, + { + "ForeName": "Matthias", + "LastName": "Klein", + "abbrevName": "Klein M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Klein", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Michel", + "abbrevName": "Michel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Michel", + "orcid": null + }, + { + "ForeName": "Markus", + "LastName": "Radsak", + "abbrevName": "Radsak MP", + "email": null, + "isCollectiveName": false, + "name": "Markus P Radsak", + "orcid": null + }, + { + "ForeName": "Sebastian", + "LastName": "Rosigkeit", + "abbrevName": "Rosigkeit S", + "email": null, + "isCollectiveName": false, + "name": "Sebastian Rosigkeit", + "orcid": null + }, + { + "ForeName": "Peter", + "LastName": "Grimminger", + "abbrevName": "Grimminger P", + "email": null, + "isCollectiveName": false, + "name": "Peter Grimminger", + "orcid": null + }, + { + "ForeName": "Hansjörg", + "LastName": "Schild", + "abbrevName": "Schild H", + "email": null, + "isCollectiveName": false, + "name": "Hansjörg Schild", + "orcid": null + }, + { + "ForeName": "Krishnaraj", + "LastName": "Rajalingam", + "abbrevName": "Rajalingam K", + "email": null, + "isCollectiveName": false, + "name": "Krishnaraj Rajalingam", + "orcid": "0000-0002-4175-9633" + } + ], + "contacts": [] + }, + "doi": "10.7554/eLife.52511", + "pmid": "32314963", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Elife 9 2020", + "title": "ERK3/MAPK6 controls IL-8 production and chemotaxis." + } + }, + { + "pmid": "32188723", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1584489600, + "timezone": "+00:00" + }, + "abstract": null, + "authors": { + "abbreviation": null, + "authorList": null, + "contacts": null + }, + "doi": "10.1126/scitranslmed.abb5995", + "pmid": "32188723", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016425", + "value": "Published Erratum" + } + ], + "reference": "Sci Transl Med 12 2020", + "title": "Erratum for the Research Article: \"PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma\" by X. Tan, P. Banerjee, E. A. Pham, F. U. N. Rutaganira, K. Basu, N. Bota-Rabassedas, H.-F. Guo, C. L. Grzeskowiak, X. Liu, J. Yu, L. Shi, D. H. Peng, B. L. Rodriguez, J. Zhang, V. Zheng, D. Y. Duose, L. M. Solis, B. Mino, M. G. Raso, C. Behrens, I. I. Wistuba, K. L. Scott, M. Smith, K. Nguyen, G. Lam, I. Choong, A. Mazumdar, J. L. Hill, D. L. Gibbons, P. H. Brown, W. K. Russell, K. Shokat, C. J. Creighton, J. S. Glenn, J. M. Kurie." + } + }, + { + "pmid": "31016619", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1559347200, + "timezone": "+00:00" + }, + "abstract": "Cervical cancer is the third most common gynecologic cancer in the world. Exploration of the molecular mechanism underlying cervical cancer pathogenesis will provide new insights into the development of novel therapies. In this study, we were aimed to characterize a novel miRNA in cervical cancer tumorigenesis. First, we measured the expressional change of miR-144-3p in clinical tissues and cancer cells. Second, we employed cell proliferation, cell migration, and invasion assays to understand its functional role in cervical cancer. Then, we confirmed in vitro findings in xenograft cancer model. Last, we mapped out a downstream target of miR-144-3p and validated its functional role in cancer cells. In the results, miR-144-3p was found significantly downregulated in cervical cancer cells and tissues. Over-expressing miR-144-3p suppressed cancer cells growth and metastasis. Consistent with in vitro results, over-expressing miR-144-3p led to tumor growth inhibition in vivo. Further on, MAPK6 was identified as an endogenous target of miR-144-3p in cervical cancer. Knocking down MAPK6 inhibited cervical cancer cells proliferation, migration, and invasion potential. Our investigation was the first time to report miR-144-3p as a tumor suppressive miRNA in cervical cancer. It inhibited tumor growth by targeting MAKP6. The newly identified signalling axis may serve as novel therapeutic targets to manage cervical cancer.", + "authors": { + "abbreviation": "Jingli Wu, Yuying Zhao, Fenglian Li, Baohua Qiao", + "authorList": [ + { + "ForeName": "Jingli", + "LastName": "Wu", + "abbrevName": "Wu J", + "email": null, + "isCollectiveName": false, + "name": "Jingli Wu", + "orcid": null + }, + { + "ForeName": "Yuying", + "LastName": "Zhao", + "abbrevName": "Zhao Y", + "email": null, + "isCollectiveName": false, + "name": "Yuying Zhao", + "orcid": null + }, + { + "ForeName": "Fenglian", + "LastName": "Li", + "abbrevName": "Li F", + "email": null, + "isCollectiveName": false, + "name": "Fenglian Li", + "orcid": null + }, + { + "ForeName": "Baohua", + "LastName": "Qiao", + "abbrevName": "Qiao B", + "email": "qiaobaohua0909@163.com", + "isCollectiveName": false, + "name": "Baohua Qiao", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Baohua", + "LastName": "Qiao", + "email": [ + "qiaobaohua0909@163.com" + ], + "name": "Baohua Qiao" + } + ] + }, + "doi": "10.1007/s13105-019-00681-9", + "pmid": "31016619", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Physiol Biochem 75 2019", + "title": "MiR-144-3p: a novel tumor suppressor targeting MAPK6 in cervical cancer." + } + }, + { + "pmid": "30688659", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.", + "authors": { + "abbreviation": "Wei Wang, Tao Shen, Bingning Dong, ..., Feng Yang", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Shen", + "abbrevName": "Shen T", + "email": null, + "isCollectiveName": false, + "name": "Tao Shen", + "orcid": null + }, + { + "ForeName": "Bingning", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bingning Dong", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Yanling", + "LastName": "Meng", + "abbrevName": "Meng Y", + "email": null, + "isCollectiveName": false, + "name": "Yanling Meng", + "orcid": null + }, + { + "ForeName": "Wolong", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wolong Zhou", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Shi", + "abbrevName": "Shi Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Shi", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Zhou", + "abbrevName": "Zhou H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhou", + "orcid": null + }, + { + "ForeName": "Yinjie", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinjie Zhang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moore", + "abbrevName": "Moore DD", + "email": null, + "isCollectiveName": false, + "name": "David D Moore", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI97712", + "pmid": "30688659", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Clin Invest 129 2019", + "title": "MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling." + } + }, + { + "pmid": "30569573", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1564617600, + "timezone": "+00:00" + }, + "abstract": "Mitogen-activated protein kinase 6 (MAPK6) represents an atypical MAPK also known as extracellular signal-regulated kinase 3 (ERK3), which has been shown to play roles in cell motility and metastasis. ERK3 promotes migration and invasion of lung cancer cells and head and neck cancer cells by regulating the expression and/or activity of proteins involved in cancer progression. For instance, ERK3 upregulates matrix metallopeptidases and thereby promotes cancer cell invasiveness, and it phosphorylates tyrosyl-DNA phosphodiesterase 2, thereby enhancing chemoresistance in lung cancer. Here we discovered that ERK3 plays a converse role in melanoma. We observed that BRAF, an oncogenic Ser/Thr kinase, upregulates ERK3 expression levels by increasing both ERK3 messenger RNA levels and protein stability. Interestingly, although BRAF's kinase activity was required for upregulating ERK3 gene transcription, BRAF stabilized ERK3 protein in a kinase-independent fashion. We further demonstrate that ERK3 inhibits the migration, proliferation and colony formation of melanoma cells. In line with this, high level of ERK3 predicted increased survival among patients with melanomas. Taken together, these results indicate that ERK3 acts as a potent suppressor of melanoma cell growth and invasiveness.", + "authors": { + "abbreviation": "Minyi Chen, Amanda K Myers, Michael P Markey, Weiwen Long", + "authorList": [ + { + "ForeName": "Minyi", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Minyi Chen", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Myers", + "abbrevName": "Myers AK", + "email": null, + "isCollectiveName": false, + "name": "Amanda K Myers", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Markey", + "abbrevName": "Markey MP", + "email": null, + "isCollectiveName": false, + "name": "Michael P Markey", + "orcid": "0000-0002-8593-2290" + }, + { + "ForeName": "Weiwen", + "LastName": "Long", + "abbrevName": "Long W", + "email": null, + "isCollectiveName": false, + "name": "Weiwen Long", + "orcid": "0000-0002-4792-242X" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcp.27994", + "pmid": "30569573", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Physiol 234 2019", + "title": "The atypical MAPK ERK3 potently suppresses melanoma cell growth and invasiveness." + } + }, + { + "pmid": "28429763", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1492732800, + "timezone": "+00:00" + }, + "abstract": "Neointima formation is the major reason for vein graft failure. However, the underlying mechanism is unclear. The aim of this study was to determine the role of miR-26a in the development of neointimal hyperplasia of autogenous vein grafts. Using autologous jugular vein grafts in the rat carotid artery as a model, we found that miR-26a was significantly downregulated in grafted veins as well as proliferating vascular smooth muscle cells (VSMCs) stimulated with platelet-derived growth factor-BB (PDGF-BB). Overexpression of miR-26a reduced the proliferation and migration of VSMCs. Further analysis revealed that the effects of miR-26a in VSMCs were mediated by targeting MAPK6 at the mRNA and protein levels. Luciferase assays showed that miR-26a repressed wild type (WT) MAPK6-3'-UTR-luciferase activity but not mutant MAPK6-3'-UTR-luciferease reporter. MAPK6 deficiency reduced proliferation and migration; in contrast, overexpression of MAPK6 enhanced the proliferation and migration of VSMCs. This study confirmed that neointimal hyperplasia in vein grafts was reduced in vivo by up-regulated miR-26a expression. In conclusion, our results showed that miR-26a is an important regulator of VSMC functions and neointimal hyperplasia, suggesting that miR-26a may be a potential therapeutic target for autologous vein graft diseases.", + "authors": { + "abbreviation": "Juanjuan Tan, Liguo Yang, Cuicui Liu, Zhiqiang Yan", + "authorList": [ + { + "ForeName": "Juanjuan", + "LastName": "Tan", + "abbrevName": "Tan J", + "email": null, + "isCollectiveName": false, + "name": "Juanjuan Tan", + "orcid": null + }, + { + "ForeName": "Liguo", + "LastName": "Yang", + "abbrevName": "Yang L", + "email": null, + "isCollectiveName": false, + "name": "Liguo Yang", + "orcid": null + }, + { + "ForeName": "Cuicui", + "LastName": "Liu", + "abbrevName": "Liu C", + "email": null, + "isCollectiveName": false, + "name": "Cuicui Liu", + "orcid": null + }, + { + "ForeName": "Zhiqiang", + "LastName": "Yan", + "abbrevName": "Yan Z", + "email": null, + "isCollectiveName": false, + "name": "Zhiqiang Yan", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/srep46602", + "pmid": "28429763", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Sci Rep 7 2017", + "title": "MicroRNA-26a targets MAPK6 to inhibit smooth muscle cell proliferation and vein graft neointimal hyperplasia." + } + }, + { + "pmid": "28241849", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1488240000, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Arsenic trioxide (ATO) is commonly used in the treatment of acute promyelocytic leukemia (APL), but does not benefit patients with solid tumors. When combined with other agents or radiation, ATO showed treatment benefits with manageable toxicity. Previously, we reported that metformin amplified the inhibitory effect of ATO on intrahepatic cholangiocarcinoma (ICC) cells more significantly than other agents. Here, we investigated the chemotherapeutic sensitization effect of metformin in ATO-based treatment in ICC in vitro and in vivo and explored the underlying mechanisms. METHODS: ICC cell lines (CCLP-1, RBE, and HCCC-9810) were treated with metformin and/or ATO; the anti-proliferation effect was evaluated by cell viability, cell apoptosis, cell cycle, and intracellular-reactive oxygen species (ROS) assays. The in vivo efficacy was determined in nude mice with CCLP-1 xenografts. The active status of AMPK/p38 MAPK and mTORC1 pathways was detected by western blot. In addition, an antibody array was used screening more than 200 molecules clustered in 12 cancer-related pathways in CCLP-1 cells treated with metformin and/or ATO. Methods of genetic modulation and pharmacology were further used to demonstrate the relationship of the molecule. Seventy-three tumor samples from ICC patients were used to detect the expression of ERK3 by immunohistochemistry. The correlation between ERK3 and the clinical information of ICC patients were further analyzed. RESULTS: Metformin and ATO synergistically inhibited proliferation of ICC cells by promoting cell apoptosis, inducing G0/G1 cell cycle arrest, and increasing intracellular ROS. Combined treatment with metformin and ATO efficiently reduced ICC growth in an ICC xenograft model. Mechanistically, the antibody array revealed that ERK3 exhibited the highest variation in CCLP-1 cells after treatment with metformin and ATO. Results of western blot confirm that metformin and ATO cooperated to inhibit mTORC1, activate AMP-activated protein kinase (AMPK), and upregulate ERK3. Metformin abrogated the activation of p38 MAPK induced by ATO, and this activity was partially dependent on AMPK activation. Inactivation of p38 MAPK by SB203580 or specific short interfering RNA (siRNA) promoted the inactivation of mTORC1 in ICC cells treated with metformin and ATO. Activation of p38 MAPK may be responsible for resistance to ATO in ICC. The relationship between p38 MAPK and ERK3 was not defined by our findings. Finally, AMPK is a newfound positive regulator of ERK3. Overexpression of EKR3 in ICC cells inhibited cell proliferation through inactivation of mTORC1. ERK3 expression is associated with a better prognosis in ICC patients. CONCLUSIONS: Metformin sensitizes arsenic trioxide to suppress intrahepatic cholangiocarcinoma via the regulation of AMPK/p38 MAPK-ERK3/mTORC1 pathways. ERK3 is a newfound potential prognostic predictor and a tumor suppressor in ICC.", + "authors": { + "abbreviation": "Sunbin Ling, Haiyang Xie, Fan Yang, ..., Shusen Zheng", + "authorList": [ + { + "ForeName": "Sunbin", + "LastName": "Ling", + "abbrevName": "Ling S", + "email": null, + "isCollectiveName": false, + "name": "Sunbin Ling", + "orcid": null + }, + { + "ForeName": "Haiyang", + "LastName": "Xie", + "abbrevName": "Xie H", + "email": null, + "isCollectiveName": false, + "name": "Haiyang Xie", + "orcid": null + }, + { + "ForeName": "Fan", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Fan Yang", + "orcid": null + }, + { + "ForeName": "Qiaonan", + "LastName": "Shan", + "abbrevName": "Shan Q", + "email": null, + "isCollectiveName": false, + "name": "Qiaonan Shan", + "orcid": null + }, + { + "ForeName": "Haojiang", + "LastName": "Dai", + "abbrevName": "Dai H", + "email": null, + "isCollectiveName": false, + "name": "Haojiang Dai", + "orcid": null + }, + { + "ForeName": "Jianyong", + "LastName": "Zhuo", + "abbrevName": "Zhuo J", + "email": null, + "isCollectiveName": false, + "name": "Jianyong Zhuo", + "orcid": null + }, + { + "ForeName": "Xuyong", + "LastName": "Wei", + "abbrevName": "Wei X", + "email": null, + "isCollectiveName": false, + "name": "Xuyong Wei", + "orcid": null + }, + { + "ForeName": "Penghong", + "LastName": "Song", + "abbrevName": "Song P", + "email": null, + "isCollectiveName": false, + "name": "Penghong Song", + "orcid": null + }, + { + "ForeName": "Lin", + "LastName": "Zhou", + "abbrevName": "Zhou L", + "email": null, + "isCollectiveName": false, + "name": "Lin Zhou", + "orcid": null + }, + { + "ForeName": "Xiao", + "LastName": "Xu", + "abbrevName": "Xu X", + "email": null, + "isCollectiveName": false, + "name": "Xiao Xu", + "orcid": null + }, + { + "ForeName": "Shusen", + "LastName": "Zheng", + "abbrevName": "Zheng S", + "email": "shusenzheng@zju.edu.cn", + "isCollectiveName": false, + "name": "Shusen Zheng", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Shusen", + "LastName": "Zheng", + "email": [ + "shusenzheng@zju.edu.cn" + ], + "name": "Shusen Zheng" + } + ] + }, + "doi": "10.1186/s13045-017-0424-0", + "pmid": "28241849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Hematol Oncol 10 2017", + "title": "Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1." + } + }, + { + "pmid": "28079973", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1485907200, + "timezone": "+00:00" + }, + "abstract": "Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i, which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i, and ERK3, which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression.", + "authors": { + "abbreviation": "Lobna Elkhadragy, Minyi Chen, Kennon Miller, ..., Weiwen Long", + "authorList": [ + { + "ForeName": "Lobna", + "LastName": "Elkhadragy", + "abbrevName": "Elkhadragy L", + "email": null, + "isCollectiveName": false, + "name": "Lobna Elkhadragy", + "orcid": null + }, + { + "ForeName": "Minyi", + "LastName": "Chen", + "abbrevName": "Chen M", + "email": null, + "isCollectiveName": false, + "name": "Minyi Chen", + "orcid": null + }, + { + "ForeName": "Kennon", + "LastName": "Miller", + "abbrevName": "Miller K", + "email": null, + "isCollectiveName": false, + "name": "Kennon Miller", + "orcid": null + }, + { + "ForeName": "Muh-Hwa", + "LastName": "Yang", + "abbrevName": "Yang MH", + "email": null, + "isCollectiveName": false, + "name": "Muh-Hwa Yang", + "orcid": null + }, + { + "ForeName": "Weiwen", + "LastName": "Long", + "abbrevName": "Long W", + "email": null, + "isCollectiveName": false, + "name": "Weiwen Long", + "orcid": "0000-0002-4792-242X" + } + ], + "contacts": [] + }, + "doi": "10.1002/1878-0261.12021", + "pmid": "28079973", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Mol Oncol 11 2017", + "title": "A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells." + } + }, + { + "pmid": "26701725", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1454976000, + "timezone": "+00:00" + }, + "abstract": "Posttranslational modifications (PTMs), such as phosphorylation and ubiquitination, play critical regulatory roles in the assembly of DNA damage response proteins on the DNA damage site and their activities in DNA damage repair. Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, thereby protecting cancer cells against Top2 inhibitors-induced growth inhibition and cell death. The regulation of TDP2 activity by post-translational modifications in DNA repair, however, remains unclear. In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. As such, our study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors.", + "authors": { + "abbreviation": "Ka Bian, Naveen Reddy Muppani, Lobna Elkhadragy, ..., Weiwen Long", + "authorList": [ + { + "ForeName": "Ka", + "LastName": "Bian", + "abbrevName": "Bian K", + "email": null, + "isCollectiveName": false, + "name": "Ka Bian", + "orcid": null + }, + { + "ForeName": "Naveen", + "LastName": "Muppani", + "abbrevName": "Muppani NR", + "email": null, + "isCollectiveName": false, + "name": "Naveen Reddy Muppani", + "orcid": null + }, + { + "ForeName": "Lobna", + "LastName": "Elkhadragy", + "abbrevName": "Elkhadragy L", + "email": null, + "isCollectiveName": false, + "name": "Lobna Elkhadragy", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Cheng", + "LastName": "Zhang", + "abbrevName": "Zhang C", + "email": null, + "isCollectiveName": false, + "name": "Cheng Zhang", + "orcid": null + }, + { + "ForeName": "Tenghui", + "LastName": "Chen", + "abbrevName": "Chen T", + "email": null, + "isCollectiveName": false, + "name": "Tenghui Chen", + "orcid": null + }, + { + "ForeName": "Sungyun", + "LastName": "Jung", + "abbrevName": "Jung S", + "email": null, + "isCollectiveName": false, + "name": "Sungyun Jung", + "orcid": null + }, + { + "ForeName": "Ole", + "LastName": "Seternes", + "abbrevName": "Seternes OM", + "email": null, + "isCollectiveName": false, + "name": "Ole Morten Seternes", + "orcid": null + }, + { + "ForeName": "Weiwen", + "LastName": "Long", + "abbrevName": "Long W", + "email": null, + "isCollectiveName": false, + "name": "Weiwen Long", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.18632/oncotarget.6682", + "pmid": "26701725", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Oncotarget 7 2016", + "title": "ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells." + } + }, + { + "pmid": "26588708", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1420070400, + "timezone": "+00:00" + }, + "abstract": "ERK3 is an atypical Mitogen-activated protein kinase (MAPK6). Despite the fact that the Erk3 gene was originally identified in 1991, its function is still unknown. MK5 (MAP kinase- activated protein kinase 5) also called PRAK is the only known substrate for ERK3. Recently, it was found that group I p21 protein activated kinases (PAKs) are critical effectors of ERK3. PAKs link Rho family of GTPases to actin cytoskeletal dynamics and are known to be involved in the regulation of cell adhesion and migration. In this study we demonstrate that ERK3 protein levels are elevated as MDA-MB-231 breast cancer cells adhere to collagen I which is concomitant with changes in cellular morphology where cells become less well spread following nascent adhesion formation. During this early cellular adhesion event we observe that the cells retain protrusive activity while reducing overall cellular area. Interestingly exogenous expression of ERK3 delivers a comparable reduction in cell spread area, while depletion of ERK3 expression increases cell spread area. Importantly, we have detected a novel specific endogenous ERK3 localization at the cell periphery. Furthermore we find that ERK3 overexpressing cells exhibit a rounded morphology and increased cell migration speed. Surprisingly, exogenous expression of a kinase inactive mutant of ERK3 phenocopies ERK3 overexpression, suggesting a novel kinase independent function for ERK3. Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior.", + "authors": { + "abbreviation": "Rania Al-Mahdi, Nouf Babteen, Kiruthikah Thillai, ..., Claire M Wells", + "authorList": [ + { + "ForeName": "Rania", + "LastName": "Al-Mahdi", + "abbrevName": "Al-Mahdi R", + "email": null, + "isCollectiveName": false, + "name": "Rania Al-Mahdi", + "orcid": null + }, + { + "ForeName": "Nouf", + "LastName": "Babteen", + "abbrevName": "Babteen N", + "email": null, + "isCollectiveName": false, + "name": "Nouf Babteen", + "orcid": null + }, + { + "ForeName": "Kiruthikah", + "LastName": "Thillai", + "abbrevName": "Thillai K", + "email": null, + "isCollectiveName": false, + "name": "Kiruthikah Thillai", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "Holt", + "abbrevName": "Holt M", + "email": null, + "isCollectiveName": false, + "name": "Mark Holt", + "orcid": null + }, + { + "ForeName": "Bjarne", + "LastName": "Johansen", + "abbrevName": "Johansen B", + "email": null, + "isCollectiveName": false, + "name": "Bjarne Johansen", + "orcid": null + }, + { + "ForeName": "Hilde", + "LastName": "Wetting", + "abbrevName": "Wetting HL", + "email": null, + "isCollectiveName": false, + "name": "Hilde Ljones Wetting", + "orcid": null + }, + { + "ForeName": "Ole-Morten", + "LastName": "Seternes", + "abbrevName": "Seternes OM", + "email": null, + "isCollectiveName": false, + "name": "Ole-Morten Seternes", + "orcid": null + }, + { + "ForeName": "Claire", + "LastName": "Wells", + "abbrevName": "Wells CM", + "email": null, + "isCollectiveName": false, + "name": "Claire M Wells", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1080/19336918.2015.1112485", + "pmid": "26588708", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Adh Migr 9 2015", + "title": "A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration." + } + }, + { + "pmid": "24585635", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1412121600, + "timezone": "+00:00" + }, + "abstract": "Despite a regain of interest recently in ERK3 kinase signaling, the molecular regulations of both ERK3 gene expression and protein kinase activity are still largely unknown. While it is shown that disruption of ERK3 gene causes neonatal lethality, cell type-specific functions of ERK3 signaling remain to be explored. In this study, we report that ERK3 gene expression is upregulated by cytokines through c-Jun in endothelial cells; c-Jun binds to the ERK3 gene and regulates its transcription. We further reveal a new role for ERK3 in regulating endothelial cell migration, proliferation and tube formation by upregulating SRC-3/SP-1-mediated VEGFR2 expression. The underlying molecular mechanism involves ERK3-stimulated formation of a transcriptional complex involving coactivator SRC-3, transcription factor SP-1 and the secondary coactivator CBP. Taken together, our study identified a molecular regulatory mechanism of ERK3 gene expression and revealed a previously unknown role of ERK3 in regulating endothelial cell functions.", + "authors": { + "abbreviation": "Wei Wang, Ka Bian, Sreeram Vallabhaneni, ..., Weiwen Long", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Ka", + "LastName": "Bian", + "abbrevName": "Bian K", + "email": null, + "isCollectiveName": false, + "name": "Ka Bian", + "orcid": null + }, + { + "ForeName": "Sreeram", + "LastName": "Vallabhaneni", + "abbrevName": "Vallabhaneni S", + "email": null, + "isCollectiveName": false, + "name": "Sreeram Vallabhaneni", + "orcid": null + }, + { + "ForeName": "Bin", + "LastName": "Zhang", + "abbrevName": "Zhang B", + "email": null, + "isCollectiveName": false, + "name": "Bin Zhang", + "orcid": null + }, + { + "ForeName": "Ray-Chang", + "LastName": "Wu", + "abbrevName": "Wu RC", + "email": null, + "isCollectiveName": false, + "name": "Ray-Chang Wu", + "orcid": null + }, + { + "ForeName": "Bert", + "LastName": "O'Malley", + "abbrevName": "O'Malley BW", + "email": null, + "isCollectiveName": false, + "name": "Bert W O'Malley", + "orcid": null + }, + { + "ForeName": "Weiwen", + "LastName": "Long", + "abbrevName": "Long W", + "email": null, + "isCollectiveName": false, + "name": "Weiwen Long", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/jcp.24596", + "pmid": "24585635", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "J Cell Physiol 229 2014", + "title": "ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression." + } + }, + { + "pmid": "24071849", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1380585600, + "timezone": "+00:00" + }, + "abstract": "The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.", + "authors": { + "abbreviation": "Cancer Genome Atlas Research Network, John N Weinstein, Eric A Collisson, ..., Joshua M Stuart", + "authorList": [ + { + "ForeName": null, + "LastName": null, + "abbrevName": "Cancer Genome Atlas Research Network", + "email": null, + "isCollectiveName": true, + "name": "Cancer Genome Atlas Research Network", + "orcid": null + }, + { + "ForeName": "John", + "LastName": "Weinstein", + "abbrevName": "Weinstein JN", + "email": null, + "isCollectiveName": false, + "name": "John N Weinstein", + "orcid": null + }, + { + "ForeName": "Eric", + "LastName": "Collisson", + "abbrevName": "Collisson EA", + "email": null, + "isCollectiveName": false, + "name": "Eric A Collisson", + "orcid": null + }, + { + "ForeName": "Gordon", + "LastName": "Mills", + "abbrevName": "Mills GB", + "email": null, + "isCollectiveName": false, + "name": "Gordon B Mills", + "orcid": null + }, + { + "ForeName": "Kenna", + "LastName": "Shaw", + "abbrevName": "Shaw KR", + "email": null, + "isCollectiveName": false, + "name": "Kenna R Mills Shaw", + "orcid": null + }, + { + "ForeName": "Brad", + "LastName": "Ozenberger", + "abbrevName": "Ozenberger BA", + "email": null, + "isCollectiveName": false, + "name": "Brad A Ozenberger", + "orcid": null + }, + { + "ForeName": "Kyle", + "LastName": "Ellrott", + "abbrevName": "Ellrott K", + "email": null, + "isCollectiveName": false, + "name": "Kyle Ellrott", + "orcid": null + }, + { + "ForeName": "Ilya", + "LastName": "Shmulevich", + "abbrevName": "Shmulevich I", + "email": null, + "isCollectiveName": false, + "name": "Ilya Shmulevich", + "orcid": null + }, + { + "ForeName": "Chris", + "LastName": "Sander", + "abbrevName": "Sander C", + "email": null, + "isCollectiveName": false, + "name": "Chris Sander", + "orcid": null + }, + { + "ForeName": "Joshua", + "LastName": "Stuart", + "abbrevName": "Stuart JM", + "email": null, + "isCollectiveName": false, + "name": "Joshua M Stuart", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/ng.2764", + "pmid": "24071849", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "Nat Genet 45 2013", + "title": "The Cancer Genome Atlas Pan-Cancer analysis project." + } + }, + { + "pmid": "22505454", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1335830400, + "timezone": "+00:00" + }, + "abstract": "In contrast to the well-studied classic MAPKs, such as ERK1/2, little is known concerning the regulation and substrates of the atypical MAPK ERK3 signaling cascade and its function in cancer progression. Here, we report that ERK3 interacted with and phosphorylated steroid receptor coactivator 3 (SRC-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (S857). This ERK3-mediated phosphorylation at S857 was essential for interaction of SRC-3 with the ETS transcription factor PEA3, which promotes upregulation of MMP gene expression and proinvasive activity in lung cancer cells. Importantly, knockdown of ERK3 or SRC-3 inhibited the ability of lung cancer cells to invade and form tumors in the lung in a xenograft mouse model. In addition, ERK3 was found to be highly upregulated in human lung carcinomas. Our study identifies a previously unknown role for ERK3 in promoting lung cancer cell invasiveness by phosphorylating SRC-3 and regulating SRC-3 proinvasive activity by site-specific phosphorylation. As such, ERK3 protein kinase may be an attractive target for therapeutic treatment of invasive lung cancer.", + "authors": { + "abbreviation": "Weiwen Long, Charles E Foulds, Jun Qin, ..., Bert W O'Malley", + "authorList": [ + { + "ForeName": "Weiwen", + "LastName": "Long", + "abbrevName": "Long W", + "email": null, + "isCollectiveName": false, + "name": "Weiwen Long", + "orcid": null + }, + { + "ForeName": "Charles", + "LastName": "Foulds", + "abbrevName": "Foulds CE", + "email": null, + "isCollectiveName": false, + "name": "Charles E Foulds", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin", + "orcid": null + }, + { + "ForeName": "Jian", + "LastName": "Liu", + "abbrevName": "Liu J", + "email": null, + "isCollectiveName": false, + "name": "Jian Liu", + "orcid": null + }, + { + "ForeName": "Chen", + "LastName": "Ding", + "abbrevName": "Ding C", + "email": null, + "isCollectiveName": false, + "name": "Chen Ding", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Lonard", + "abbrevName": "Lonard DM", + "email": null, + "isCollectiveName": false, + "name": "David M Lonard", + "orcid": null + }, + { + "ForeName": "Luisa", + "LastName": "Solis", + "abbrevName": "Solis LM", + "email": null, + "isCollectiveName": false, + "name": "Luisa M Solis", + "orcid": null + }, + { + "ForeName": "Ignacio", + "LastName": "Wistuba", + "abbrevName": "Wistuba II", + "email": null, + "isCollectiveName": false, + "name": "Ignacio I Wistuba", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Qin", + "abbrevName": "Qin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Qin", + "orcid": null + }, + { + "ForeName": "Sophia", + "LastName": "Tsai", + "abbrevName": "Tsai SY", + "email": null, + "isCollectiveName": false, + "name": "Sophia Y Tsai", + "orcid": null + }, + { + "ForeName": "Ming-Jer", + "LastName": "Tsai", + "abbrevName": "Tsai MJ", + "email": null, + "isCollectiveName": false, + "name": "Ming-Jer Tsai", + "orcid": null + }, + { + "ForeName": "Bert", + "LastName": "O'Malley", + "abbrevName": "O'Malley BW", + "email": null, + "isCollectiveName": false, + "name": "Bert W O'Malley", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI61492", + "pmid": "22505454", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Clin Invest 122 2012", + "title": "ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion." + } + }, + { + "pmid": "22367541", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1329868800, + "timezone": "+00:00" + }, + "abstract": "The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.", + "authors": { + "abbreviation": "Andrew C Hsieh, Yi Liu, Merritt P Edlind, ..., Davide Ruggero", + "authorList": [ + { + "ForeName": "Andrew", + "LastName": "Hsieh", + "abbrevName": "Hsieh AC", + "email": null, + "isCollectiveName": false, + "name": "Andrew C Hsieh", + "orcid": null + }, + { + "ForeName": "Yi", + "LastName": "Liu", + "abbrevName": "Liu Y", + "email": null, + "isCollectiveName": false, + "name": "Yi Liu", + "orcid": null + }, + { + "ForeName": "Merritt", + "LastName": "Edlind", + "abbrevName": "Edlind MP", + "email": null, + "isCollectiveName": false, + "name": "Merritt P Edlind", + "orcid": null + }, + { + "ForeName": "Nicholas", + "LastName": "Ingolia", + "abbrevName": "Ingolia NT", + "email": null, + "isCollectiveName": false, + "name": "Nicholas T Ingolia", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Janes", + "abbrevName": "Janes MR", + "email": null, + "isCollectiveName": false, + "name": "Matthew R Janes", + "orcid": null + }, + { + "ForeName": "Annie", + "LastName": "Sher", + "abbrevName": "Sher A", + "email": null, + "isCollectiveName": false, + "name": "Annie Sher", + "orcid": null + }, + { + "ForeName": "Evan", + "LastName": "Shi", + "abbrevName": "Shi EY", + "email": null, + "isCollectiveName": false, + "name": "Evan Y Shi", + "orcid": null + }, + { + "ForeName": "Craig", + "LastName": "Stumpf", + "abbrevName": "Stumpf CR", + "email": null, + "isCollectiveName": false, + "name": "Craig R Stumpf", + "orcid": null + }, + { + "ForeName": "Carly", + "LastName": "Christensen", + "abbrevName": "Christensen C", + "email": null, + "isCollectiveName": false, + "name": "Carly Christensen", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Bonham", + "abbrevName": "Bonham MJ", + "email": null, + "isCollectiveName": false, + "name": "Michael J Bonham", + "orcid": null + }, + { + "ForeName": "Shunyou", + "LastName": "Wang", + "abbrevName": "Wang S", + "email": null, + "isCollectiveName": false, + "name": "Shunyou Wang", + "orcid": null + }, + { + "ForeName": "Pingda", + "LastName": "Ren", + "abbrevName": "Ren P", + "email": null, + "isCollectiveName": false, + "name": "Pingda Ren", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Martin", + "abbrevName": "Martin M", + "email": null, + "isCollectiveName": false, + "name": "Michael Martin", + "orcid": null + }, + { + "ForeName": "Katti", + "LastName": "Jessen", + "abbrevName": "Jessen K", + "email": null, + "isCollectiveName": false, + "name": "Katti Jessen", + "orcid": null + }, + { + "ForeName": "Morris", + "LastName": "Feldman", + "abbrevName": "Feldman ME", + "email": null, + "isCollectiveName": false, + "name": "Morris E Feldman", + "orcid": null + }, + { + "ForeName": "Jonathan", + "LastName": "Weissman", + "abbrevName": "Weissman JS", + "email": null, + "isCollectiveName": false, + "name": "Jonathan S Weissman", + "orcid": null + }, + { + "ForeName": "Kevan", + "LastName": "Shokat", + "abbrevName": "Shokat KM", + "email": null, + "isCollectiveName": false, + "name": "Kevan M Shokat", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Rommel", + "abbrevName": "Rommel C", + "email": null, + "isCollectiveName": false, + "name": "Christian Rommel", + "orcid": null + }, + { + "ForeName": "Davide", + "LastName": "Ruggero", + "abbrevName": "Ruggero D", + "email": null, + "isCollectiveName": false, + "name": "Davide Ruggero", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/nature10912", + "pmid": "22367541", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Nature 485 2012", + "title": "The translational landscape of mTOR signalling steers cancer initiation and metastasis." + } + }, + { + "pmid": "22157079", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1327017600, + "timezone": "+00:00" + }, + "abstract": "Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers.", + "authors": { + "abbreviation": "Jessica D Kessler, Kristopher T Kahle, Tingting Sun, ..., Thomas F Westbrook", + "authorList": [ + { + "ForeName": "Jessica", + "LastName": "Kessler", + "abbrevName": "Kessler JD", + "email": null, + "isCollectiveName": false, + "name": "Jessica D Kessler", + "orcid": null + }, + { + "ForeName": "Kristopher", + "LastName": "Kahle", + "abbrevName": "Kahle KT", + "email": null, + "isCollectiveName": false, + "name": "Kristopher T Kahle", + "orcid": null + }, + { + "ForeName": "Tingting", + "LastName": "Sun", + "abbrevName": "Sun T", + "email": null, + "isCollectiveName": false, + "name": "Tingting Sun", + "orcid": null + }, + { + "ForeName": "Kristen", + "LastName": "Meerbrey", + "abbrevName": "Meerbrey KL", + "email": null, + "isCollectiveName": false, + "name": "Kristen L Meerbrey", + "orcid": null + }, + { + "ForeName": "Michael", + "LastName": "Schlabach", + "abbrevName": "Schlabach MR", + "email": null, + "isCollectiveName": false, + "name": "Michael R Schlabach", + "orcid": null + }, + { + "ForeName": "Earlene", + "LastName": "Schmitt", + "abbrevName": "Schmitt EM", + "email": null, + "isCollectiveName": false, + "name": "Earlene M Schmitt", + "orcid": null + }, + { + "ForeName": "Samuel", + "LastName": "Skinner", + "abbrevName": "Skinner SO", + "email": null, + "isCollectiveName": false, + "name": "Samuel O Skinner", + "orcid": null + }, + { + "ForeName": "Qikai", + "LastName": "Xu", + "abbrevName": "Xu Q", + "email": null, + "isCollectiveName": false, + "name": "Qikai Xu", + "orcid": null + }, + { + "ForeName": "Mamie", + "LastName": "Li", + "abbrevName": "Li MZ", + "email": null, + "isCollectiveName": false, + "name": "Mamie Z Li", + "orcid": null + }, + { + "ForeName": "Zachary", + "LastName": "Hartman", + "abbrevName": "Hartman ZC", + "email": null, + "isCollectiveName": false, + "name": "Zachary C Hartman", + "orcid": null + }, + { + "ForeName": "Mitchell", + "LastName": "Rao", + "abbrevName": "Rao M", + "email": null, + "isCollectiveName": false, + "name": "Mitchell Rao", + "orcid": null + }, + { + "ForeName": "Peng", + "LastName": "Yu", + "abbrevName": "Yu P", + "email": null, + "isCollectiveName": false, + "name": "Peng Yu", + "orcid": null + }, + { + "ForeName": "Rocio", + "LastName": "Dominguez-Vidana", + "abbrevName": "Dominguez-Vidana R", + "email": null, + "isCollectiveName": false, + "name": "Rocio Dominguez-Vidana", + "orcid": null + }, + { + "ForeName": "Anthony", + "LastName": "Liang", + "abbrevName": "Liang AC", + "email": null, + "isCollectiveName": false, + "name": "Anthony C Liang", + "orcid": null + }, + { + "ForeName": "Nicole", + "LastName": "Solimini", + "abbrevName": "Solimini NL", + "email": null, + "isCollectiveName": false, + "name": "Nicole L Solimini", + "orcid": null + }, + { + "ForeName": "Ronald", + "LastName": "Bernardi", + "abbrevName": "Bernardi RJ", + "email": null, + "isCollectiveName": false, + "name": "Ronald J Bernardi", + "orcid": null + }, + { + "ForeName": "Bing", + "LastName": "Yu", + "abbrevName": "Yu B", + "email": null, + "isCollectiveName": false, + "name": "Bing Yu", + "orcid": null + }, + { + "ForeName": "Tiffany", + "LastName": "Hsu", + "abbrevName": "Hsu T", + "email": null, + "isCollectiveName": false, + "name": "Tiffany Hsu", + "orcid": null + }, + { + "ForeName": "Ido", + "LastName": "Golding", + "abbrevName": "Golding I", + "email": null, + "isCollectiveName": false, + "name": "Ido Golding", + "orcid": null + }, + { + "ForeName": "Ji", + "LastName": "Luo", + "abbrevName": "Luo J", + "email": null, + "isCollectiveName": false, + "name": "Ji Luo", + "orcid": null + }, + { + "ForeName": "C", + "LastName": "Osborne", + "abbrevName": "Osborne CK", + "email": null, + "isCollectiveName": false, + "name": "C Kent Osborne", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Susan", + "LastName": "Hilsenbeck", + "abbrevName": "Hilsenbeck SG", + "email": null, + "isCollectiveName": false, + "name": "Susan G Hilsenbeck", + "orcid": null + }, + { + "ForeName": "Rachel", + "LastName": "Schiff", + "abbrevName": "Schiff R", + "email": null, + "isCollectiveName": false, + "name": "Rachel Schiff", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Shaw", + "abbrevName": "Shaw CA", + "email": null, + "isCollectiveName": false, + "name": "Chad A Shaw", + "orcid": null + }, + { + "ForeName": "Stephen", + "LastName": "Elledge", + "abbrevName": "Elledge SJ", + "email": null, + "isCollectiveName": false, + "name": "Stephen J Elledge", + "orcid": null + }, + { + "ForeName": "Thomas", + "LastName": "Westbrook", + "abbrevName": "Westbrook TF", + "email": null, + "isCollectiveName": false, + "name": "Thomas F Westbrook", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1212728", + "pmid": "22157079", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Science 335 2012", + "title": "A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis." + } + }, + { + "pmid": "21372320", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1298937600, + "timezone": "+00:00" + }, + "abstract": "The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.", + "authors": { + "abbreviation": "Marie Cargnello, Philippe P Roux", + "authorList": [ + { + "ForeName": "Marie", + "LastName": "Cargnello", + "abbrevName": "Cargnello M", + "email": null, + "isCollectiveName": false, + "name": "Marie Cargnello", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Roux", + "abbrevName": "Roux PP", + "email": null, + "isCollectiveName": false, + "name": "Philippe P Roux", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1128/MMBR.00031-10", + "pmid": "21372320", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Microbiol Mol Biol Rev 75 2011", + "title": "Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases." + } + }, + { + "pmid": "21317288", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1302825600, + "timezone": "+00:00" + }, + "abstract": "The class I p21-activated kinases (Pak1-3) regulate many essential biological processes, including cytoskeletal rearrangement, cell cycle progression, apoptosis, and cellular transformation. Although many Pak substrates, including elements of MAPK signaling cascades, have been identified, it is likely that additional substrates remain to be discovered. Identification of such substrates, and determination of the consequences of their phosphorylation, is essential for a better understanding of class I Pak activity. To identify novel class I Pak substrates, we used recombinant Pak2 to screen high density protein microarrays. This approach identified the atypical MAPK Erk3 as a potential Pak2 substrate. Solution-based in vitro kinase assays using recombinant Erk3 confirmed the protein microarray results, and phospho-specific antisera identified serine 189, within the Erk3 activation loop, as a site directly phosphorylated by Pak2 in vitro. Erk3 protein is known to shuttle between the cytoplasm and the nucleus, and we showed that selective inhibition of class I Pak kinase activity in cells promoted increased nuclear accumulation of Erk3. Pak inhibition in cells additionally reduced the extent of Ser(189) phosphorylation and inhibited the formation of Erk3-Prak complexes. Collectively, our results identify the Erk3 protein as a novel class I Pak substrate and further suggest a role for Pak kinase activity in atypical MAPK signaling.", + "authors": { + "abbreviation": "Alina De la Mota-Peynado, Jonathan Chernoff, Alexander Beeser", + "authorList": [ + { + "ForeName": "Alina", + "LastName": "De la Mota-Peynado", + "abbrevName": "De la Mota-Peynado A", + "email": null, + "isCollectiveName": false, + "name": "Alina De la Mota-Peynado", + "orcid": null + }, + { + "ForeName": "Jonathan", + "LastName": "Chernoff", + "abbrevName": "Chernoff J", + "email": null, + "isCollectiveName": false, + "name": "Jonathan Chernoff", + "orcid": null + }, + { + "ForeName": "Alexander", + "LastName": "Beeser", + "abbrevName": "Beeser A", + "email": null, + "isCollectiveName": false, + "name": "Alexander Beeser", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.181743", + "pmid": "21317288", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 286 2011", + "title": "Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity." + } + }, + { + "pmid": "21177870", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1298592000, + "timezone": "+00:00" + }, + "abstract": "Classical mitogen-activated protein (MAP) kinases are activated by dual phosphorylation of the Thr-Xxx-Tyr motif in their activation loop, which is catalyzed by members of the MAP kinase kinase family. The atypical MAP kinases extracellular signal-regulated kinase 3 (ERK3) and ERK4 contain a single phospho-acceptor site in this segment and are not substrates of MAP kinase kinases. Previous studies have shown that ERK3 and ERK4 are phosphorylated on activation loop residue Ser-189/Ser-186, resulting in their catalytic activation. However, the identity of the protein kinase mediating this regulatory event has remained elusive. We have used an unbiased biochemical purification approach to isolate the kinase activity responsible for ERK3 Ser-189 phosphorylation. Here, we report the identification of group I p21-activated kinases (PAKs) as ERK3/ERK4 activation loop kinases. We show that group I PAKs phosphorylate ERK3 and ERK4 on Ser-189 and Ser-186, respectively, both in vitro and in vivo, and that expression of activated Rac1 augments this response. Reciprocally, silencing of PAK1/2/3 expression by RNA interference (RNAi) completely abolishes Rac1-induced Ser-189 phosphorylation of ERK3. Importantly, we demonstrate that PAK-mediated phosphorylation of ERK3/ERK4 results in their enzymatic activation and in downstream activation of MAP kinase-activated protein kinase 5 (MK5) in vivo. Our results reveal that group I PAKs act as upstream activators of ERK3 and ERK4 and unravel a novel PAK-ERK3/ERK4-MK5 signaling pathway.", + "authors": { + "abbreviation": "Paul Déléris, Matthias Trost, Ivan Topisirovic, ..., Sylvain Meloche", + "authorList": [ + { + "ForeName": "Paul", + "LastName": "Déléris", + "abbrevName": "Déléris P", + "email": null, + "isCollectiveName": false, + "name": "Paul Déléris", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Trost", + "abbrevName": "Trost M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Trost", + "orcid": null + }, + { + "ForeName": "Ivan", + "LastName": "Topisirovic", + "abbrevName": "Topisirovic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Topisirovic", + "orcid": null + }, + { + "ForeName": "Pierre-Luc", + "LastName": "Tanguay", + "abbrevName": "Tanguay PL", + "email": null, + "isCollectiveName": false, + "name": "Pierre-Luc Tanguay", + "orcid": null + }, + { + "ForeName": "Katherine", + "LastName": "Borden", + "abbrevName": "Borden KL", + "email": null, + "isCollectiveName": false, + "name": "Katherine L B Borden", + "orcid": null + }, + { + "ForeName": "Pierre", + "LastName": "Thibault", + "abbrevName": "Thibault P", + "email": null, + "isCollectiveName": false, + "name": "Pierre Thibault", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": null, + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M110.181529", + "pmid": "21177870", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 286 2011", + "title": "Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway." + } + }, + { + "pmid": "19209957", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1234224000, + "timezone": "+00:00" + }, + "abstract": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.", + "authors": { + "abbreviation": "Morris E Feldman, Beth Apsel, Aino Uotila, ..., Kevan M Shokat", + "authorList": [ + { + "ForeName": "Morris", + "LastName": "Feldman", + "abbrevName": "Feldman ME", + "email": null, + "isCollectiveName": false, + "name": "Morris E Feldman", + "orcid": null + }, + { + "ForeName": "Beth", + "LastName": "Apsel", + "abbrevName": "Apsel B", + "email": null, + "isCollectiveName": false, + "name": "Beth Apsel", + "orcid": null + }, + { + "ForeName": "Aino", + "LastName": "Uotila", + "abbrevName": "Uotila A", + "email": null, + "isCollectiveName": false, + "name": "Aino Uotila", + "orcid": null + }, + { + "ForeName": "Robbie", + "LastName": "Loewith", + "abbrevName": "Loewith R", + "email": null, + "isCollectiveName": false, + "name": "Robbie Loewith", + "orcid": null + }, + { + "ForeName": "Zachary", + "LastName": "Knight", + "abbrevName": "Knight ZA", + "email": null, + "isCollectiveName": false, + "name": "Zachary A Knight", + "orcid": null + }, + { + "ForeName": "Davide", + "LastName": "Ruggero", + "abbrevName": "Ruggero D", + "email": null, + "isCollectiveName": false, + "name": "Davide Ruggero", + "orcid": null + }, + { + "ForeName": "Kevan", + "LastName": "Shokat", + "abbrevName": "Shokat KM", + "email": null, + "isCollectiveName": false, + "name": "Kevan M Shokat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.1000038", + "pmid": "19209957", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 7 2009", + "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." + } + }, + { + "pmid": "17637743", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1200528000, + "timezone": "+00:00" + }, + "abstract": "Transforming growth factor-beta (TGF-beta) is overexpressed at sites of wound repair and in most adenocarcinomas including prostate cancer. In stromal tissues, TGF-beta regulates cell proliferation, phenotype and matrix synthesis. To address mechanisms of TGF-beta action in cancer-associated reactive stroma, we developed prostate stromal cells null for TGF-beta receptor II (TbetaRII) or engineered to express a dominant-negative Smad3 to attenuate TGF-beta signaling. The differential reactive stroma (DRS) xenograft model was used to evaluate altered stromal TGF-beta signaling on LNCaP tumor progression. LNCaP xenograft tumors constructed with TbetaRII null or dominant-negative Smad3 stromal cells exhibited a significant reduction in mass and microvessel density relative to controls. Additionally, decreased cellular fibroblast growth factor-2 (FGF-2) immunostaining was associated with attenuated TGF-beta signaling in stroma. In vitro, TGF-beta stimulated stromal FGF-2 expression and release. However, stromal cells with attenuated TGF-beta signaling were refractory to TGF-beta-stimulated FGF-2 expression and release. Re-expression of FGF-2 in these stromal cells in DRS xenografts resulted in restored tumor mass and microvessel density. In summary, these data show that TGF-beta signaling in reactive stroma is angiogenic and tumor promoting and that this effect is mediated in part through a TbetaRII/Smad3-dependent upregulation of FGF-2 expression and release.", + "authors": { + "abbreviation": "F Yang, D W Strand, D R Rowley", + "authorList": [ + { + "ForeName": "F", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "F Yang", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Strand", + "abbrevName": "Strand DW", + "email": null, + "isCollectiveName": false, + "name": "D W Strand", + "orcid": null + }, + { + "ForeName": "D", + "LastName": "Rowley", + "abbrevName": "Rowley DR", + "email": null, + "isCollectiveName": false, + "name": "D R Rowley", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.onc.1210663", + "pmid": "17637743", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "Oncogene 27 2008", + "title": "Fibroblast growth factor-2 mediates transforming growth factor-beta action in prostate cancer reactive stroma." + } + }, + { + "pmid": "17496909", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1179100800, + "timezone": "+00:00" + }, + "abstract": "Mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs including embryogenesis, proliferation, differentiation and apoptosis based on cues derived from the cell surface and the metabolic state and environment of the cell. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK(1-3)) and p38(alpha, beta, gamma and delta) families. ERK3, ERK5 and ERK7 are other MAPKs that have distinct regulation and functions. MAPK cascades consist of a core of three protein kinases. Despite the apparently simple architecture of this pathway, these enzymes are capable of responding to a bewildering number of stimuli to produce exquisitely specific cellular outcomes. These responses depend on the kinetics of their activation and inactivation, the subcellular localization of the kinases, the complexes in which they act, and the availability of substrates. Fine-tuning of cascade activity can occur through modulatory inputs to cascade component from the primary kinases to the scaffolding accessory proteins. Here, we describe some of the properties of the three major MAPK pathways and discuss how these properties govern pathway regulation and activity.", + "authors": { + "abbreviation": "M Raman, W Chen, M H Cobb", + "authorList": [ + { + "ForeName": "M", + "LastName": "Raman", + "abbrevName": "Raman M", + "email": null, + "isCollectiveName": false, + "name": "M Raman", + "orcid": null + }, + { + "ForeName": "W", + "LastName": "Chen", + "abbrevName": "Chen W", + "email": null, + "isCollectiveName": false, + "name": "W Chen", + "orcid": null + }, + { + "ForeName": "M", + "LastName": "Cobb", + "abbrevName": "Cobb MH", + "email": null, + "isCollectiveName": false, + "name": "M H Cobb", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.onc.1210392", + "pmid": "17496909", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Oncogene 26 2007", + "title": "Differential regulation and properties of MAPKs." + } + }, + { + "pmid": "17161475", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1185926400, + "timezone": "+00:00" + }, + "abstract": "Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that play a central role in transducing extracellular cues into a variety of intracellular responses ranging from lineage specification to cell division and adaptation. Fourteen MAP kinase genes have been identified in the human genome, which define 7 distinct MAP kinase signaling pathways. MAP kinases can be classified into conventional or atypical enzymes, based on their ability to get phosphorylated and activated by members of the MAP kinase kinase (MAPKK)/MEK family. Conventional MAP kinases comprise ERK1/ERK2, p38s, JNKs, and ERK5, which are all substrates of MAPKKs. Atypical MAP kinases include ERK3/ERK4, NLK and ERK7. Much less is known about the regulation, substrate specificity and physiological functions of atypical MAP kinases.", + "authors": { + "abbreviation": "Phillipe Coulombe, Sylvain Meloche", + "authorList": [ + { + "ForeName": "Phillipe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Phillipe Coulombe", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": null, + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.bbamcr.2006.11.001", + "pmid": "17161475", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Biochim Biophys Acta 1773 2007", + "title": "Atypical mitogen-activated protein kinases: structure, regulation and functions." + } + }, + { + "pmid": "16973613", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1163721600, + "timezone": "+00:00" + }, + "abstract": "The extracellular-regulated kinase (ERK) 4 (MAPK4) and ERK3 (MAPK6) are structurally related atypical MAPKs displaying major differences only in the C-terminal extension. ERK3 is known as an unstable mostly cytoplasmic protein that binds, translocates, and activates the MAPK-activated protein kinase (MK) 5. Here we have investigated the stability and expression of ERK4 and have analyzed its ability to bind, translocate, and activate MK5. We show that, in contrast to ERK3, ERK4 is a stable protein that binds to endogenous MK5. Interaction of ERK4 with MK5 leads to translocation of MK5 to the cytoplasm and to its activation by phosphorylation. In transfected HEK293 cells, where overexpressed catalytically dead ERK3 is able to activate MK5, catalytic activity of ERK4 is necessary for activation of MK5, indicating that ERK4 directly phosphorylates MK5. Interestingly, ERK4 dimerizes and/or oligomerizes with ERK3, suggesting that overexpressed inactive ERK3 recruits active endogenous ERK4 to MK5 for its activation. Hence, ERK3 and ERK4 cooperate in activation of MK5.", + "authors": { + "abbreviation": "Shashi Kant, Stefanie Schumacher, Manvendra Kumar Singh, ..., Matthias Gaestel", + "authorList": [ + { + "ForeName": "Shashi", + "LastName": "Kant", + "abbrevName": "Kant S", + "email": null, + "isCollectiveName": false, + "name": "Shashi Kant", + "orcid": null + }, + { + "ForeName": "Stefanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stefanie Schumacher", + "orcid": null + }, + { + "ForeName": "Manvendra", + "LastName": "Singh", + "abbrevName": "Singh MK", + "email": null, + "isCollectiveName": false, + "name": "Manvendra Kumar Singh", + "orcid": null + }, + { + "ForeName": "Andreas", + "LastName": "Kispert", + "abbrevName": "Kispert A", + "email": null, + "isCollectiveName": false, + "name": "Andreas Kispert", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M606693200", + "pmid": "16973613", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 281 2006", + "title": "Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5." + } + }, + { + "pmid": "16962829", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1159660800, + "timezone": "+00:00" + }, + "abstract": "The rapamycin-insensitive mTOR complex 2 (mTORC2) has been suggested to play an important role in growth factor-dependent signaling. To explore this possibility further in a mammalian model system, we disrupted the expression of rictor, a specific component of mTORC2, in mice by using a multiallelic gene targeting strategy. Embryos that lack rictor develop normally until E9.5, and then exhibit growth arrest and die by E11.5. Although placental defects occur in null embryos, an epiblast-specific knockout of rictor only delayed lethality by a few days, thereby suggesting other important roles for this complex in the embryo proper. Analyses of rictor null embryos and fibroblasts indicate that mTORC2 is a primary kinase for Ser473 of Akt/PKB. Rictor null fibroblasts exhibit low proliferation rates, impaired Akt/PKB activity, and diminished metabolic activity. Taken together, these findings indicate that both rictor and mTORC2 are essential for the development of both embryonic and extraembryonic tissues.", + "authors": { + "abbreviation": "Chiyo Shiota, Jeong-Taek Woo, Jill Lindner, ..., Mark A Magnuson", + "authorList": [ + { + "ForeName": "Chiyo", + "LastName": "Shiota", + "abbrevName": "Shiota C", + "email": null, + "isCollectiveName": false, + "name": "Chiyo Shiota", + "orcid": null + }, + { + "ForeName": "Jeong-Taek", + "LastName": "Woo", + "abbrevName": "Woo JT", + "email": null, + "isCollectiveName": false, + "name": "Jeong-Taek Woo", + "orcid": null + }, + { + "ForeName": "Jill", + "LastName": "Lindner", + "abbrevName": "Lindner J", + "email": null, + "isCollectiveName": false, + "name": "Jill Lindner", + "orcid": null + }, + { + "ForeName": "Kathy", + "LastName": "Shelton", + "abbrevName": "Shelton KD", + "email": null, + "isCollectiveName": false, + "name": "Kathy D Shelton", + "orcid": null + }, + { + "ForeName": "Mark", + "LastName": "Magnuson", + "abbrevName": "Magnuson MA", + "email": null, + "isCollectiveName": false, + "name": "Mark A Magnuson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1016/j.devcel.2006.08.013", + "pmid": "16962829", + "pubTypes": [ + { + "UI": "D003160", + "value": "Comparative Study" + }, + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Dev Cell 11 2006", + "title": "Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability." + } + }, + { + "pmid": "15718470", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1108684800, + "timezone": "+00:00" + }, + "abstract": "Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation.", + "authors": { + "abbreviation": "D D Sarbassov, David A Guertin, Siraj M Ali, David M Sabatini", + "authorList": [ + { + "ForeName": "D", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov DD", + "email": null, + "isCollectiveName": false, + "name": "D D Sarbassov", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Guertin", + "abbrevName": "Guertin DA", + "email": null, + "isCollectiveName": false, + "name": "David A Guertin", + "orcid": null + }, + { + "ForeName": "Siraj", + "LastName": "Ali", + "abbrevName": "Ali SM", + "email": null, + "isCollectiveName": false, + "name": "Siraj M Ali", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Sabatini", + "abbrevName": "Sabatini DM", + "email": null, + "isCollectiveName": false, + "name": "David M Sabatini", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1126/science.1106148", + "pmid": "15718470", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Science 307 2005", + "title": "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex." + } + }, + { + "pmid": "15577943", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1102464000, + "timezone": "+00:00" + }, + "abstract": "Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), which is regulated by protein stability. However, its function is unknown and no physiological substrates for ERK3 have yet been identified. Here we demonstrate a specific interaction between ERK3 and MAPK-activated protein kinase-5 (MK5). Binding results in nuclear exclusion of both ERK3 and MK5 and is accompanied by ERK3-dependent phosphorylation and activation of MK5 in vitro and in vivo. Endogenous MK5 activity is significantly reduced by siRNA-mediated knockdown of ERK3 and also in fibroblasts derived from ERK3-/- mice. Furthermore, increased levels of ERK3 protein detected during nerve growth factor-induced differentiation of PC12 cells are accompanied by an increase in MK5 activity. Conversely, MK5 depletion causes a dramatic reduction in endogenous ERK3 levels. Our data identify the first physiological protein substrate for ERK3 and suggest a functional link between these kinases in which MK5 is a downstream target of ERK3, while MK5 acts as a chaperone for ERK3. Our findings provide valuable tools to further dissect the regulation and biological roles of both ERK3 and MK5.", + "authors": { + "abbreviation": "Ole-Morten Seternes, Theresa Mikalsen, Bjarne Johansen, ..., Stephen M Keyse", + "authorList": [ + { + "ForeName": "Ole-Morten", + "LastName": "Seternes", + "abbrevName": "Seternes OM", + "email": "olems@fagmed.uit.no", + "isCollectiveName": false, + "name": "Ole-Morten Seternes", + "orcid": null + }, + { + "ForeName": "Theresa", + "LastName": "Mikalsen", + "abbrevName": "Mikalsen T", + "email": null, + "isCollectiveName": false, + "name": "Theresa Mikalsen", + "orcid": null + }, + { + "ForeName": "Bjarne", + "LastName": "Johansen", + "abbrevName": "Johansen B", + "email": null, + "isCollectiveName": false, + "name": "Bjarne Johansen", + "orcid": null + }, + { + "ForeName": "Espen", + "LastName": "Michaelsen", + "abbrevName": "Michaelsen E", + "email": null, + "isCollectiveName": false, + "name": "Espen Michaelsen", + "orcid": null + }, + { + "ForeName": "Chris", + "LastName": "Armstrong", + "abbrevName": "Armstrong CG", + "email": null, + "isCollectiveName": false, + "name": "Chris G Armstrong", + "orcid": null + }, + { + "ForeName": "Nick", + "LastName": "Morrice", + "abbrevName": "Morrice NA", + "email": null, + "isCollectiveName": false, + "name": "Nick A Morrice", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Turgeon", + "abbrevName": "Turgeon B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Turgeon", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": null, + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + }, + { + "ForeName": "Ugo", + "LastName": "Moens", + "abbrevName": "Moens U", + "email": null, + "isCollectiveName": false, + "name": "Ugo Moens", + "orcid": null + }, + { + "ForeName": "Stephen", + "LastName": "Keyse", + "abbrevName": "Keyse SM", + "email": null, + "isCollectiveName": false, + "name": "Stephen M Keyse", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Ole-Morten", + "LastName": "Seternes", + "email": [ + "olems@fagmed.uit.no" + ], + "name": "Ole-Morten Seternes" + } + ] + }, + "doi": "10.1038/sj.emboj.7600489", + "pmid": "15577943", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway." + } + }, + { + "pmid": "15538386", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1102464000, + "timezone": "+00:00" + }, + "abstract": "Extracellular-regulated kinase 3 (ERK3, MAPK6) is an atypical member of the ERKs, lacking the threonine and tyrosine residues in the activation loop, carrying a unique C-terminal extension and being mainly regulated by its own protein stability and/or by autophosphorylation. Here we show that ERK3 specifically interacts with the MAPK-activated protein kinase 5 (MK5 or PRAK) in vitro and in vivo. Expression of ERK3 in mammalian cells leads to nuclear-cytoplasmic translocation and activation of MK5 and to phosphorylation of both ERK3 and MK5. Remarkably, activation of MK5 is independent of ERK3 enzymatic activity, but depends on its own catalytic activity as well as on a region in the C-terminal extension of ERK3. In mouse embryonic development, mRNA expression patterns of ERK3 and MK5 suggest spatiotemporal coexpression of both kinases. Deletion of MK5 leads to strong reduction of ERK3 protein levels and embryonic lethality at about stage E11, where ERK3 expression in wild-type mice is maximum, indicating a role of this signalling module in development.", + "authors": { + "abbreviation": "Stefanie Schumacher, Kathrin Laass, Shashi Kant, ..., Matthias Gaestel", + "authorList": [ + { + "ForeName": "Stefanie", + "LastName": "Schumacher", + "abbrevName": "Schumacher S", + "email": null, + "isCollectiveName": false, + "name": "Stefanie Schumacher", + "orcid": null + }, + { + "ForeName": "Kathrin", + "LastName": "Laass", + "abbrevName": "Laass K", + "email": null, + "isCollectiveName": false, + "name": "Kathrin Laass", + "orcid": null + }, + { + "ForeName": "Shashi", + "LastName": "Kant", + "abbrevName": "Kant S", + "email": null, + "isCollectiveName": false, + "name": "Shashi Kant", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Shi", + "abbrevName": "Shi Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Shi", + "orcid": null + }, + { + "ForeName": "Axel", + "LastName": "Visel", + "abbrevName": "Visel A", + "email": null, + "isCollectiveName": false, + "name": "Axel Visel", + "orcid": null + }, + { + "ForeName": "Achim", + "LastName": "Gruber", + "abbrevName": "Gruber AD", + "email": null, + "isCollectiveName": false, + "name": "Achim D Gruber", + "orcid": null + }, + { + "ForeName": "Alexey", + "LastName": "Kotlyarov", + "abbrevName": "Kotlyarov A", + "email": null, + "isCollectiveName": false, + "name": "Alexey Kotlyarov", + "orcid": null + }, + { + "ForeName": "Matthias", + "LastName": "Gaestel", + "abbrevName": "Gaestel M", + "email": null, + "isCollectiveName": false, + "name": "Matthias Gaestel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1038/sj.emboj.7600467", + "pmid": "15538386", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "EMBO J 23 2004", + "title": "Scaffolding by ERK3 regulates MK5 in development." + } + }, + { + "pmid": "12915405", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1066953600, + "timezone": "+00:00" + }, + "abstract": "Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase family of serine/threonine kinases. Little is known on the regulation of ERK3 function. Here, we report that ERK3 is constitutively localized in the cytoplasmic and nuclear compartments. In contrast to other mitogen-activated protein kinases, the cellular distribution of ERK3 remains unchanged in response to common mitogenic or stress stimuli and is independent of the enzymatic activity or phosphorylation of the kinase. The cytoplasmic localization of ERK3 is directed by a CRM1-dependent nuclear export mechanism. Treatment of cells with leptomycin B causes the nuclear accumulation of ERK3 in a high percentage of cells. Moreover, ectopic expression of CRM1 promotes the cytoplasmic relocalization of ERK3, whereas overexpression of snurportin 1, which binds CRM1 with high affinity, inhibits the nuclear export of ERK3. We also show that CRM1 binds to ERK3 in vitro. Importantly, we show that enforced localization of ERK3 in the nucleus or cytoplasm markedly attenuates the ability of the kinase to induce cell cycle arrest in fibroblasts. Our results suggest that nucleocytoplasmic shuttling of ERK3 is required for its negative regulatory effect on cell cycle progression.", + "authors": { + "abbreviation": "Catherine Julien, Philippe Coulombe, Sylvain Meloche", + "authorList": [ + { + "ForeName": "Catherine", + "LastName": "Julien", + "abbrevName": "Julien C", + "email": null, + "isCollectiveName": false, + "name": "Catherine Julien", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Coulombe", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": null, + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1074/jbc.M302724200", + "pmid": "12915405", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "J Biol Chem 278 2003", + "title": "Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression." + } + }, + { + "pmid": "12808096", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1057017600, + "timezone": "+00:00" + }, + "abstract": "Mitogen-activated protein (MAP) kinases are stable enzymes that are mainly regulated by phosphorylation and subcellular targeting. Here we report that extracellular signal-regulated kinase 3 (ERK3), unlike other MAP kinases, is an unstable protein that is constitutively degraded in proliferating cells with a half-life of 30 min. The proteolysis of ERK3 is executed by the proteasome and requires ubiquitination of the protein. Contrary to other protein kinases, the catalytic activity of ERK3 is not responsible for its short half-life. Instead, analysis of ERK1/ERK3 chimeras revealed the presence of two destabilization regions (NDR1 and -2) in the N-terminal lobe of the ERK3 kinase domain that are both necessary and sufficient to target ERK3 and heterologous proteins for proteasomal degradation. To assess the physiological relevance of the rapid turnover of ERK3, we monitored the expression of the kinase in different cellular models of differentiation. We observed that ERK3 markedly accumulates during differentiation of PC12 and C2C12 cells into the neuronal and muscle lineage, respectively. The accumulation of ERK3 during myogenic differentiation is associated with the time-dependent stabilization of the protein. Terminal skeletal muscle differentiation is accompanied by cell cycle withdrawal. Interestingly, we found that expression of stabilized forms of ERK3 causes G(1) arrest in NIH 3T3 cells. We propose that ERK3 biological activity is regulated by its cellular abundance through the control of protein stability.", + "authors": { + "abbreviation": "Philippe Coulombe, Geneviève Rodier, Stéphane Pelletier, ..., Sylvain Meloche", + "authorList": [ + { + "ForeName": "Philippe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Coulombe", + "orcid": null + }, + { + "ForeName": "Geneviève", + "LastName": "Rodier", + "abbrevName": "Rodier G", + "email": null, + "isCollectiveName": false, + "name": "Geneviève Rodier", + "orcid": null + }, + { + "ForeName": "Stéphane", + "LastName": "Pelletier", + "abbrevName": "Pelletier S", + "email": null, + "isCollectiveName": false, + "name": "Stéphane Pelletier", + "orcid": null + }, + { + "ForeName": "Johanne", + "LastName": "Pellerin", + "abbrevName": "Pellerin J", + "email": null, + "isCollectiveName": false, + "name": "Johanne Pellerin", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": null, + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1128/MCB.23.13.4542-4558.2003", + "pmid": "12808096", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Biol 23 2003", + "title": "Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation." + } + } + ], + "relatedPapers": [ + { + "pmid": "30542835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1569888000, + "timezone": "+00:00" + }, + "abstract": "Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt's two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1 with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.", + "authors": { + "abbreviation": "Blair P Curless, Nne E Uko, Diane F Matesic", + "authorList": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "abbrevName": "Curless BP", + "email": "Blair.curless@live.mercer.edu", + "isCollectiveName": false, + "name": "Blair P Curless", + "orcid": "0000-0003-3158-745X" + }, + { + "ForeName": "Nne", + "LastName": "Uko", + "abbrevName": "Uko NE", + "email": null, + "isCollectiveName": false, + "name": "Nne E Uko", + "orcid": null + }, + { + "ForeName": "Diane", + "LastName": "Matesic", + "abbrevName": "Matesic DF", + "email": null, + "isCollectiveName": false, + "name": "Diane F Matesic", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "email": [ + "Blair.curless@live.mercer.edu" + ], + "name": "Blair P Curless" + } + ] + }, + "doi": "10.1007/s10637-018-0705-7", + "pmid": "30542835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Invest New Drugs 37 2019", + "title": "Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells." + } + }, + { + "pmid": "27197158", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1471219200, + "timezone": "+00:00" + }, + "abstract": "HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752-64. ©2016 AACR.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Donna J Hicks, Bayley Jones, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Monica", + "LastName": "Estrada", + "abbrevName": "Estrada MV", + "email": null, + "isCollectiveName": false, + "name": "Monica Valeria Estrada", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young C", + "email": null, + "isCollectiveName": false, + "name": "Christian Young", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Williams", + "orcid": null + }, + { + "ForeName": "Brent", + "LastName": "Rexer", + "abbrevName": "Rexer BN", + "email": null, + "isCollectiveName": false, + "name": "Brent N Rexer", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov dos D", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-3393", + "pmid": "27197158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers." + } + }, + { + "pmid": "30688659", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.", + "authors": { + "abbreviation": "Wei Wang, Tao Shen, Bingning Dong, ..., Feng Yang", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Shen", + "abbrevName": "Shen T", + "email": null, + "isCollectiveName": false, + "name": "Tao Shen", + "orcid": null + }, + { + "ForeName": "Bingning", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bingning Dong", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Yanling", + "LastName": "Meng", + "abbrevName": "Meng Y", + "email": null, + "isCollectiveName": false, + "name": "Yanling Meng", + "orcid": null + }, + { + "ForeName": "Wolong", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wolong Zhou", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Shi", + "abbrevName": "Shi Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Shi", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Zhou", + "abbrevName": "Zhou H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhou", + "orcid": null + }, + { + "ForeName": "Yinjie", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinjie Zhang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moore", + "abbrevName": "Moore DD", + "email": null, + "isCollectiveName": false, + "name": "David D Moore", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI97712", + "pmid": "30688659", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Clin Invest 129 2019", + "title": "MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling." + } + }, + { + "pmid": "23272152", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "OBJECTIVE: Tetrameric α(2)-macroglobulin (α(2)M), a plasma panproteinase inhibitor, is activated upon interaction with a proteinase, and undergoes a major conformational change exposing a receptor recognition site in each of its subunits. Activated α(2)M (α(2)M*) binds to cancer cell surface GRP78 and triggers proliferative and antiapoptotic signaling. We have studied the role of α(2)M* in the regulation of mTORC1 and TORC2 signaling in the growth of human prostate cancer cells. METHODS: Employing immunoprecipitation techniques and Western blotting as well as kinase assays, activation of the mTORC1 and mTORC2 complexes, as well as down stream targets were studied. RNAi was also employed to silence expression of Raptor, Rictor, or GRP78 in parallel studies. RESULTS: Stimulation of cells with α(2)M* promotes phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt(T308), and Akt(S473) in a concentration and time-dependent manner. Rheb, Raptor, and Rictor also increased. α(2)M* treatment of cells elevated mTORC1 kinase activity as determined by kinase assays of mTOR or Raptor immunoprecipitates. mTORC1 activity was sensitive to LY294002 and rapamycin or transfection of cells with GRP78 dsRNA. Down regulation of Raptor expression by RNAi significantly reduced α(2)M*-induced S6-Kinase phosphorylation at T389 and kinase activity in Raptor immunoprecipitates. α(2)M*-treated cells demonstrate about a twofold increase in mTORC2 kinase activity as determined by kinase assay of Akt(S473) phosphorylation and levels of p-Akt(S473) in mTOR and Rictor immunoprecipitates. mTORC2 activity was sensitive to LY294002 and transfection of cells with GRP78 dsRNA, but insensitive to rapamycin. Down regulation of Rictor expression by RNAi significantly reduces α(2)M*-induced phosphorylation of Akt(S473) phosphorylation in Rictor immunoprecipitates. CONCLUSION: Binding of α(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0051735", + "pmid": "23272152", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 7 2012", + "title": "Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells." + } + }, + { + "pmid": "22140653", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1312156800, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. SIGNIFICANCE: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.", + "authors": { + "abbreviation": "Vanessa S Rodrik-Outmezguine, Sarat Chandarlapaty, Nen C Pagano, ..., Neal Rosen", + "authorList": [ + { + "ForeName": "Vanessa", + "LastName": "Rodrik-Outmezguine", + "abbrevName": "Rodrik-Outmezguine VS", + "email": null, + "isCollectiveName": false, + "name": "Vanessa S Rodrik-Outmezguine", + "orcid": null + }, + { + "ForeName": "Sarat", + "LastName": "Chandarlapaty", + "abbrevName": "Chandarlapaty S", + "email": null, + "isCollectiveName": false, + "name": "Sarat Chandarlapaty", + "orcid": null + }, + { + "ForeName": "Nen", + "LastName": "Pagano", + "abbrevName": "Pagano NC", + "email": null, + "isCollectiveName": false, + "name": "Nen C Pagano", + "orcid": null + }, + { + "ForeName": "Poulikos", + "LastName": "Poulikakos", + "abbrevName": "Poulikakos PI", + "email": null, + "isCollectiveName": false, + "name": "Poulikos I Poulikakos", + "orcid": null + }, + { + "ForeName": "Maurizio", + "LastName": "Scaltriti", + "abbrevName": "Scaltriti M", + "email": null, + "isCollectiveName": false, + "name": "Maurizio Scaltriti", + "orcid": null + }, + { + "ForeName": "Elizabeth", + "LastName": "Moskatel", + "abbrevName": "Moskatel E", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth Moskatel", + "orcid": null + }, + { + "ForeName": "José", + "LastName": "Baselga", + "abbrevName": "Baselga J", + "email": null, + "isCollectiveName": false, + "name": "José Baselga", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Guichard", + "abbrevName": "Guichard S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Guichard", + "orcid": null + }, + { + "ForeName": "Neal", + "LastName": "Rosen", + "abbrevName": "Rosen N", + "email": null, + "isCollectiveName": false, + "name": "Neal Rosen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0085", + "pmid": "22140653", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling." + } + }, + { + "pmid": "24562770", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1396310400, + "timezone": "+00:00" + }, + "abstract": "Resistance of breast cancers to targeted hormone receptor (HR) or human epidermal growth factor receptor 2 (HER2) inhibitors often occurs through dysregulation of the phosphoinositide 3-kinase, protein kinase B/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Presently, no targeted therapies exist for breast cancers lacking HR and HER2 overexpression, many of which also exhibit PI3K/AKT/mTOR hyper-activation. Resistance of breast cancers to current therapeutics also results, in part, from aberrant epigenetic modifications including protein acetylation regulated by histone deacetylases (HDACs). We show that the investigational drug MLN0128, which inhibits both complexes of mTOR (mTORC1 and mTORC2), and the hydroxamic acid pan-HDAC inhibitor TSA synergistically inhibit the viability of a phenotypically diverse panel of five breast cancer cell lines (HR-/+, HER2-/+). The combination of MLN0128 and TSA induces apoptosis in most breast cancer cell lines tested, but not in the non-malignant MCF-10A mammary epithelial cells. In parallel, the MLN0128/TSA combination reduces phosphorylation of AKT at S473 more than single agents alone and more so in the 5 malignant breast cancer cell lines than in the non-malignant mammary epithelial cells. Examining polysome profiles from one of the most sensitive breast cancer cell lines (SKBR3), we demonstrate that this MLN0128/TSA treatment combination synergistically impairs polysome assembly in conjunction with enhanced inhibition of 4eBP1 phosphorylation at S65. Taken together, these data indicate that the synergistic growth inhibiting consequence of combining a mTORC1/C2 inhibitor like MLN0128 with a pan-HDAC inhibitor like TSA results from their mechanistic convergence onto the PI3K/AKT/mTOR pathway, profoundly inhibiting both AKT S473 and 4eBP1 S65 phosphorylation, reducing polysome formation and cancer cell viability.", + "authors": { + "abbreviation": "Kathleen A Wilson-Edell, Mariya A Yevtushenko, Daniel E Rothschild, ..., Christopher C Benz", + "authorList": [ + { + "ForeName": "Kathleen", + "LastName": "Wilson-Edell", + "abbrevName": "Wilson-Edell KA", + "email": null, + "isCollectiveName": false, + "name": "Kathleen A Wilson-Edell", + "orcid": null + }, + { + "ForeName": "Mariya", + "LastName": "Yevtushenko", + "abbrevName": "Yevtushenko MA", + "email": null, + "isCollectiveName": false, + "name": "Mariya A Yevtushenko", + "orcid": null + }, + { + "ForeName": "Daniel", + "LastName": "Rothschild", + "abbrevName": "Rothschild DE", + "email": null, + "isCollectiveName": false, + "name": "Daniel E Rothschild", + "orcid": null + }, + { + "ForeName": "Aric", + "LastName": "Rogers", + "abbrevName": "Rogers AN", + "email": null, + "isCollectiveName": false, + "name": "Aric N Rogers", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Benz", + "abbrevName": "Benz CC", + "email": "cbenz@buckinstitute.org", + "isCollectiveName": false, + "name": "Christopher C Benz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Christopher", + "LastName": "Benz", + "email": [ + "cbenz@buckinstitute.org" + ], + "name": "Christopher C Benz" + } + ] + }, + "doi": "10.1007/s10549-014-2877-y", + "pmid": "24562770", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 144 2014", + "title": "mTORC1/C2 and pan-HDAC inhibitors synergistically impair breast cancer growth by convergent AKT and polysome inhibiting mechanisms." + } + }, + { + "pmid": "29808317", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1533081600, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21/BTG2, that inhibits both growth and invasion of triple negative breast cancer cells via AKT1 activation by differential regulation of mTORc1 and mTORc2 activity. METHODS: Transduction of adenovirus carrying TIS21/BTG2 gene and transfection of short interfering RNAs were employed to regulate TIS21/BTG2 gene expression in various cell lines. Treatment of mTOR inhibitors and mTOR kinase assays can evaluate the role of mTORc in the regulation of AKT phosphorylation at S473 residue by TIS21/BTG2 in breast cancer cells. Open data and immunohistochemical analysis were performed to confirm the role of TIS21/BTG2 expression in various human breast cancer tissues. RESULTS: We observed that TIS21/BTG2 inhibited mTORc1 activity by reducing Raptor-mTOR interaction along with upregulation of tsc1 expression, which lead to significant reduction of p70S6K activation as opposed to AKT1S473, but not AKT2, phosphorylation via downregulating PHLPP2 (AKT1-specific phosphatase) in breast cancers. TIS21/BTG2-induced pAKTS473 required Rictor-bound mTOR kinase, indicating activation of mTORc2 by TIS21/BTG2 gene. Additionally, the TIS21/BTG2-induced pAKTS473 could reduce expression of NFAT1 (nuclear factor of activated T cells) and its target genes, which regulate cancer microenvironment. CONCLUSIONS: TIS21/BTG2 significantly lost in the infiltrating ductal carcinoma, but it can inhibit cancer growth via the TIS21/BTG2-tsc1/2-mTORc1-p70S6K axis and downregulate cancer progression via the TIS21/BTG2-mTORc2-AKT1-NFAT1-PHLPP2 pathway.", + "authors": { + "abbreviation": "Santhoshkumar Sundaramoorthy, Preethi Devanand, Min Sook Ryu, ..., In Kyoung Lim", + "authorList": [ + { + "ForeName": "Santhoshkumar", + "LastName": "Sundaramoorthy", + "abbrevName": "Sundaramoorthy S", + "email": null, + "isCollectiveName": false, + "name": "Santhoshkumar Sundaramoorthy", + "orcid": null + }, + { + "ForeName": "Preethi", + "LastName": "Devanand", + "abbrevName": "Devanand P", + "email": null, + "isCollectiveName": false, + "name": "Preethi Devanand", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ryu", + "abbrevName": "Ryu MS", + "email": null, + "isCollectiveName": false, + "name": "Min Sook Ryu", + "orcid": null + }, + { + "ForeName": "Kye", + "LastName": "Song", + "abbrevName": "Song KY", + "email": null, + "isCollectiveName": false, + "name": "Kye Yong Song", + "orcid": null + }, + { + "ForeName": "Dong", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong Young Noh", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Lim", + "abbrevName": "Lim IK", + "email": "iklim@ajou.ac.kr", + "isCollectiveName": false, + "name": "In Kyoung Lim", + "orcid": "0000-0002-2399-607X" + } + ], + "contacts": [ + { + "ForeName": "In", + "LastName": "Lim", + "email": [ + "iklim@ajou.ac.kr" + ], + "name": "In Kyoung Lim" + } + ] + }, + "doi": "10.1007/s00432-018-2677-6", + "pmid": "29808317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cancer Res Clin Oncol 144 2018", + "title": "TIS21/BTG2 inhibits breast cancer growth and progression by differential regulation of mTORc1 and mTORc2-AKT1-NFAT1-PHLPP2 signaling axis." + } + }, + { + "pmid": "19372546", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1238544000, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.", + "authors": { + "abbreviation": "Madlaina Breuleux, Matthieu Klopfenstein, Christine Stephan, ..., Heidi A Lane", + "authorList": [ + { + "ForeName": "Madlaina", + "LastName": "Breuleux", + "abbrevName": "Breuleux M", + "email": null, + "isCollectiveName": false, + "name": "Madlaina Breuleux", + "orcid": null + }, + { + "ForeName": "Matthieu", + "LastName": "Klopfenstein", + "abbrevName": "Klopfenstein M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Klopfenstein", + "orcid": null + }, + { + "ForeName": "Christine", + "LastName": "Stephan", + "abbrevName": "Stephan C", + "email": null, + "isCollectiveName": false, + "name": "Christine Stephan", + "orcid": null + }, + { + "ForeName": "Cheryl", + "LastName": "Doughty", + "abbrevName": "Doughty CA", + "email": null, + "isCollectiveName": false, + "name": "Cheryl A Doughty", + "orcid": null + }, + { + "ForeName": "Louise", + "LastName": "Barys", + "abbrevName": "Barys L", + "email": null, + "isCollectiveName": false, + "name": "Louise Barys", + "orcid": null + }, + { + "ForeName": "Saveur-Michel", + "LastName": "Maira", + "abbrevName": "Maira SM", + "email": null, + "isCollectiveName": false, + "name": "Saveur-Michel Maira", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Kwiatkowski", + "abbrevName": "Kwiatkowski D", + "email": null, + "isCollectiveName": false, + "name": "David Kwiatkowski", + "orcid": null + }, + { + "ForeName": "Heidi", + "LastName": "Lane", + "abbrevName": "Lane HA", + "email": null, + "isCollectiveName": false, + "name": "Heidi A Lane", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/1535-7163.MCT-08-0668", + "pmid": "19372546", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cancer Ther 8 2009", + "title": "Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition." + } + }, + { + "pmid": "24966685", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1388534400, + "timezone": "+00:00" + }, + "abstract": "Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as \"231/Gem\"), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.", + "authors": { + "abbreviation": "Xiao Li Yang, Feng Juan Lin, Ya Jie Guo, ..., Zhou Luo Ou", + "authorList": [ + { + "ForeName": "Xiao", + "LastName": "Yang", + "abbrevName": "Yang XL", + "email": null, + "isCollectiveName": false, + "name": "Xiao Li Yang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Lin", + "abbrevName": "Lin FJ", + "email": null, + "isCollectiveName": false, + "name": "Feng Juan Lin", + "orcid": null + }, + { + "ForeName": "Ya", + "LastName": "Guo", + "abbrevName": "Guo YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jie Guo", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi Min Shao", + "orcid": null + }, + { + "ForeName": "Zhou", + "LastName": "Ou", + "abbrevName": "Ou ZL", + "email": null, + "isCollectiveName": false, + "name": "Zhou Luo Ou", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2147/OTT.S63145", + "pmid": "24966685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Onco Targets Ther 7 2014", + "title": "Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways." + } + }, + { + "pmid": "22808163", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.", + "authors": { + "abbreviation": "Alan L Ho, Elgilda Musi, Grazia Ambrosini, ..., Gary K Schwartz", + "authorList": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "abbrevName": "Ho AL", + "email": "hoa@mskcc.org", + "isCollectiveName": false, + "name": "Alan L Ho", + "orcid": null + }, + { + "ForeName": "Elgilda", + "LastName": "Musi", + "abbrevName": "Musi E", + "email": null, + "isCollectiveName": false, + "name": "Elgilda Musi", + "orcid": null + }, + { + "ForeName": "Grazia", + "LastName": "Ambrosini", + "abbrevName": "Ambrosini G", + "email": null, + "isCollectiveName": false, + "name": "Grazia Ambrosini", + "orcid": null + }, + { + "ForeName": "Jayasree", + "LastName": "Nair", + "abbrevName": "Nair JS", + "email": null, + "isCollectiveName": false, + "name": "Jayasree S Nair", + "orcid": null + }, + { + "ForeName": "Shyamprasad", + "LastName": "Deraje Vasudeva", + "abbrevName": "Deraje Vasudeva S", + "email": null, + "isCollectiveName": false, + "name": "Shyamprasad Deraje Vasudeva", + "orcid": null + }, + { + "ForeName": "Elisa", + "LastName": "de Stanchina", + "abbrevName": "de Stanchina E", + "email": null, + "isCollectiveName": false, + "name": "Elisa de Stanchina", + "orcid": null + }, + { + "ForeName": "Gary", + "LastName": "Schwartz", + "abbrevName": "Schwartz GK", + "email": null, + "isCollectiveName": false, + "name": "Gary K Schwartz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "email": [ + "hoa@mskcc.org" + ], + "name": "Alan L Ho" + } + ] + }, + "doi": "10.1371/journal.pone.0040439", + "pmid": "22808163", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype." + } + }, + { + "pmid": "30887599", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1561939200, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin-Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)-induced G1/S cell-cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF-induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal-regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c-Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP-1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate-bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage-independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage-independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR-Akt-p70S6K and mTOR-Akt-GSK3β-AP-1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2-Akt-p70S6k signaling pathway.", + "authors": { + "abbreviation": "Sun-Mi Yoo, Cheol-Jung Lee, Han Chang Kang, ..., Yong-Yeon Cho", + "authorList": [ + { + "ForeName": "Sun-Mi", + "LastName": "Yoo", + "abbrevName": "Yoo SM", + "email": null, + "isCollectiveName": false, + "name": "Sun-Mi Yoo", + "orcid": null + }, + { + "ForeName": "Cheol-Jung", + "LastName": "Lee", + "abbrevName": "Lee CJ", + "email": null, + "isCollectiveName": false, + "name": "Cheol-Jung Lee", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Han Chang Kang", + "orcid": null + }, + { + "ForeName": "Hye", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Hye Suk Lee", + "orcid": null + }, + { + "ForeName": "Joo", + "LastName": "Lee", + "abbrevName": "Lee JY", + "email": null, + "isCollectiveName": false, + "name": "Joo Young Lee", + "orcid": null + }, + { + "ForeName": "Kwang", + "LastName": "Kim", + "abbrevName": "Kim KD", + "email": null, + "isCollectiveName": false, + "name": "Kwang Dong Kim", + "orcid": null + }, + { + "ForeName": "Dae", + "LastName": "Kim", + "abbrevName": "Kim DJ", + "email": null, + "isCollectiveName": false, + "name": "Dae Joon Kim", + "orcid": "0000-0002-7977-9955" + }, + { + "ForeName": "Hyun-Jung", + "LastName": "An", + "abbrevName": "An HJ", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Jung An", + "orcid": null + }, + { + "ForeName": "Yong-Yeon", + "LastName": "Cho", + "abbrevName": "Cho YY", + "email": null, + "isCollectiveName": false, + "name": "Yong-Yeon Cho", + "orcid": "0000-0003-1107-2651" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23005", + "pmid": "30887599", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells." + } + }, + { + "pmid": "19209957", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1234224000, + "timezone": "+00:00" + }, + "abstract": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.", + "authors": { + "abbreviation": "Morris E Feldman, Beth Apsel, Aino Uotila, ..., Kevan M Shokat", + "authorList": [ + { + "ForeName": "Morris", + "LastName": "Feldman", + "abbrevName": "Feldman ME", + "email": null, + "isCollectiveName": false, + "name": "Morris E Feldman", + "orcid": null + }, + { + "ForeName": "Beth", + "LastName": "Apsel", + "abbrevName": "Apsel B", + "email": null, + "isCollectiveName": false, + "name": "Beth Apsel", + "orcid": null + }, + { + "ForeName": "Aino", + "LastName": "Uotila", + "abbrevName": "Uotila A", + "email": null, + "isCollectiveName": false, + "name": "Aino Uotila", + "orcid": null + }, + { + "ForeName": "Robbie", + "LastName": "Loewith", + "abbrevName": "Loewith R", + "email": null, + "isCollectiveName": false, + "name": "Robbie Loewith", + "orcid": null + }, + { + "ForeName": "Zachary", + "LastName": "Knight", + "abbrevName": "Knight ZA", + "email": null, + "isCollectiveName": false, + "name": "Zachary A Knight", + "orcid": null + }, + { + "ForeName": "Davide", + "LastName": "Ruggero", + "abbrevName": "Ruggero D", + "email": null, + "isCollectiveName": false, + "name": "Davide Ruggero", + "orcid": null + }, + { + "ForeName": "Kevan", + "LastName": "Shokat", + "abbrevName": "Shokat KM", + "email": null, + "isCollectiveName": false, + "name": "Kevan M Shokat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.1000038", + "pmid": "19209957", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 7 2009", + "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." + } + }, + { + "pmid": "28666462", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1498780800, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear. METHODS: Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays. RESULTS: We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility. CONCLUSION: These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Michelle M Williams, Donna J Hicks, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams MM", + "email": null, + "isCollectiveName": false, + "name": "Michelle M Williams", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young CD", + "email": null, + "isCollectiveName": false, + "name": "Christian D Young", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov DD", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "Rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "Rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1186/s13058-017-0868-8", + "pmid": "28666462", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res 19 2017", + "title": "Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis." + } + }, + { + "pmid": "30285764", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1538352000, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin. METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells. RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells. CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.", + "authors": { + "abbreviation": "Masoud Razmara, Azita Monazzam, Britt Skogseid", + "authorList": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "abbrevName": "Razmara M", + "email": "Masoud.Razmara@medsci.uu.se", + "isCollectiveName": false, + "name": "Masoud Razmara", + "orcid": "0000-0002-1037-4810" + }, + { + "ForeName": "Azita", + "LastName": "Monazzam", + "abbrevName": "Monazzam A", + "email": null, + "isCollectiveName": false, + "name": "Azita Monazzam", + "orcid": null + }, + { + "ForeName": "Britt", + "LastName": "Skogseid", + "abbrevName": "Skogseid B", + "email": null, + "isCollectiveName": false, + "name": "Britt Skogseid", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "email": [ + "Masoud.Razmara@medsci.uu.se" + ], + "name": "Masoud Razmara" + } + ] + }, + "doi": "10.1186/s12964-018-0278-2", + "pmid": "30285764", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Commun Signal 16 2018", + "title": "Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration." + } + }, + { + "pmid": "19661225", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1262304000, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: Activated B-Raf alone cannot induce melanoma but must cooperate with other signaling pathways. The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR)/p70S6K pathways are critical for tumorigenesis. The authors investigated the role of these pathways in uveal melanoma cells. METHODS: The effects of PI3K and mTOR activation and inhibition on the proliferation of human uveal melanoma cell lines expressing either activated (WT)B-Raf or (V600E)B-Raf were investigated. Interactions among PI3K, mTOR, and B-Raf/ERK were studied. RESULTS: Inhibition of PI3K deactivated P70S6 kinase, reduced cell proliferation by 71% to 84%, and increased apoptosis by a factor of 5.0 to 8.4 without reducing ERK1/2 activation, indicating that ERK plays no role in mediating PI3K in these processes. In contrast, rapamycin-induced inhibition of mTOR did not significantly affect cell proliferation because it simultaneously stimulated PI3K/Akt activation and cyclin D1 expression. Regardless of B-Raf mutation status, cotreatment with the PI3K inhibitor effectively sensitized all melanoma cell lines to the B-Raf or ERK1/2 inhibition-induced reduction of cell proliferation. B-Raf/ERK and PI3K signaling, but not mTOR signaling, converged to control cyclin D1 expression. Moreover, p70S6K required the activation of ERK1/2. These data demonstrate that PI3K/Akt and mTOR/P70S6K interact with B-Raf/ERK. CONCLUSIONS: Activated PI3K/Akt attenuates the inhibitory effects of rapamycin on cell proliferation and thus serves as a negative feedback mechanism. This finding suggests that rapamycin is unlikely to inhibit uveal melanoma growth. In contrast, targeting PI3K while inhibiting B-Raf/ERK may be a promising approach to reduce the proliferation of uveal melanoma cells.", + "authors": { + "abbreviation": "Narjes Babchia, Armelle Calipel, Frédéric Mouriaux, ..., Frédéric Mascarelli", + "authorList": [ + { + "ForeName": "Narjes", + "LastName": "Babchia", + "abbrevName": "Babchia N", + "email": null, + "isCollectiveName": false, + "name": "Narjes Babchia", + "orcid": null + }, + { + "ForeName": "Armelle", + "LastName": "Calipel", + "abbrevName": "Calipel A", + "email": null, + "isCollectiveName": false, + "name": "Armelle Calipel", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mouriaux", + "abbrevName": "Mouriaux F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mouriaux", + "orcid": null + }, + { + "ForeName": "Anne-Marie", + "LastName": "Faussat", + "abbrevName": "Faussat AM", + "email": null, + "isCollectiveName": false, + "name": "Anne-Marie Faussat", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mascarelli", + "abbrevName": "Mascarelli F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mascarelli", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1167/iovs.09-3974", + "pmid": "19661225", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Invest Ophthalmol Vis Sci 51 2010", + "title": "The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK." + } + }, + { + "pmid": "23991179", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin complex 1 and 2 (mTORC1/2) are overactive in colorectal carcinomas; however, the first generation of mTOR inhibitors such as rapamycin have failed to show clinical benefits in treating colorectal carcinoma in part due to their effects only on mTORC1. The second generation of mTOR inhibitors such as PP242 targets mTOR kinase; thus, they are capable of inhibiting both mTORC1 and mTORC2. To examine the therapeutic potential of the mTOR kinase inhibitors, we treated a panel of colorectal carcinoma cell lines with PP242. Western blotting showed that the PP242 inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT(S473)) was transient only in the first few hours of the PP242 treatment. Receptor tyrosine kinase arrays further revealed that PP242 treatment increased the phosphorylated epidermal growth factor receptor (EGFR) at Tyr 1068 (EGFR(T1068)). The parallel increase of AKT(S473) and EGFR(T1068) in the cells following PP242 treatment raised the possibility that EGFR phosphorylation might contribute to the PP242 incomplete inhibition of mTORC2. To test this notion, we showed that the combination of PP242 with erlotinib, an EGFR small molecule inhibitor, blocked both mTORC1 and mTORC2 kinase activity. In addition, we showed that the combination treatment inhibited colony formation, blocked cell growth and induced apoptotic cell death. A systemic administration of PP242 and erlotinib resulted in the progression suppression of colorectal carcinoma xenografts in mice. This study suggests that the combination of mTOR kinase and EGFR inhibitors may provide an effective treatment of colorectal carcinoma.", + "authors": { + "abbreviation": "Quan Wang, Feng Wei, Chunsheng Li, ..., Chunhai Hao", + "authorList": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": "wangquan-jlcc@hotmail.com", + "isCollectiveName": false, + "name": "Quan Wang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Wei", + "abbrevName": "Wei F", + "email": null, + "isCollectiveName": false, + "name": "Feng Wei", + "orcid": null + }, + { + "ForeName": "Chunsheng", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunsheng Li", + "orcid": null + }, + { + "ForeName": "Guoyue", + "LastName": "Lv", + "abbrevName": "Lv G", + "email": null, + "isCollectiveName": false, + "name": "Guoyue Lv", + "orcid": null + }, + { + "ForeName": "Guangyi", + "LastName": "Wang", + "abbrevName": "Wang G", + "email": null, + "isCollectiveName": false, + "name": "Guangyi Wang", + "orcid": null + }, + { + "ForeName": "Tongjun", + "LastName": "Liu", + "abbrevName": "Liu T", + "email": null, + "isCollectiveName": false, + "name": "Tongjun Liu", + "orcid": null + }, + { + "ForeName": "Anita", + "LastName": "Bellail", + "abbrevName": "Bellail AC", + "email": null, + "isCollectiveName": false, + "name": "Anita C Bellail", + "orcid": null + }, + { + "ForeName": "Chunhai", + "LastName": "Hao", + "abbrevName": "Hao C", + "email": null, + "isCollectiveName": false, + "name": "Chunhai Hao", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "email": [ + "wangquan-jlcc@hotmail.com" + ], + "name": "Quan Wang" + } + ] + }, + "doi": "10.1371/journal.pone.0073175", + "pmid": "23991179", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 8 2013", + "title": "Combination of mTOR and EGFR kinase inhibitors blocks mTORC1 and mTORC2 kinase activity and suppresses the progression of colorectal carcinoma." + } + }, + { + "pmid": "33495824", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1614556800, + "timezone": "+00:00" + }, + "abstract": "Breast cancer is the worldwide leading cause of cancer‑related deaths among women. Increasing evidence has demonstrated that microRNAs (miRNAs) play critical roles in the carcinogenesis and progression of breast cancer. miR‑653‑5p was previously reported to be involved in cell proliferation and apoptosis. However, the role of miR‑653‑5p in the progression of breast cancer has not been studied. In the present study, it was found that overexpression of miR‑653‑5p significantly inhibited the proliferation, migration and invasion of breast cancer cells in vitro. Moreover, overexpression of miR‑653‑5p promoted cell apoptosis in breast cancer by regulating the Bcl‑2/Bax axis and caspase‑9 activation. Additionally, the epithelial‑mesenchymal transition and activation of the Akt/mammalian target of rapamycin signaling pathway were also inhibited by miR‑653‑5p. Furthermore, the data demonstrated that miR‑653‑5p directly targeted mitogen‑activated protein kinase 6 (MAPK6) and negatively regulated its expression in breast cancer cells. Upregulation of MAPK6 could overcome the inhibitory effects of miR‑653‑5p on cell proliferation and migration in breast cancer. In conclusion, this study suggested that miR‑653‑5p functions as a tumor suppressor by targeting MAPK6 in the progression of breast cancer, and it may be a potential target for breast cancer therapy.", + "authors": { + "abbreviation": "Mei Zhang, Hongwei Wang, Xiaomei Zhang, Fengping Liu", + "authorList": [ + { + "ForeName": "Mei", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Zhang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Wang", + "orcid": null + }, + { + "ForeName": "Xiaomei", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaomei Zhang", + "orcid": null + }, + { + "ForeName": "Fengping", + "LastName": "Liu", + "abbrevName": "Liu F", + "email": null, + "isCollectiveName": false, + "name": "Fengping Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3892/mmr.2021.11839", + "pmid": "33495824", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Med Rep 23 2021", + "title": "miR‑653‑5p suppresses the growth and migration of breast cancer cells by targeting MAPK6." + } + }, + { + "pmid": "29095526", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "Long noncoding RNAs (lncRNAs) or microRNAs belong to the two most important noncoding RNAs and they are involved in a lot of cancers, including non-small-cell lung cancer (NSCLC). Therefore, currently, we focused on the biological and clinical significance of lncRNA nuclear enriched abundant transcript 1 (NEAT1) and hsa-mir-98-5p in NSCLC. It was observed that NEAT1 was upregulated while hsa-mir-98-5p was downregulated respectively in NSCLC cell lines compared to human normal lung epithelial BES-2B cells. Inhibition of NEAT1 can suppress the progression of NSCLC cells and hsa-mir-98-5p can reverse this phenomenon. Bioinformatics search was used to elucidate the correlation between NEAT1 and hsa-mir-98-5p. Additionally, a novel messenger RNA target of hsa-mir-98-5p, mitogen-activated protein kinase 6 (MAPK6), was predicted. Overexpression and knockdown studies were conducted to verify whether NEAT1 exhibits its biological functions through regulating hsa-mir-98-5p and MAPK6 in vitro. NEAT1 was able to increase MAPK6 expression and hsa-mir-98-5p mimics can inhibit MAPK6 via downregulating NEAT1 levels. We speculated that NEAT1 may act as a competing endogenous lncRNA to upregulate MAPK6 by attaching hsa-mir-98-5p in lung cancers. Taken these together, NEAT1/hsa-mir-98-5p/MAPK6 is involved in the development and progress in NSCLC. NEAT1 could be recommended as a prognostic biomarker and therapeutic indicator in NSCLC diagnosis and treatment.", + "authors": { + "abbreviation": "Feima Wu, Qiang Mo, Xiaoling Wan, ..., Haibo Hu", + "authorList": [ + { + "ForeName": "Feima", + "LastName": "Wu", + "abbrevName": "Wu F", + "email": null, + "isCollectiveName": false, + "name": "Feima Wu", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Mo", + "abbrevName": "Mo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Mo", + "orcid": null + }, + { + "ForeName": "Xiaoling", + "LastName": "Wan", + "abbrevName": "Wan X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoling Wan", + "orcid": null + }, + { + "ForeName": "Jialong", + "LastName": "Dan", + "abbrevName": "Dan J", + "email": null, + "isCollectiveName": false, + "name": "Jialong Dan", + "orcid": null + }, + { + "ForeName": "Haibo", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Haibo Hu", + "orcid": "0000-0003-1851-7756" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.26442", + "pmid": "29095526", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 120 2019", + "title": "NEAT1/hsa-mir-98-5p/MAPK6 axis is involved in non-small-cell lung cancer development." + } + }, + { + "pmid": "22173835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1335830400, + "timezone": "+00:00" + }, + "abstract": "Ligation of cell surface-associated GRP78 by activated α(2) -macroglobulin triggers pro-proliferative cellular responses. In part, this results from activation of adenylyl cyclase leading to an increase in cAMP. We have previously employed the cAMP analog 8-CPT-2Me-cAMP to probe these responses. Here we show in 1-LN prostate cancer cells that 8-CPT-2Me-cAMP causes a dose-dependent increase in Epac1, p-Akt(T308) , p-Akt(S473) , but not p-CREB. By contrast, the PKA activator 6-Benz-cAMP caused a dose-dependent increase in p-CREB, but not Epac1. We measured mTORC2-dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells. 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt(S473) and Akt(S473) kinase activity in Rictor immunoprecipitates. By contrast, there was only a negligible effect on p-Akt(T308) in Rictor immunoprecipitates. Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of Akt at Ser(473) . These studies represent the first report that Epac1 mediates mTORC2-dependent phosphorylation of Akt(S473) . Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP-dependent p-Akt(S473) and p-Akt(S473) kinase activities, and both effects were rapamycin insensitive. This treatment caused a two to threefold increase in S6 Kinase and 4EBP1 phosphorylation, indices of mTORC1 activation. Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of S6 Kinase and 4EBP1. We further demonstrate that in 8-CPT-2Me-cAMP-treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1-induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a \"scaffold\" protein.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24018", + "pmid": "22173835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 113 2012", + "title": "Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex." + } + }, + { + "pmid": "32899862", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1599177600, + "timezone": "+00:00" + }, + "abstract": "Recently, we have reported that blockade/deletion of P2X7 receptor (P2X7R), an ATP-gated ion channel, exacerbates heat shock protein 25 (HSP25)-mediated astroglial autophagy (clasmatodendrosis) following kainic acid (KA) injection. In P2X7R knockout (KO) mice, prolonged astroglial HSP25 induction exerts 5' adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1-mediated autophagic pathway independent of mammalian target of rapamycin (mTOR) activity following KA injection. Sustained HSP25 expression also enhances AKT-serine (S) 473 phosphorylation leading to astroglial autophagy via glycogen synthase kinase-3β/bax interacting factor 1 signaling pathway. However, it is unanswered how P2X7R deletion induces AKT-S473 hyperphosphorylation during autophagic process in astrocytes. In the present study, we found that AKT-S473 phosphorylation was increased by enhancing activity of focal adhesion kinase (FAK), independent of mTOR complex (mTORC) 1 and 2 activities in isolated astrocytes of P2X7R knockout (KO) mice following KA injection. In addition, HSP25 overexpression in P2X7R KO mice acted as a chaperone of AKT, which retained AKT-S473 phosphorylation by inhibiting the pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1- and 2-binding to AKT. Therefore, our findings suggest that P2X7R may be a fine-tuner of AKT-S473 activity during astroglial autophagy by regulating FAK phosphorylation and HSP25-mediated inhibition of PHLPP1/2-AKT binding following KA treatment.", + "authors": { + "abbreviation": "Duk-Shin Lee, Ji-Eun Kim", + "authorList": [ + { + "ForeName": "Duk-Shin", + "LastName": "Lee", + "abbrevName": "Lee DS", + "email": null, + "isCollectiveName": false, + "name": "Duk-Shin Lee", + "orcid": null + }, + { + "ForeName": "Ji-Eun", + "LastName": "Kim", + "abbrevName": "Kim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Kim", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21186476", + "pmid": "32899862", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures." + } + }, + { + "pmid": "32630372", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1593043200, + "timezone": "+00:00" + }, + "abstract": "Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.", + "authors": { + "abbreviation": "Boris Y Shorning, Manisha S Dass, Matthew J Smalley, Helen B Pearson", + "authorList": [ + { + "ForeName": "Boris", + "LastName": "Shorning", + "abbrevName": "Shorning BY", + "email": null, + "isCollectiveName": false, + "name": "Boris Y Shorning", + "orcid": null + }, + { + "ForeName": "Manisha", + "LastName": "Dass", + "abbrevName": "Dass MS", + "email": null, + "isCollectiveName": false, + "name": "Manisha S Dass", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Smalley", + "abbrevName": "Smalley MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J Smalley", + "orcid": "0000-0001-9540-1146" + }, + { + "ForeName": "Helen", + "LastName": "Pearson", + "abbrevName": "Pearson HB", + "email": null, + "isCollectiveName": false, + "name": "Helen B Pearson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21124507", + "pmid": "32630372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling." + } + }, + { + "pmid": "30642949", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1552608000, + "timezone": "+00:00" + }, + "abstract": "The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6lacZ ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6KD ) or conditional (Mapk6Δ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6lacZ mice but not in Mapk6KD or Mapk6Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6lacZ mutant mice.", + "authors": { + "abbreviation": "Mathilde Soulez, Marc K Saba-El-Leil, Benjamin Turgeon, ..., Sylvain Meloche", + "authorList": [ + { + "ForeName": "Mathilde", + "LastName": "Soulez", + "abbrevName": "Soulez M", + "email": null, + "isCollectiveName": false, + "name": "Mathilde Soulez", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Saba-El-Leil", + "abbrevName": "Saba-El-Leil MK", + "email": null, + "isCollectiveName": false, + "name": "Marc K Saba-El-Leil", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Turgeon", + "abbrevName": "Turgeon B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Turgeon", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Mathien", + "abbrevName": "Mathien S", + "email": null, + "isCollectiveName": false, + "name": "Simon Mathien", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Coulombe", + "orcid": null + }, + { + "ForeName": "Sonia", + "LastName": "Klinger", + "abbrevName": "Klinger S", + "email": null, + "isCollectiveName": false, + "name": "Sonia Klinger", + "orcid": null + }, + { + "ForeName": "Justine", + "LastName": "Rousseau", + "abbrevName": "Rousseau J", + "email": null, + "isCollectiveName": false, + "name": "Justine Rousseau", + "orcid": null + }, + { + "ForeName": "Kim", + "LastName": "Lévesque", + "abbrevName": "Lévesque K", + "email": null, + "isCollectiveName": false, + "name": "Kim Lévesque", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": "sylvain.meloche@umontreal.ca", + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "email": [ + "sylvain.meloche@umontreal.ca" + ], + "name": "Sylvain Meloche" + } + ] + }, + "doi": "10.1128/MCB.00527-18", + "pmid": "30642949", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Biol 39 2019", + "title": "Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models." + } + }, + { + "pmid": "12181443", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1030838400, + "timezone": "+00:00" + }, + "abstract": "The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.", + "authors": { + "abbreviation": "Linnea M Baudhuin, Kelly L Cristina, Jun Lu, Yan Xu", + "authorList": [ + { + "ForeName": "Linnea", + "LastName": "Baudhuin", + "abbrevName": "Baudhuin LM", + "email": null, + "isCollectiveName": false, + "name": "Linnea M Baudhuin", + "orcid": null + }, + { + "ForeName": "Kelly", + "LastName": "Cristina", + "abbrevName": "Cristina KL", + "email": null, + "isCollectiveName": false, + "name": "Kelly L Cristina", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lu", + "abbrevName": "Lu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lu", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Xu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1124/mol.62.3.660", + "pmid": "12181443", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Pharmacol 62 2002", + "title": "Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific." + } + }, + { + "pmid": "22845486", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1349049600, + "timezone": "+00:00" + }, + "abstract": "The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.", + "authors": { + "abbreviation": "David Barrett, Valerie I Brown, Stephan A Grupp, David T Teachey", + "authorList": [ + { + "ForeName": "David", + "LastName": "Barrett", + "abbrevName": "Barrett D", + "email": null, + "isCollectiveName": false, + "name": "David Barrett", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Brown", + "abbrevName": "Brown VI", + "email": null, + "isCollectiveName": false, + "name": "Valerie I Brown", + "orcid": null + }, + { + "ForeName": "Stephan", + "LastName": "Grupp", + "abbrevName": "Grupp SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Grupp", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Teachey", + "abbrevName": "Teachey DT", + "email": null, + "isCollectiveName": false, + "name": "David T Teachey", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2165/11594740-000000000-00000", + "pmid": "22845486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Paediatr Drugs 14 2012", + "title": "Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies." + } + }, + { + "pmid": "24112608", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1381363200, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. METHODS: A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. RESULTS: ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK. CONCLUSIONS: Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.", + "authors": { + "abbreviation": "Ju Gao, Minzhi Yin, Yiping Zhu, ..., Zhigui Ma", + "authorList": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": "ma_zg@yahoo.com", + "isCollectiveName": false, + "name": "Ju Gao", + "orcid": null + }, + { + "ForeName": "Minzhi", + "LastName": "Yin", + "abbrevName": "Yin M", + "email": null, + "isCollectiveName": false, + "name": "Minzhi Yin", + "orcid": null + }, + { + "ForeName": "Yiping", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yiping Zhu", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Gu", + "abbrevName": "Gu L", + "email": null, + "isCollectiveName": false, + "name": "Ling Gu", + "orcid": null + }, + { + "ForeName": "Yanle", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanle Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Li", + "orcid": null + }, + { + "ForeName": "Cangsong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Cangsong Jia", + "orcid": null + }, + { + "ForeName": "Zhigui", + "LastName": "Ma", + "abbrevName": "Ma Z", + "email": null, + "isCollectiveName": false, + "name": "Zhigui Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "email": [ + "ma_zg@yahoo.com" + ], + "name": "Ju Gao" + } + ] + }, + "doi": "10.1186/1471-2407-13-471", + "pmid": "24112608", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cancer 13 2013", + "title": "Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma." + } + }, + { + "pmid": "23874880", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "AIMS: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic clinical benefits in advanced non-small cell lung cancer (NSCLC); however, resistance remains a serious problem in clinical practice. The present study analyzed mTOR-associated signaling-pathway differences between the EGFR TKI-sensitive and -resistant NSCLC cell lines and investigated the feasibility of targeting mTOR with specific mTOR inhibitor in EGFR TKI resistant NSCLC cells. METHODS: We selected four different types of EGFR TKI-sensitive and -resistant NSCLC cells: PC9, PC9GR, H1650 and H1975 cells as models to detect mTOR-associated signaling-pathway differences by western blot and Immunoprecipitation and evaluated the antiproliferative effect and cell cycle arrest of ku-0063794 by MTT method and flow cytometry. RESULTS: In the present study, we observed that mTORC2-associated Akt ser473-FOXO1 signaling pathway in a basal state was highly activated in resistant cells. In vitro mTORC1 and mTORC2 kinase activities assays showed that EGFR TKI-resistant NSCLC cell lines had higher mTORC2 kinase activity, whereas sensitive cells had higher mTORC1 kinase activity in the basal state. The ATP-competitive mTOR inhibitor ku-0063794 showed dramatic antiproliferative effects and G1-cell cycle arrest in both sensitive and resistant cells. Ku-0063794 at the IC50 concentration effectively inhibited both mTOR and p70S6K phosphorylation levels; the latter is an mTORC1 substrate and did not upregulate Akt ser473 phosphorylation which would be induced by rapamycin and resulted in partial inhibition of FOXO1 phosphorylation. We also observed that EGFR TKI-sensitive and -resistant clinical NSCLC tumor specimens had higher total and phosphorylated p70S6K expression levels. CONCLUSION: Our results indicate mTORC2-associated signaling-pathway was hyperactivated in EGFR TKI-resistant cells and targeting mTOR with specific mTOR inhibitors is likely a good strategy for patients with EGFR mutant NSCLC who develop EGFR TKI resistance; the potential specific roles of mTORC2 in EGFR TKI-resistant NSCLC cells were still unknown and should be further investigated.", + "authors": { + "abbreviation": "Shi-Jiang Fei, Xu-Chao Zhang, Song Dong, ..., Yi-Long Wu", + "authorList": [ + { + "ForeName": "Shi-Jiang", + "LastName": "Fei", + "abbrevName": "Fei SJ", + "email": null, + "isCollectiveName": false, + "name": "Shi-Jiang Fei", + "orcid": null + }, + { + "ForeName": "Xu-Chao", + "LastName": "Zhang", + "abbrevName": "Zhang XC", + "email": null, + "isCollectiveName": false, + "name": "Xu-Chao Zhang", + "orcid": null + }, + { + "ForeName": "Song", + "LastName": "Dong", + "abbrevName": "Dong S", + "email": null, + "isCollectiveName": false, + "name": "Song Dong", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Cheng", + "abbrevName": "Cheng H", + "email": null, + "isCollectiveName": false, + "name": "Hua Cheng", + "orcid": null + }, + { + "ForeName": "Yi-Fang", + "LastName": "Zhang", + "abbrevName": "Zhang YF", + "email": null, + "isCollectiveName": false, + "name": "Yi-Fang Zhang", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Huang", + "abbrevName": "Huang L", + "email": null, + "isCollectiveName": false, + "name": "Ling Huang", + "orcid": null + }, + { + "ForeName": "Hai-Yu", + "LastName": "Zhou", + "abbrevName": "Zhou HY", + "email": null, + "isCollectiveName": false, + "name": "Hai-Yu Zhou", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Xie", + "abbrevName": "Xie Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Xie", + "orcid": null + }, + { + "ForeName": "Zhi-Hong", + "LastName": "Chen", + "abbrevName": "Chen ZH", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Hong Chen", + "orcid": null + }, + { + "ForeName": "Yi-Long", + "LastName": "Wu", + "abbrevName": "Wu YL", + "email": null, + "isCollectiveName": false, + "name": "Yi-Long Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0069104", + "pmid": "23874880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells." + } + }, + { + "pmid": "23802099", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review \"PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle\" we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty.", + "authors": { + "abbreviation": "Lakshmipathi Vadlakonda, Abhinandita Dash, Mukesh Pasupuleti, ..., Pallu Reddanna", + "authorList": [ + { + "ForeName": "Lakshmipathi", + "LastName": "Vadlakonda", + "abbrevName": "Vadlakonda L", + "email": null, + "isCollectiveName": false, + "name": "Lakshmipathi Vadlakonda", + "orcid": null + }, + { + "ForeName": "Abhinandita", + "LastName": "Dash", + "abbrevName": "Dash A", + "email": null, + "isCollectiveName": false, + "name": "Abhinandita Dash", + "orcid": null + }, + { + "ForeName": "Mukesh", + "LastName": "Pasupuleti", + "abbrevName": "Pasupuleti M", + "email": null, + "isCollectiveName": false, + "name": "Mukesh Pasupuleti", + "orcid": null + }, + { + "ForeName": "Kotha", + "LastName": "Anil Kumar", + "abbrevName": "Anil Kumar K", + "email": null, + "isCollectiveName": false, + "name": "Kotha Anil Kumar", + "orcid": null + }, + { + "ForeName": "Pallu", + "LastName": "Reddanna", + "abbrevName": "Reddanna P", + "email": null, + "isCollectiveName": false, + "name": "Pallu Reddanna", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3389/fonc.2013.00165", + "pmid": "23802099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Front Oncol 3 2013", + "title": "The Paradox of Akt-mTOR Interactions." + } + }, + { + "pmid": "22476852", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1343779200, + "timezone": "+00:00" + }, + "abstract": "Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.", + "authors": { + "abbreviation": "Haiyan Li, Jun Lin, Xiaokai Wang, ..., Xiaochun Bai", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Li", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lin", + "orcid": null + }, + { + "ForeName": "Xiaokai", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaokai Wang", + "orcid": null + }, + { + "ForeName": "Guangyu", + "LastName": "Yao", + "abbrevName": "Yao G", + "email": null, + "isCollectiveName": false, + "name": "Guangyu Yao", + "orcid": null + }, + { + "ForeName": "Liping", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Liping Wang", + "orcid": null + }, + { + "ForeName": "Hang", + "LastName": "Zheng", + "abbrevName": "Zheng H", + "email": null, + "isCollectiveName": false, + "name": "Hang Zheng", + "orcid": null + }, + { + "ForeName": "Cuilan", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuilan Yang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Jia", + "orcid": null + }, + { + "ForeName": "Anling", + "LastName": "Liu", + "abbrevName": "Liu A", + "email": null, + "isCollectiveName": false, + "name": "Anling Liu", + "orcid": null + }, + { + "ForeName": "Xiaochun", + "LastName": "Bai", + "abbrevName": "Bai X", + "email": null, + "isCollectiveName": false, + "name": "Xiaochun Bai", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s10549-012-2036-2", + "pmid": "22476852", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 134 2012", + "title": "Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer." + } + }, + { + "pmid": "22145100", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1320105600, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. SIGNIFICANCE: This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.", + "authors": { + "abbreviation": "Kazuhiro Tanaka, Ivan Babic, David Nathanson, ..., Paul S Mischel", + "authorList": [ + { + "ForeName": "Kazuhiro", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Tanaka", + "orcid": null + }, + { + "ForeName": "Ivan", + "LastName": "Babic", + "abbrevName": "Babic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Babic", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Nathanson", + "abbrevName": "Nathanson D", + "email": null, + "isCollectiveName": false, + "name": "David Nathanson", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Akhavan", + "abbrevName": "Akhavan D", + "email": null, + "isCollectiveName": false, + "name": "David Akhavan", + "orcid": null + }, + { + "ForeName": "Deliang", + "LastName": "Guo", + "abbrevName": "Guo D", + "email": null, + "isCollectiveName": false, + "name": "Deliang Guo", + "orcid": null + }, + { + "ForeName": "Beatrice", + "LastName": "Gini", + "abbrevName": "Gini B", + "email": null, + "isCollectiveName": false, + "name": "Beatrice Gini", + "orcid": null + }, + { + "ForeName": "Julie", + "LastName": "Dang", + "abbrevName": "Dang J", + "email": null, + "isCollectiveName": false, + "name": "Julie Dang", + "orcid": null + }, + { + "ForeName": "Shaojun", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Shaojun Zhu", + "orcid": null + }, + { + "ForeName": "Huijun", + "LastName": "Yang", + "abbrevName": "Yang H", + "email": null, + "isCollectiveName": false, + "name": "Huijun Yang", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "De Jesus", + "abbrevName": "De Jesus J", + "email": null, + "isCollectiveName": false, + "name": "Jason De Jesus", + "orcid": null + }, + { + "ForeName": "Ali", + "LastName": "Amzajerdi", + "abbrevName": "Amzajerdi AN", + "email": null, + "isCollectiveName": false, + "name": "Ali Nael Amzajerdi", + "orcid": null + }, + { + "ForeName": "Yinan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinan Zhang", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Dibble", + "abbrevName": "Dibble CC", + "email": null, + "isCollectiveName": false, + "name": "Christian C Dibble", + "orcid": null + }, + { + "ForeName": "Hancai", + "LastName": "Dan", + "abbrevName": "Dan H", + "email": null, + "isCollectiveName": false, + "name": "Hancai Dan", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Rinkenbaugh", + "abbrevName": "Rinkenbaugh A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Rinkenbaugh", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Yong", + "abbrevName": "Yong WH", + "email": null, + "isCollectiveName": false, + "name": "William H Yong", + "orcid": null + }, + { + "ForeName": "Harry", + "LastName": "Vinters", + "abbrevName": "Vinters HV", + "email": null, + "isCollectiveName": false, + "name": "Harry V Vinters", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Gera", + "abbrevName": "Gera JF", + "email": null, + "isCollectiveName": false, + "name": "Joseph F Gera", + "orcid": null + }, + { + "ForeName": "Webster", + "LastName": "Cavenee", + "abbrevName": "Cavenee WK", + "email": null, + "isCollectiveName": false, + "name": "Webster K Cavenee", + "orcid": null + }, + { + "ForeName": "Timothy", + "LastName": "Cloughesy", + "abbrevName": "Cloughesy TF", + "email": null, + "isCollectiveName": false, + "name": "Timothy F Cloughesy", + "orcid": null + }, + { + "ForeName": "Brendan", + "LastName": "Manning", + "abbrevName": "Manning BD", + "email": null, + "isCollectiveName": false, + "name": "Brendan D Manning", + "orcid": null + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Mischel", + "abbrevName": "Mischel PS", + "email": null, + "isCollectiveName": false, + "name": "Paul S Mischel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0124", + "pmid": "22145100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance." + } + }, + { + "pmid": "24374738", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1401580800, + "timezone": "+00:00" + }, + "abstract": "To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.", + "authors": { + "abbreviation": "Victor Jeannot, Benoît Busser, Elisabeth Brambilla, ..., Amandine Hurbin", + "authorList": [ + { + "ForeName": "Victor", + "LastName": "Jeannot", + "abbrevName": "Jeannot V", + "email": null, + "isCollectiveName": false, + "name": "Victor Jeannot", + "orcid": null + }, + { + "ForeName": "Benoît", + "LastName": "Busser", + "abbrevName": "Busser B", + "email": null, + "isCollectiveName": false, + "name": "Benoît Busser", + "orcid": null + }, + { + "ForeName": "Elisabeth", + "LastName": "Brambilla", + "abbrevName": "Brambilla E", + "email": null, + "isCollectiveName": false, + "name": "Elisabeth Brambilla", + "orcid": null + }, + { + "ForeName": "Marie", + "LastName": "Wislez", + "abbrevName": "Wislez M", + "email": null, + "isCollectiveName": false, + "name": "Marie Wislez", + "orcid": null + }, + { + "ForeName": "Blaise", + "LastName": "Robin", + "abbrevName": "Robin B", + "email": null, + "isCollectiveName": false, + "name": "Blaise Robin", + "orcid": null + }, + { + "ForeName": "Jacques", + "LastName": "Cadranel", + "abbrevName": "Cadranel J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Cadranel", + "orcid": null + }, + { + "ForeName": "Jean-Luc", + "LastName": "Coll", + "abbrevName": "Coll JL", + "email": null, + "isCollectiveName": false, + "name": "Jean-Luc Coll", + "orcid": null + }, + { + "ForeName": "Amandine", + "LastName": "Hurbin", + "abbrevName": "Hurbin A", + "email": null, + "isCollectiveName": false, + "name": "Amandine Hurbin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28594", + "pmid": "24374738", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Cancer 134 2014", + "title": "The PI3K/AKT pathway promotes gefitinib resistance in mutant KRAS lung adenocarcinoma by a deacetylase-dependent mechanism." + } + } + ], + "relatedPapersNotified": true, + "secret": "998d53dc-8150-40b9-b59f-b5b54439e22d", + "source": "admin", + "status": "public", + "tweet": null, + "verified": false + } + ], + "element": [ + { + "_creationTimestamp": { + "$reql_type$": "TIME", + "epoch_time": 1671052665.794, + "timezone": "+00:00" + }, + "_newestOpId": "cfab0463-2f44-4a77-86bd-429bd81406c7", + "_ops": [], + "association": { + "combinedOrganismIndex": 2, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "602904" + }, + { + "db": "HGNC", + "id": "HGNC:6879" + }, + { + "db": "Ensembl", + "id": "ENSG00000069956" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 11.3388, + "id": "5597", + "name": "MAPK6", + "nameDistance": 0, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 200000, + "shortSynonyms": [ + "ERK3", + "HsT17250", + "PRKM6", + "p97MAPK", + "mitogen-activated protein kinase 6", + "MAPK 6", + "p97-MAPK", + "MAP kinase 6", + "protein kinase, mitogen-activated 5", + "ERK-3" + ], + "synonyms": [ + "ERK3", + "HsT17250", + "PRKM6", + "p97MAPK", + "mitogen-activated protein kinase 6", + "ERK-3", + "MAP kinase 6", + "MAPK 6", + "extracellular signal-regulated kinase 3", + "extracellular signal-regulated kinase, p97", + "p97-MAPK", + "protein kinase, mitogen-activated 5", + "protein kinase, mitogen-activated 6" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "598f8bef-f858-4dd0-b1c6-5168a8ae5349", + "liveId": "2e3a79f3-3340-4742-9bb3-8a902907236d", + "lock": null, + "locked": false, + "name": "MAPK6", + "position": { + "x": -293.62739490935775, + "y": -99.72685471867636 + }, + "relatedPapers": [ + { + "pmid": "30688659", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.", + "authors": { + "abbreviation": "Wei Wang, Tao Shen, Bingning Dong, ..., Feng Yang", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Shen", + "abbrevName": "Shen T", + "email": null, + "isCollectiveName": false, + "name": "Tao Shen", + "orcid": null + }, + { + "ForeName": "Bingning", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bingning Dong", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Yanling", + "LastName": "Meng", + "abbrevName": "Meng Y", + "email": null, + "isCollectiveName": false, + "name": "Yanling Meng", + "orcid": null + }, + { + "ForeName": "Wolong", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wolong Zhou", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Shi", + "abbrevName": "Shi Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Shi", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Zhou", + "abbrevName": "Zhou H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhou", + "orcid": null + }, + { + "ForeName": "Yinjie", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinjie Zhang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moore", + "abbrevName": "Moore DD", + "email": null, + "isCollectiveName": false, + "name": "David D Moore", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI97712", + "pmid": "30688659", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Clin Invest 129 2019", + "title": "MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling." + } + }, + { + "pmid": "19661225", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1262304000, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: Activated B-Raf alone cannot induce melanoma but must cooperate with other signaling pathways. The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR)/p70S6K pathways are critical for tumorigenesis. The authors investigated the role of these pathways in uveal melanoma cells. METHODS: The effects of PI3K and mTOR activation and inhibition on the proliferation of human uveal melanoma cell lines expressing either activated (WT)B-Raf or (V600E)B-Raf were investigated. Interactions among PI3K, mTOR, and B-Raf/ERK were studied. RESULTS: Inhibition of PI3K deactivated P70S6 kinase, reduced cell proliferation by 71% to 84%, and increased apoptosis by a factor of 5.0 to 8.4 without reducing ERK1/2 activation, indicating that ERK plays no role in mediating PI3K in these processes. In contrast, rapamycin-induced inhibition of mTOR did not significantly affect cell proliferation because it simultaneously stimulated PI3K/Akt activation and cyclin D1 expression. Regardless of B-Raf mutation status, cotreatment with the PI3K inhibitor effectively sensitized all melanoma cell lines to the B-Raf or ERK1/2 inhibition-induced reduction of cell proliferation. B-Raf/ERK and PI3K signaling, but not mTOR signaling, converged to control cyclin D1 expression. Moreover, p70S6K required the activation of ERK1/2. These data demonstrate that PI3K/Akt and mTOR/P70S6K interact with B-Raf/ERK. CONCLUSIONS: Activated PI3K/Akt attenuates the inhibitory effects of rapamycin on cell proliferation and thus serves as a negative feedback mechanism. This finding suggests that rapamycin is unlikely to inhibit uveal melanoma growth. In contrast, targeting PI3K while inhibiting B-Raf/ERK may be a promising approach to reduce the proliferation of uveal melanoma cells.", + "authors": { + "abbreviation": "Narjes Babchia, Armelle Calipel, Frédéric Mouriaux, ..., Frédéric Mascarelli", + "authorList": [ + { + "ForeName": "Narjes", + "LastName": "Babchia", + "abbrevName": "Babchia N", + "email": null, + "isCollectiveName": false, + "name": "Narjes Babchia", + "orcid": null + }, + { + "ForeName": "Armelle", + "LastName": "Calipel", + "abbrevName": "Calipel A", + "email": null, + "isCollectiveName": false, + "name": "Armelle Calipel", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mouriaux", + "abbrevName": "Mouriaux F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mouriaux", + "orcid": null + }, + { + "ForeName": "Anne-Marie", + "LastName": "Faussat", + "abbrevName": "Faussat AM", + "email": null, + "isCollectiveName": false, + "name": "Anne-Marie Faussat", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mascarelli", + "abbrevName": "Mascarelli F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mascarelli", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1167/iovs.09-3974", + "pmid": "19661225", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Invest Ophthalmol Vis Sci 51 2010", + "title": "The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK." + } + }, + { + "pmid": "30642949", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1552608000, + "timezone": "+00:00" + }, + "abstract": "The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6lacZ ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6KD ) or conditional (Mapk6Δ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6lacZ mice but not in Mapk6KD or Mapk6Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6lacZ mutant mice.", + "authors": { + "abbreviation": "Mathilde Soulez, Marc K Saba-El-Leil, Benjamin Turgeon, ..., Sylvain Meloche", + "authorList": [ + { + "ForeName": "Mathilde", + "LastName": "Soulez", + "abbrevName": "Soulez M", + "email": null, + "isCollectiveName": false, + "name": "Mathilde Soulez", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Saba-El-Leil", + "abbrevName": "Saba-El-Leil MK", + "email": null, + "isCollectiveName": false, + "name": "Marc K Saba-El-Leil", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Turgeon", + "abbrevName": "Turgeon B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Turgeon", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Mathien", + "abbrevName": "Mathien S", + "email": null, + "isCollectiveName": false, + "name": "Simon Mathien", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Coulombe", + "orcid": null + }, + { + "ForeName": "Sonia", + "LastName": "Klinger", + "abbrevName": "Klinger S", + "email": null, + "isCollectiveName": false, + "name": "Sonia Klinger", + "orcid": null + }, + { + "ForeName": "Justine", + "LastName": "Rousseau", + "abbrevName": "Rousseau J", + "email": null, + "isCollectiveName": false, + "name": "Justine Rousseau", + "orcid": null + }, + { + "ForeName": "Kim", + "LastName": "Lévesque", + "abbrevName": "Lévesque K", + "email": null, + "isCollectiveName": false, + "name": "Kim Lévesque", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": "sylvain.meloche@umontreal.ca", + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "email": [ + "sylvain.meloche@umontreal.ca" + ], + "name": "Sylvain Meloche" + } + ] + }, + "doi": "10.1128/MCB.00527-18", + "pmid": "30642949", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Biol 39 2019", + "title": "Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models." + } + }, + { + "pmid": "24562770", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1396310400, + "timezone": "+00:00" + }, + "abstract": "Resistance of breast cancers to targeted hormone receptor (HR) or human epidermal growth factor receptor 2 (HER2) inhibitors often occurs through dysregulation of the phosphoinositide 3-kinase, protein kinase B/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Presently, no targeted therapies exist for breast cancers lacking HR and HER2 overexpression, many of which also exhibit PI3K/AKT/mTOR hyper-activation. Resistance of breast cancers to current therapeutics also results, in part, from aberrant epigenetic modifications including protein acetylation regulated by histone deacetylases (HDACs). We show that the investigational drug MLN0128, which inhibits both complexes of mTOR (mTORC1 and mTORC2), and the hydroxamic acid pan-HDAC inhibitor TSA synergistically inhibit the viability of a phenotypically diverse panel of five breast cancer cell lines (HR-/+, HER2-/+). The combination of MLN0128 and TSA induces apoptosis in most breast cancer cell lines tested, but not in the non-malignant MCF-10A mammary epithelial cells. In parallel, the MLN0128/TSA combination reduces phosphorylation of AKT at S473 more than single agents alone and more so in the 5 malignant breast cancer cell lines than in the non-malignant mammary epithelial cells. Examining polysome profiles from one of the most sensitive breast cancer cell lines (SKBR3), we demonstrate that this MLN0128/TSA treatment combination synergistically impairs polysome assembly in conjunction with enhanced inhibition of 4eBP1 phosphorylation at S65. Taken together, these data indicate that the synergistic growth inhibiting consequence of combining a mTORC1/C2 inhibitor like MLN0128 with a pan-HDAC inhibitor like TSA results from their mechanistic convergence onto the PI3K/AKT/mTOR pathway, profoundly inhibiting both AKT S473 and 4eBP1 S65 phosphorylation, reducing polysome formation and cancer cell viability.", + "authors": { + "abbreviation": "Kathleen A Wilson-Edell, Mariya A Yevtushenko, Daniel E Rothschild, ..., Christopher C Benz", + "authorList": [ + { + "ForeName": "Kathleen", + "LastName": "Wilson-Edell", + "abbrevName": "Wilson-Edell KA", + "email": null, + "isCollectiveName": false, + "name": "Kathleen A Wilson-Edell", + "orcid": null + }, + { + "ForeName": "Mariya", + "LastName": "Yevtushenko", + "abbrevName": "Yevtushenko MA", + "email": null, + "isCollectiveName": false, + "name": "Mariya A Yevtushenko", + "orcid": null + }, + { + "ForeName": "Daniel", + "LastName": "Rothschild", + "abbrevName": "Rothschild DE", + "email": null, + "isCollectiveName": false, + "name": "Daniel E Rothschild", + "orcid": null + }, + { + "ForeName": "Aric", + "LastName": "Rogers", + "abbrevName": "Rogers AN", + "email": null, + "isCollectiveName": false, + "name": "Aric N Rogers", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Benz", + "abbrevName": "Benz CC", + "email": "cbenz@buckinstitute.org", + "isCollectiveName": false, + "name": "Christopher C Benz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Christopher", + "LastName": "Benz", + "email": [ + "cbenz@buckinstitute.org" + ], + "name": "Christopher C Benz" + } + ] + }, + "doi": "10.1007/s10549-014-2877-y", + "pmid": "24562770", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 144 2014", + "title": "mTORC1/C2 and pan-HDAC inhibitors synergistically impair breast cancer growth by convergent AKT and polysome inhibiting mechanisms." + } + }, + { + "pmid": "22173835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1335830400, + "timezone": "+00:00" + }, + "abstract": "Ligation of cell surface-associated GRP78 by activated α(2) -macroglobulin triggers pro-proliferative cellular responses. In part, this results from activation of adenylyl cyclase leading to an increase in cAMP. We have previously employed the cAMP analog 8-CPT-2Me-cAMP to probe these responses. Here we show in 1-LN prostate cancer cells that 8-CPT-2Me-cAMP causes a dose-dependent increase in Epac1, p-Akt(T308) , p-Akt(S473) , but not p-CREB. By contrast, the PKA activator 6-Benz-cAMP caused a dose-dependent increase in p-CREB, but not Epac1. We measured mTORC2-dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells. 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt(S473) and Akt(S473) kinase activity in Rictor immunoprecipitates. By contrast, there was only a negligible effect on p-Akt(T308) in Rictor immunoprecipitates. Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of Akt at Ser(473) . These studies represent the first report that Epac1 mediates mTORC2-dependent phosphorylation of Akt(S473) . Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP-dependent p-Akt(S473) and p-Akt(S473) kinase activities, and both effects were rapamycin insensitive. This treatment caused a two to threefold increase in S6 Kinase and 4EBP1 phosphorylation, indices of mTORC1 activation. Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of S6 Kinase and 4EBP1. We further demonstrate that in 8-CPT-2Me-cAMP-treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1-induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a \"scaffold\" protein.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24018", + "pmid": "22173835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 113 2012", + "title": "Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex." + } + }, + { + "pmid": "30542835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1569888000, + "timezone": "+00:00" + }, + "abstract": "Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt's two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1 with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.", + "authors": { + "abbreviation": "Blair P Curless, Nne E Uko, Diane F Matesic", + "authorList": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "abbrevName": "Curless BP", + "email": "Blair.curless@live.mercer.edu", + "isCollectiveName": false, + "name": "Blair P Curless", + "orcid": "0000-0003-3158-745X" + }, + { + "ForeName": "Nne", + "LastName": "Uko", + "abbrevName": "Uko NE", + "email": null, + "isCollectiveName": false, + "name": "Nne E Uko", + "orcid": null + }, + { + "ForeName": "Diane", + "LastName": "Matesic", + "abbrevName": "Matesic DF", + "email": null, + "isCollectiveName": false, + "name": "Diane F Matesic", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "email": [ + "Blair.curless@live.mercer.edu" + ], + "name": "Blair P Curless" + } + ] + }, + "doi": "10.1007/s10637-018-0705-7", + "pmid": "30542835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Invest New Drugs 37 2019", + "title": "Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells." + } + }, + { + "pmid": "29095526", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "Long noncoding RNAs (lncRNAs) or microRNAs belong to the two most important noncoding RNAs and they are involved in a lot of cancers, including non-small-cell lung cancer (NSCLC). Therefore, currently, we focused on the biological and clinical significance of lncRNA nuclear enriched abundant transcript 1 (NEAT1) and hsa-mir-98-5p in NSCLC. It was observed that NEAT1 was upregulated while hsa-mir-98-5p was downregulated respectively in NSCLC cell lines compared to human normal lung epithelial BES-2B cells. Inhibition of NEAT1 can suppress the progression of NSCLC cells and hsa-mir-98-5p can reverse this phenomenon. Bioinformatics search was used to elucidate the correlation between NEAT1 and hsa-mir-98-5p. Additionally, a novel messenger RNA target of hsa-mir-98-5p, mitogen-activated protein kinase 6 (MAPK6), was predicted. Overexpression and knockdown studies were conducted to verify whether NEAT1 exhibits its biological functions through regulating hsa-mir-98-5p and MAPK6 in vitro. NEAT1 was able to increase MAPK6 expression and hsa-mir-98-5p mimics can inhibit MAPK6 via downregulating NEAT1 levels. We speculated that NEAT1 may act as a competing endogenous lncRNA to upregulate MAPK6 by attaching hsa-mir-98-5p in lung cancers. Taken these together, NEAT1/hsa-mir-98-5p/MAPK6 is involved in the development and progress in NSCLC. NEAT1 could be recommended as a prognostic biomarker and therapeutic indicator in NSCLC diagnosis and treatment.", + "authors": { + "abbreviation": "Feima Wu, Qiang Mo, Xiaoling Wan, ..., Haibo Hu", + "authorList": [ + { + "ForeName": "Feima", + "LastName": "Wu", + "abbrevName": "Wu F", + "email": null, + "isCollectiveName": false, + "name": "Feima Wu", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Mo", + "abbrevName": "Mo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Mo", + "orcid": null + }, + { + "ForeName": "Xiaoling", + "LastName": "Wan", + "abbrevName": "Wan X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoling Wan", + "orcid": null + }, + { + "ForeName": "Jialong", + "LastName": "Dan", + "abbrevName": "Dan J", + "email": null, + "isCollectiveName": false, + "name": "Jialong Dan", + "orcid": null + }, + { + "ForeName": "Haibo", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Haibo Hu", + "orcid": "0000-0003-1851-7756" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.26442", + "pmid": "29095526", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 120 2019", + "title": "NEAT1/hsa-mir-98-5p/MAPK6 axis is involved in non-small-cell lung cancer development." + } + }, + { + "pmid": "27197158", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1471219200, + "timezone": "+00:00" + }, + "abstract": "HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752-64. ©2016 AACR.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Donna J Hicks, Bayley Jones, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Monica", + "LastName": "Estrada", + "abbrevName": "Estrada MV", + "email": null, + "isCollectiveName": false, + "name": "Monica Valeria Estrada", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young C", + "email": null, + "isCollectiveName": false, + "name": "Christian Young", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Williams", + "orcid": null + }, + { + "ForeName": "Brent", + "LastName": "Rexer", + "abbrevName": "Rexer BN", + "email": null, + "isCollectiveName": false, + "name": "Brent N Rexer", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov dos D", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-3393", + "pmid": "27197158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers." + } + }, + { + "pmid": "28666462", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1498780800, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear. METHODS: Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays. RESULTS: We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility. CONCLUSION: These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Michelle M Williams, Donna J Hicks, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams MM", + "email": null, + "isCollectiveName": false, + "name": "Michelle M Williams", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young CD", + "email": null, + "isCollectiveName": false, + "name": "Christian D Young", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov DD", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "Rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "Rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1186/s13058-017-0868-8", + "pmid": "28666462", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res 19 2017", + "title": "Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis." + } + }, + { + "pmid": "23991179", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin complex 1 and 2 (mTORC1/2) are overactive in colorectal carcinomas; however, the first generation of mTOR inhibitors such as rapamycin have failed to show clinical benefits in treating colorectal carcinoma in part due to their effects only on mTORC1. The second generation of mTOR inhibitors such as PP242 targets mTOR kinase; thus, they are capable of inhibiting both mTORC1 and mTORC2. To examine the therapeutic potential of the mTOR kinase inhibitors, we treated a panel of colorectal carcinoma cell lines with PP242. Western blotting showed that the PP242 inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT(S473)) was transient only in the first few hours of the PP242 treatment. Receptor tyrosine kinase arrays further revealed that PP242 treatment increased the phosphorylated epidermal growth factor receptor (EGFR) at Tyr 1068 (EGFR(T1068)). The parallel increase of AKT(S473) and EGFR(T1068) in the cells following PP242 treatment raised the possibility that EGFR phosphorylation might contribute to the PP242 incomplete inhibition of mTORC2. To test this notion, we showed that the combination of PP242 with erlotinib, an EGFR small molecule inhibitor, blocked both mTORC1 and mTORC2 kinase activity. In addition, we showed that the combination treatment inhibited colony formation, blocked cell growth and induced apoptotic cell death. A systemic administration of PP242 and erlotinib resulted in the progression suppression of colorectal carcinoma xenografts in mice. This study suggests that the combination of mTOR kinase and EGFR inhibitors may provide an effective treatment of colorectal carcinoma.", + "authors": { + "abbreviation": "Quan Wang, Feng Wei, Chunsheng Li, ..., Chunhai Hao", + "authorList": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": "wangquan-jlcc@hotmail.com", + "isCollectiveName": false, + "name": "Quan Wang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Wei", + "abbrevName": "Wei F", + "email": null, + "isCollectiveName": false, + "name": "Feng Wei", + "orcid": null + }, + { + "ForeName": "Chunsheng", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunsheng Li", + "orcid": null + }, + { + "ForeName": "Guoyue", + "LastName": "Lv", + "abbrevName": "Lv G", + "email": null, + "isCollectiveName": false, + "name": "Guoyue Lv", + "orcid": null + }, + { + "ForeName": "Guangyi", + "LastName": "Wang", + "abbrevName": "Wang G", + "email": null, + "isCollectiveName": false, + "name": "Guangyi Wang", + "orcid": null + }, + { + "ForeName": "Tongjun", + "LastName": "Liu", + "abbrevName": "Liu T", + "email": null, + "isCollectiveName": false, + "name": "Tongjun Liu", + "orcid": null + }, + { + "ForeName": "Anita", + "LastName": "Bellail", + "abbrevName": "Bellail AC", + "email": null, + "isCollectiveName": false, + "name": "Anita C Bellail", + "orcid": null + }, + { + "ForeName": "Chunhai", + "LastName": "Hao", + "abbrevName": "Hao C", + "email": null, + "isCollectiveName": false, + "name": "Chunhai Hao", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "email": [ + "wangquan-jlcc@hotmail.com" + ], + "name": "Quan Wang" + } + ] + }, + "doi": "10.1371/journal.pone.0073175", + "pmid": "23991179", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 8 2013", + "title": "Combination of mTOR and EGFR kinase inhibitors blocks mTORC1 and mTORC2 kinase activity and suppresses the progression of colorectal carcinoma." + } + }, + { + "pmid": "29808317", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1533081600, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21/BTG2, that inhibits both growth and invasion of triple negative breast cancer cells via AKT1 activation by differential regulation of mTORc1 and mTORc2 activity. METHODS: Transduction of adenovirus carrying TIS21/BTG2 gene and transfection of short interfering RNAs were employed to regulate TIS21/BTG2 gene expression in various cell lines. Treatment of mTOR inhibitors and mTOR kinase assays can evaluate the role of mTORc in the regulation of AKT phosphorylation at S473 residue by TIS21/BTG2 in breast cancer cells. Open data and immunohistochemical analysis were performed to confirm the role of TIS21/BTG2 expression in various human breast cancer tissues. RESULTS: We observed that TIS21/BTG2 inhibited mTORc1 activity by reducing Raptor-mTOR interaction along with upregulation of tsc1 expression, which lead to significant reduction of p70S6K activation as opposed to AKT1S473, but not AKT2, phosphorylation via downregulating PHLPP2 (AKT1-specific phosphatase) in breast cancers. TIS21/BTG2-induced pAKTS473 required Rictor-bound mTOR kinase, indicating activation of mTORc2 by TIS21/BTG2 gene. Additionally, the TIS21/BTG2-induced pAKTS473 could reduce expression of NFAT1 (nuclear factor of activated T cells) and its target genes, which regulate cancer microenvironment. CONCLUSIONS: TIS21/BTG2 significantly lost in the infiltrating ductal carcinoma, but it can inhibit cancer growth via the TIS21/BTG2-tsc1/2-mTORc1-p70S6K axis and downregulate cancer progression via the TIS21/BTG2-mTORc2-AKT1-NFAT1-PHLPP2 pathway.", + "authors": { + "abbreviation": "Santhoshkumar Sundaramoorthy, Preethi Devanand, Min Sook Ryu, ..., In Kyoung Lim", + "authorList": [ + { + "ForeName": "Santhoshkumar", + "LastName": "Sundaramoorthy", + "abbrevName": "Sundaramoorthy S", + "email": null, + "isCollectiveName": false, + "name": "Santhoshkumar Sundaramoorthy", + "orcid": null + }, + { + "ForeName": "Preethi", + "LastName": "Devanand", + "abbrevName": "Devanand P", + "email": null, + "isCollectiveName": false, + "name": "Preethi Devanand", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ryu", + "abbrevName": "Ryu MS", + "email": null, + "isCollectiveName": false, + "name": "Min Sook Ryu", + "orcid": null + }, + { + "ForeName": "Kye", + "LastName": "Song", + "abbrevName": "Song KY", + "email": null, + "isCollectiveName": false, + "name": "Kye Yong Song", + "orcid": null + }, + { + "ForeName": "Dong", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong Young Noh", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Lim", + "abbrevName": "Lim IK", + "email": "iklim@ajou.ac.kr", + "isCollectiveName": false, + "name": "In Kyoung Lim", + "orcid": "0000-0002-2399-607X" + } + ], + "contacts": [ + { + "ForeName": "In", + "LastName": "Lim", + "email": [ + "iklim@ajou.ac.kr" + ], + "name": "In Kyoung Lim" + } + ] + }, + "doi": "10.1007/s00432-018-2677-6", + "pmid": "29808317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cancer Res Clin Oncol 144 2018", + "title": "TIS21/BTG2 inhibits breast cancer growth and progression by differential regulation of mTORc1 and mTORc2-AKT1-NFAT1-PHLPP2 signaling axis." + } + }, + { + "pmid": "23802099", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review \"PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle\" we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty.", + "authors": { + "abbreviation": "Lakshmipathi Vadlakonda, Abhinandita Dash, Mukesh Pasupuleti, ..., Pallu Reddanna", + "authorList": [ + { + "ForeName": "Lakshmipathi", + "LastName": "Vadlakonda", + "abbrevName": "Vadlakonda L", + "email": null, + "isCollectiveName": false, + "name": "Lakshmipathi Vadlakonda", + "orcid": null + }, + { + "ForeName": "Abhinandita", + "LastName": "Dash", + "abbrevName": "Dash A", + "email": null, + "isCollectiveName": false, + "name": "Abhinandita Dash", + "orcid": null + }, + { + "ForeName": "Mukesh", + "LastName": "Pasupuleti", + "abbrevName": "Pasupuleti M", + "email": null, + "isCollectiveName": false, + "name": "Mukesh Pasupuleti", + "orcid": null + }, + { + "ForeName": "Kotha", + "LastName": "Anil Kumar", + "abbrevName": "Anil Kumar K", + "email": null, + "isCollectiveName": false, + "name": "Kotha Anil Kumar", + "orcid": null + }, + { + "ForeName": "Pallu", + "LastName": "Reddanna", + "abbrevName": "Reddanna P", + "email": null, + "isCollectiveName": false, + "name": "Pallu Reddanna", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3389/fonc.2013.00165", + "pmid": "23802099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Front Oncol 3 2013", + "title": "The Paradox of Akt-mTOR Interactions." + } + }, + { + "pmid": "24374738", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1401580800, + "timezone": "+00:00" + }, + "abstract": "To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.", + "authors": { + "abbreviation": "Victor Jeannot, Benoît Busser, Elisabeth Brambilla, ..., Amandine Hurbin", + "authorList": [ + { + "ForeName": "Victor", + "LastName": "Jeannot", + "abbrevName": "Jeannot V", + "email": null, + "isCollectiveName": false, + "name": "Victor Jeannot", + "orcid": null + }, + { + "ForeName": "Benoît", + "LastName": "Busser", + "abbrevName": "Busser B", + "email": null, + "isCollectiveName": false, + "name": "Benoît Busser", + "orcid": null + }, + { + "ForeName": "Elisabeth", + "LastName": "Brambilla", + "abbrevName": "Brambilla E", + "email": null, + "isCollectiveName": false, + "name": "Elisabeth Brambilla", + "orcid": null + }, + { + "ForeName": "Marie", + "LastName": "Wislez", + "abbrevName": "Wislez M", + "email": null, + "isCollectiveName": false, + "name": "Marie Wislez", + "orcid": null + }, + { + "ForeName": "Blaise", + "LastName": "Robin", + "abbrevName": "Robin B", + "email": null, + "isCollectiveName": false, + "name": "Blaise Robin", + "orcid": null + }, + { + "ForeName": "Jacques", + "LastName": "Cadranel", + "abbrevName": "Cadranel J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Cadranel", + "orcid": null + }, + { + "ForeName": "Jean-Luc", + "LastName": "Coll", + "abbrevName": "Coll JL", + "email": null, + "isCollectiveName": false, + "name": "Jean-Luc Coll", + "orcid": null + }, + { + "ForeName": "Amandine", + "LastName": "Hurbin", + "abbrevName": "Hurbin A", + "email": null, + "isCollectiveName": false, + "name": "Amandine Hurbin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28594", + "pmid": "24374738", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Cancer 134 2014", + "title": "The PI3K/AKT pathway promotes gefitinib resistance in mutant KRAS lung adenocarcinoma by a deacetylase-dependent mechanism." + } + }, + { + "pmid": "33495824", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1614556800, + "timezone": "+00:00" + }, + "abstract": "Breast cancer is the worldwide leading cause of cancer‑related deaths among women. Increasing evidence has demonstrated that microRNAs (miRNAs) play critical roles in the carcinogenesis and progression of breast cancer. miR‑653‑5p was previously reported to be involved in cell proliferation and apoptosis. However, the role of miR‑653‑5p in the progression of breast cancer has not been studied. In the present study, it was found that overexpression of miR‑653‑5p significantly inhibited the proliferation, migration and invasion of breast cancer cells in vitro. Moreover, overexpression of miR‑653‑5p promoted cell apoptosis in breast cancer by regulating the Bcl‑2/Bax axis and caspase‑9 activation. Additionally, the epithelial‑mesenchymal transition and activation of the Akt/mammalian target of rapamycin signaling pathway were also inhibited by miR‑653‑5p. Furthermore, the data demonstrated that miR‑653‑5p directly targeted mitogen‑activated protein kinase 6 (MAPK6) and negatively regulated its expression in breast cancer cells. Upregulation of MAPK6 could overcome the inhibitory effects of miR‑653‑5p on cell proliferation and migration in breast cancer. In conclusion, this study suggested that miR‑653‑5p functions as a tumor suppressor by targeting MAPK6 in the progression of breast cancer, and it may be a potential target for breast cancer therapy.", + "authors": { + "abbreviation": "Mei Zhang, Hongwei Wang, Xiaomei Zhang, Fengping Liu", + "authorList": [ + { + "ForeName": "Mei", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Zhang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Wang", + "orcid": null + }, + { + "ForeName": "Xiaomei", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaomei Zhang", + "orcid": null + }, + { + "ForeName": "Fengping", + "LastName": "Liu", + "abbrevName": "Liu F", + "email": null, + "isCollectiveName": false, + "name": "Fengping Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3892/mmr.2021.11839", + "pmid": "33495824", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Med Rep 23 2021", + "title": "miR‑653‑5p suppresses the growth and migration of breast cancer cells by targeting MAPK6." + } + }, + { + "pmid": "22145100", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1320105600, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. SIGNIFICANCE: This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.", + "authors": { + "abbreviation": "Kazuhiro Tanaka, Ivan Babic, David Nathanson, ..., Paul S Mischel", + "authorList": [ + { + "ForeName": "Kazuhiro", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Tanaka", + "orcid": null + }, + { + "ForeName": "Ivan", + "LastName": "Babic", + "abbrevName": "Babic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Babic", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Nathanson", + "abbrevName": "Nathanson D", + "email": null, + "isCollectiveName": false, + "name": "David Nathanson", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Akhavan", + "abbrevName": "Akhavan D", + "email": null, + "isCollectiveName": false, + "name": "David Akhavan", + "orcid": null + }, + { + "ForeName": "Deliang", + "LastName": "Guo", + "abbrevName": "Guo D", + "email": null, + "isCollectiveName": false, + "name": "Deliang Guo", + "orcid": null + }, + { + "ForeName": "Beatrice", + "LastName": "Gini", + "abbrevName": "Gini B", + "email": null, + "isCollectiveName": false, + "name": "Beatrice Gini", + "orcid": null + }, + { + "ForeName": "Julie", + "LastName": "Dang", + "abbrevName": "Dang J", + "email": null, + "isCollectiveName": false, + "name": "Julie Dang", + "orcid": null + }, + { + "ForeName": "Shaojun", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Shaojun Zhu", + "orcid": null + }, + { + "ForeName": "Huijun", + "LastName": "Yang", + "abbrevName": "Yang H", + "email": null, + "isCollectiveName": false, + "name": "Huijun Yang", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "De Jesus", + "abbrevName": "De Jesus J", + "email": null, + "isCollectiveName": false, + "name": "Jason De Jesus", + "orcid": null + }, + { + "ForeName": "Ali", + "LastName": "Amzajerdi", + "abbrevName": "Amzajerdi AN", + "email": null, + "isCollectiveName": false, + "name": "Ali Nael Amzajerdi", + "orcid": null + }, + { + "ForeName": "Yinan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinan Zhang", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Dibble", + "abbrevName": "Dibble CC", + "email": null, + "isCollectiveName": false, + "name": "Christian C Dibble", + "orcid": null + }, + { + "ForeName": "Hancai", + "LastName": "Dan", + "abbrevName": "Dan H", + "email": null, + "isCollectiveName": false, + "name": "Hancai Dan", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Rinkenbaugh", + "abbrevName": "Rinkenbaugh A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Rinkenbaugh", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Yong", + "abbrevName": "Yong WH", + "email": null, + "isCollectiveName": false, + "name": "William H Yong", + "orcid": null + }, + { + "ForeName": "Harry", + "LastName": "Vinters", + "abbrevName": "Vinters HV", + "email": null, + "isCollectiveName": false, + "name": "Harry V Vinters", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Gera", + "abbrevName": "Gera JF", + "email": null, + "isCollectiveName": false, + "name": "Joseph F Gera", + "orcid": null + }, + { + "ForeName": "Webster", + "LastName": "Cavenee", + "abbrevName": "Cavenee WK", + "email": null, + "isCollectiveName": false, + "name": "Webster K Cavenee", + "orcid": null + }, + { + "ForeName": "Timothy", + "LastName": "Cloughesy", + "abbrevName": "Cloughesy TF", + "email": null, + "isCollectiveName": false, + "name": "Timothy F Cloughesy", + "orcid": null + }, + { + "ForeName": "Brendan", + "LastName": "Manning", + "abbrevName": "Manning BD", + "email": null, + "isCollectiveName": false, + "name": "Brendan D Manning", + "orcid": null + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Mischel", + "abbrevName": "Mischel PS", + "email": null, + "isCollectiveName": false, + "name": "Paul S Mischel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0124", + "pmid": "22145100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance." + } + }, + { + "pmid": "23874880", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "AIMS: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic clinical benefits in advanced non-small cell lung cancer (NSCLC); however, resistance remains a serious problem in clinical practice. The present study analyzed mTOR-associated signaling-pathway differences between the EGFR TKI-sensitive and -resistant NSCLC cell lines and investigated the feasibility of targeting mTOR with specific mTOR inhibitor in EGFR TKI resistant NSCLC cells. METHODS: We selected four different types of EGFR TKI-sensitive and -resistant NSCLC cells: PC9, PC9GR, H1650 and H1975 cells as models to detect mTOR-associated signaling-pathway differences by western blot and Immunoprecipitation and evaluated the antiproliferative effect and cell cycle arrest of ku-0063794 by MTT method and flow cytometry. RESULTS: In the present study, we observed that mTORC2-associated Akt ser473-FOXO1 signaling pathway in a basal state was highly activated in resistant cells. In vitro mTORC1 and mTORC2 kinase activities assays showed that EGFR TKI-resistant NSCLC cell lines had higher mTORC2 kinase activity, whereas sensitive cells had higher mTORC1 kinase activity in the basal state. The ATP-competitive mTOR inhibitor ku-0063794 showed dramatic antiproliferative effects and G1-cell cycle arrest in both sensitive and resistant cells. Ku-0063794 at the IC50 concentration effectively inhibited both mTOR and p70S6K phosphorylation levels; the latter is an mTORC1 substrate and did not upregulate Akt ser473 phosphorylation which would be induced by rapamycin and resulted in partial inhibition of FOXO1 phosphorylation. We also observed that EGFR TKI-sensitive and -resistant clinical NSCLC tumor specimens had higher total and phosphorylated p70S6K expression levels. CONCLUSION: Our results indicate mTORC2-associated signaling-pathway was hyperactivated in EGFR TKI-resistant cells and targeting mTOR with specific mTOR inhibitors is likely a good strategy for patients with EGFR mutant NSCLC who develop EGFR TKI resistance; the potential specific roles of mTORC2 in EGFR TKI-resistant NSCLC cells were still unknown and should be further investigated.", + "authors": { + "abbreviation": "Shi-Jiang Fei, Xu-Chao Zhang, Song Dong, ..., Yi-Long Wu", + "authorList": [ + { + "ForeName": "Shi-Jiang", + "LastName": "Fei", + "abbrevName": "Fei SJ", + "email": null, + "isCollectiveName": false, + "name": "Shi-Jiang Fei", + "orcid": null + }, + { + "ForeName": "Xu-Chao", + "LastName": "Zhang", + "abbrevName": "Zhang XC", + "email": null, + "isCollectiveName": false, + "name": "Xu-Chao Zhang", + "orcid": null + }, + { + "ForeName": "Song", + "LastName": "Dong", + "abbrevName": "Dong S", + "email": null, + "isCollectiveName": false, + "name": "Song Dong", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Cheng", + "abbrevName": "Cheng H", + "email": null, + "isCollectiveName": false, + "name": "Hua Cheng", + "orcid": null + }, + { + "ForeName": "Yi-Fang", + "LastName": "Zhang", + "abbrevName": "Zhang YF", + "email": null, + "isCollectiveName": false, + "name": "Yi-Fang Zhang", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Huang", + "abbrevName": "Huang L", + "email": null, + "isCollectiveName": false, + "name": "Ling Huang", + "orcid": null + }, + { + "ForeName": "Hai-Yu", + "LastName": "Zhou", + "abbrevName": "Zhou HY", + "email": null, + "isCollectiveName": false, + "name": "Hai-Yu Zhou", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Xie", + "abbrevName": "Xie Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Xie", + "orcid": null + }, + { + "ForeName": "Zhi-Hong", + "LastName": "Chen", + "abbrevName": "Chen ZH", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Hong Chen", + "orcid": null + }, + { + "ForeName": "Yi-Long", + "LastName": "Wu", + "abbrevName": "Wu YL", + "email": null, + "isCollectiveName": false, + "name": "Yi-Long Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0069104", + "pmid": "23874880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells." + } + }, + { + "pmid": "24112608", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1381363200, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. METHODS: A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. RESULTS: ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK. CONCLUSIONS: Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.", + "authors": { + "abbreviation": "Ju Gao, Minzhi Yin, Yiping Zhu, ..., Zhigui Ma", + "authorList": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": "ma_zg@yahoo.com", + "isCollectiveName": false, + "name": "Ju Gao", + "orcid": null + }, + { + "ForeName": "Minzhi", + "LastName": "Yin", + "abbrevName": "Yin M", + "email": null, + "isCollectiveName": false, + "name": "Minzhi Yin", + "orcid": null + }, + { + "ForeName": "Yiping", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yiping Zhu", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Gu", + "abbrevName": "Gu L", + "email": null, + "isCollectiveName": false, + "name": "Ling Gu", + "orcid": null + }, + { + "ForeName": "Yanle", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanle Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Li", + "orcid": null + }, + { + "ForeName": "Cangsong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Cangsong Jia", + "orcid": null + }, + { + "ForeName": "Zhigui", + "LastName": "Ma", + "abbrevName": "Ma Z", + "email": null, + "isCollectiveName": false, + "name": "Zhigui Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "email": [ + "ma_zg@yahoo.com" + ], + "name": "Ju Gao" + } + ] + }, + "doi": "10.1186/1471-2407-13-471", + "pmid": "24112608", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cancer 13 2013", + "title": "Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma." + } + }, + { + "pmid": "30887599", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1561939200, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin-Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)-induced G1/S cell-cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF-induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal-regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c-Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP-1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate-bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage-independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage-independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR-Akt-p70S6K and mTOR-Akt-GSK3β-AP-1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2-Akt-p70S6k signaling pathway.", + "authors": { + "abbreviation": "Sun-Mi Yoo, Cheol-Jung Lee, Han Chang Kang, ..., Yong-Yeon Cho", + "authorList": [ + { + "ForeName": "Sun-Mi", + "LastName": "Yoo", + "abbrevName": "Yoo SM", + "email": null, + "isCollectiveName": false, + "name": "Sun-Mi Yoo", + "orcid": null + }, + { + "ForeName": "Cheol-Jung", + "LastName": "Lee", + "abbrevName": "Lee CJ", + "email": null, + "isCollectiveName": false, + "name": "Cheol-Jung Lee", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Han Chang Kang", + "orcid": null + }, + { + "ForeName": "Hye", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Hye Suk Lee", + "orcid": null + }, + { + "ForeName": "Joo", + "LastName": "Lee", + "abbrevName": "Lee JY", + "email": null, + "isCollectiveName": false, + "name": "Joo Young Lee", + "orcid": null + }, + { + "ForeName": "Kwang", + "LastName": "Kim", + "abbrevName": "Kim KD", + "email": null, + "isCollectiveName": false, + "name": "Kwang Dong Kim", + "orcid": null + }, + { + "ForeName": "Dae", + "LastName": "Kim", + "abbrevName": "Kim DJ", + "email": null, + "isCollectiveName": false, + "name": "Dae Joon Kim", + "orcid": "0000-0002-7977-9955" + }, + { + "ForeName": "Hyun-Jung", + "LastName": "An", + "abbrevName": "An HJ", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Jung An", + "orcid": null + }, + { + "ForeName": "Yong-Yeon", + "LastName": "Cho", + "abbrevName": "Cho YY", + "email": null, + "isCollectiveName": false, + "name": "Yong-Yeon Cho", + "orcid": "0000-0003-1107-2651" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23005", + "pmid": "30887599", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells." + } + }, + { + "pmid": "32899862", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1599177600, + "timezone": "+00:00" + }, + "abstract": "Recently, we have reported that blockade/deletion of P2X7 receptor (P2X7R), an ATP-gated ion channel, exacerbates heat shock protein 25 (HSP25)-mediated astroglial autophagy (clasmatodendrosis) following kainic acid (KA) injection. In P2X7R knockout (KO) mice, prolonged astroglial HSP25 induction exerts 5' adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1-mediated autophagic pathway independent of mammalian target of rapamycin (mTOR) activity following KA injection. Sustained HSP25 expression also enhances AKT-serine (S) 473 phosphorylation leading to astroglial autophagy via glycogen synthase kinase-3β/bax interacting factor 1 signaling pathway. However, it is unanswered how P2X7R deletion induces AKT-S473 hyperphosphorylation during autophagic process in astrocytes. In the present study, we found that AKT-S473 phosphorylation was increased by enhancing activity of focal adhesion kinase (FAK), independent of mTOR complex (mTORC) 1 and 2 activities in isolated astrocytes of P2X7R knockout (KO) mice following KA injection. In addition, HSP25 overexpression in P2X7R KO mice acted as a chaperone of AKT, which retained AKT-S473 phosphorylation by inhibiting the pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1- and 2-binding to AKT. Therefore, our findings suggest that P2X7R may be a fine-tuner of AKT-S473 activity during astroglial autophagy by regulating FAK phosphorylation and HSP25-mediated inhibition of PHLPP1/2-AKT binding following KA treatment.", + "authors": { + "abbreviation": "Duk-Shin Lee, Ji-Eun Kim", + "authorList": [ + { + "ForeName": "Duk-Shin", + "LastName": "Lee", + "abbrevName": "Lee DS", + "email": null, + "isCollectiveName": false, + "name": "Duk-Shin Lee", + "orcid": null + }, + { + "ForeName": "Ji-Eun", + "LastName": "Kim", + "abbrevName": "Kim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Kim", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21186476", + "pmid": "32899862", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures." + } + }, + { + "pmid": "22808163", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.", + "authors": { + "abbreviation": "Alan L Ho, Elgilda Musi, Grazia Ambrosini, ..., Gary K Schwartz", + "authorList": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "abbrevName": "Ho AL", + "email": "hoa@mskcc.org", + "isCollectiveName": false, + "name": "Alan L Ho", + "orcid": null + }, + { + "ForeName": "Elgilda", + "LastName": "Musi", + "abbrevName": "Musi E", + "email": null, + "isCollectiveName": false, + "name": "Elgilda Musi", + "orcid": null + }, + { + "ForeName": "Grazia", + "LastName": "Ambrosini", + "abbrevName": "Ambrosini G", + "email": null, + "isCollectiveName": false, + "name": "Grazia Ambrosini", + "orcid": null + }, + { + "ForeName": "Jayasree", + "LastName": "Nair", + "abbrevName": "Nair JS", + "email": null, + "isCollectiveName": false, + "name": "Jayasree S Nair", + "orcid": null + }, + { + "ForeName": "Shyamprasad", + "LastName": "Deraje Vasudeva", + "abbrevName": "Deraje Vasudeva S", + "email": null, + "isCollectiveName": false, + "name": "Shyamprasad Deraje Vasudeva", + "orcid": null + }, + { + "ForeName": "Elisa", + "LastName": "de Stanchina", + "abbrevName": "de Stanchina E", + "email": null, + "isCollectiveName": false, + "name": "Elisa de Stanchina", + "orcid": null + }, + { + "ForeName": "Gary", + "LastName": "Schwartz", + "abbrevName": "Schwartz GK", + "email": null, + "isCollectiveName": false, + "name": "Gary K Schwartz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "email": [ + "hoa@mskcc.org" + ], + "name": "Alan L Ho" + } + ] + }, + "doi": "10.1371/journal.pone.0040439", + "pmid": "22808163", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype." + } + }, + { + "pmid": "22476852", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1343779200, + "timezone": "+00:00" + }, + "abstract": "Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.", + "authors": { + "abbreviation": "Haiyan Li, Jun Lin, Xiaokai Wang, ..., Xiaochun Bai", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Li", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lin", + "orcid": null + }, + { + "ForeName": "Xiaokai", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaokai Wang", + "orcid": null + }, + { + "ForeName": "Guangyu", + "LastName": "Yao", + "abbrevName": "Yao G", + "email": null, + "isCollectiveName": false, + "name": "Guangyu Yao", + "orcid": null + }, + { + "ForeName": "Liping", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Liping Wang", + "orcid": null + }, + { + "ForeName": "Hang", + "LastName": "Zheng", + "abbrevName": "Zheng H", + "email": null, + "isCollectiveName": false, + "name": "Hang Zheng", + "orcid": null + }, + { + "ForeName": "Cuilan", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuilan Yang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Jia", + "orcid": null + }, + { + "ForeName": "Anling", + "LastName": "Liu", + "abbrevName": "Liu A", + "email": null, + "isCollectiveName": false, + "name": "Anling Liu", + "orcid": null + }, + { + "ForeName": "Xiaochun", + "LastName": "Bai", + "abbrevName": "Bai X", + "email": null, + "isCollectiveName": false, + "name": "Xiaochun Bai", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s10549-012-2036-2", + "pmid": "22476852", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 134 2012", + "title": "Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer." + } + }, + { + "pmid": "32630372", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1593043200, + "timezone": "+00:00" + }, + "abstract": "Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.", + "authors": { + "abbreviation": "Boris Y Shorning, Manisha S Dass, Matthew J Smalley, Helen B Pearson", + "authorList": [ + { + "ForeName": "Boris", + "LastName": "Shorning", + "abbrevName": "Shorning BY", + "email": null, + "isCollectiveName": false, + "name": "Boris Y Shorning", + "orcid": null + }, + { + "ForeName": "Manisha", + "LastName": "Dass", + "abbrevName": "Dass MS", + "email": null, + "isCollectiveName": false, + "name": "Manisha S Dass", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Smalley", + "abbrevName": "Smalley MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J Smalley", + "orcid": "0000-0001-9540-1146" + }, + { + "ForeName": "Helen", + "LastName": "Pearson", + "abbrevName": "Pearson HB", + "email": null, + "isCollectiveName": false, + "name": "Helen B Pearson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21124507", + "pmid": "32630372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling." + } + }, + { + "pmid": "24966685", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1388534400, + "timezone": "+00:00" + }, + "abstract": "Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as \"231/Gem\"), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.", + "authors": { + "abbreviation": "Xiao Li Yang, Feng Juan Lin, Ya Jie Guo, ..., Zhou Luo Ou", + "authorList": [ + { + "ForeName": "Xiao", + "LastName": "Yang", + "abbrevName": "Yang XL", + "email": null, + "isCollectiveName": false, + "name": "Xiao Li Yang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Lin", + "abbrevName": "Lin FJ", + "email": null, + "isCollectiveName": false, + "name": "Feng Juan Lin", + "orcid": null + }, + { + "ForeName": "Ya", + "LastName": "Guo", + "abbrevName": "Guo YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jie Guo", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi Min Shao", + "orcid": null + }, + { + "ForeName": "Zhou", + "LastName": "Ou", + "abbrevName": "Ou ZL", + "email": null, + "isCollectiveName": false, + "name": "Zhou Luo Ou", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2147/OTT.S63145", + "pmid": "24966685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Onco Targets Ther 7 2014", + "title": "Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways." + } + }, + { + "pmid": "22845486", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1349049600, + "timezone": "+00:00" + }, + "abstract": "The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.", + "authors": { + "abbreviation": "David Barrett, Valerie I Brown, Stephan A Grupp, David T Teachey", + "authorList": [ + { + "ForeName": "David", + "LastName": "Barrett", + "abbrevName": "Barrett D", + "email": null, + "isCollectiveName": false, + "name": "David Barrett", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Brown", + "abbrevName": "Brown VI", + "email": null, + "isCollectiveName": false, + "name": "Valerie I Brown", + "orcid": null + }, + { + "ForeName": "Stephan", + "LastName": "Grupp", + "abbrevName": "Grupp SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Grupp", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Teachey", + "abbrevName": "Teachey DT", + "email": null, + "isCollectiveName": false, + "name": "David T Teachey", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2165/11594740-000000000-00000", + "pmid": "22845486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Paediatr Drugs 14 2012", + "title": "Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies." + } + }, + { + "pmid": "23272152", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "OBJECTIVE: Tetrameric α(2)-macroglobulin (α(2)M), a plasma panproteinase inhibitor, is activated upon interaction with a proteinase, and undergoes a major conformational change exposing a receptor recognition site in each of its subunits. Activated α(2)M (α(2)M*) binds to cancer cell surface GRP78 and triggers proliferative and antiapoptotic signaling. We have studied the role of α(2)M* in the regulation of mTORC1 and TORC2 signaling in the growth of human prostate cancer cells. METHODS: Employing immunoprecipitation techniques and Western blotting as well as kinase assays, activation of the mTORC1 and mTORC2 complexes, as well as down stream targets were studied. RNAi was also employed to silence expression of Raptor, Rictor, or GRP78 in parallel studies. RESULTS: Stimulation of cells with α(2)M* promotes phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt(T308), and Akt(S473) in a concentration and time-dependent manner. Rheb, Raptor, and Rictor also increased. α(2)M* treatment of cells elevated mTORC1 kinase activity as determined by kinase assays of mTOR or Raptor immunoprecipitates. mTORC1 activity was sensitive to LY294002 and rapamycin or transfection of cells with GRP78 dsRNA. Down regulation of Raptor expression by RNAi significantly reduced α(2)M*-induced S6-Kinase phosphorylation at T389 and kinase activity in Raptor immunoprecipitates. α(2)M*-treated cells demonstrate about a twofold increase in mTORC2 kinase activity as determined by kinase assay of Akt(S473) phosphorylation and levels of p-Akt(S473) in mTOR and Rictor immunoprecipitates. mTORC2 activity was sensitive to LY294002 and transfection of cells with GRP78 dsRNA, but insensitive to rapamycin. Down regulation of Rictor expression by RNAi significantly reduces α(2)M*-induced phosphorylation of Akt(S473) phosphorylation in Rictor immunoprecipitates. CONCLUSION: Binding of α(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0051735", + "pmid": "23272152", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 7 2012", + "title": "Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells." + } + }, + { + "pmid": "19209957", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1234224000, + "timezone": "+00:00" + }, + "abstract": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.", + "authors": { + "abbreviation": "Morris E Feldman, Beth Apsel, Aino Uotila, ..., Kevan M Shokat", + "authorList": [ + { + "ForeName": "Morris", + "LastName": "Feldman", + "abbrevName": "Feldman ME", + "email": null, + "isCollectiveName": false, + "name": "Morris E Feldman", + "orcid": null + }, + { + "ForeName": "Beth", + "LastName": "Apsel", + "abbrevName": "Apsel B", + "email": null, + "isCollectiveName": false, + "name": "Beth Apsel", + "orcid": null + }, + { + "ForeName": "Aino", + "LastName": "Uotila", + "abbrevName": "Uotila A", + "email": null, + "isCollectiveName": false, + "name": "Aino Uotila", + "orcid": null + }, + { + "ForeName": "Robbie", + "LastName": "Loewith", + "abbrevName": "Loewith R", + "email": null, + "isCollectiveName": false, + "name": "Robbie Loewith", + "orcid": null + }, + { + "ForeName": "Zachary", + "LastName": "Knight", + "abbrevName": "Knight ZA", + "email": null, + "isCollectiveName": false, + "name": "Zachary A Knight", + "orcid": null + }, + { + "ForeName": "Davide", + "LastName": "Ruggero", + "abbrevName": "Ruggero D", + "email": null, + "isCollectiveName": false, + "name": "Davide Ruggero", + "orcid": null + }, + { + "ForeName": "Kevan", + "LastName": "Shokat", + "abbrevName": "Shokat KM", + "email": null, + "isCollectiveName": false, + "name": "Kevan M Shokat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.1000038", + "pmid": "19209957", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 7 2009", + "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." + } + }, + { + "pmid": "30285764", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1538352000, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin. METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells. RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells. CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.", + "authors": { + "abbreviation": "Masoud Razmara, Azita Monazzam, Britt Skogseid", + "authorList": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "abbrevName": "Razmara M", + "email": "Masoud.Razmara@medsci.uu.se", + "isCollectiveName": false, + "name": "Masoud Razmara", + "orcid": "0000-0002-1037-4810" + }, + { + "ForeName": "Azita", + "LastName": "Monazzam", + "abbrevName": "Monazzam A", + "email": null, + "isCollectiveName": false, + "name": "Azita Monazzam", + "orcid": null + }, + { + "ForeName": "Britt", + "LastName": "Skogseid", + "abbrevName": "Skogseid B", + "email": null, + "isCollectiveName": false, + "name": "Britt Skogseid", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "email": [ + "Masoud.Razmara@medsci.uu.se" + ], + "name": "Masoud Razmara" + } + ] + }, + "doi": "10.1186/s12964-018-0278-2", + "pmid": "30285764", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Commun Signal 16 2018", + "title": "Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration." + } + }, + { + "pmid": "19372546", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1238544000, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.", + "authors": { + "abbreviation": "Madlaina Breuleux, Matthieu Klopfenstein, Christine Stephan, ..., Heidi A Lane", + "authorList": [ + { + "ForeName": "Madlaina", + "LastName": "Breuleux", + "abbrevName": "Breuleux M", + "email": null, + "isCollectiveName": false, + "name": "Madlaina Breuleux", + "orcid": null + }, + { + "ForeName": "Matthieu", + "LastName": "Klopfenstein", + "abbrevName": "Klopfenstein M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Klopfenstein", + "orcid": null + }, + { + "ForeName": "Christine", + "LastName": "Stephan", + "abbrevName": "Stephan C", + "email": null, + "isCollectiveName": false, + "name": "Christine Stephan", + "orcid": null + }, + { + "ForeName": "Cheryl", + "LastName": "Doughty", + "abbrevName": "Doughty CA", + "email": null, + "isCollectiveName": false, + "name": "Cheryl A Doughty", + "orcid": null + }, + { + "ForeName": "Louise", + "LastName": "Barys", + "abbrevName": "Barys L", + "email": null, + "isCollectiveName": false, + "name": "Louise Barys", + "orcid": null + }, + { + "ForeName": "Saveur-Michel", + "LastName": "Maira", + "abbrevName": "Maira SM", + "email": null, + "isCollectiveName": false, + "name": "Saveur-Michel Maira", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Kwiatkowski", + "abbrevName": "Kwiatkowski D", + "email": null, + "isCollectiveName": false, + "name": "David Kwiatkowski", + "orcid": null + }, + { + "ForeName": "Heidi", + "LastName": "Lane", + "abbrevName": "Lane HA", + "email": null, + "isCollectiveName": false, + "name": "Heidi A Lane", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/1535-7163.MCT-08-0668", + "pmid": "19372546", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cancer Ther 8 2009", + "title": "Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition." + } + }, + { + "pmid": "22140653", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1312156800, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. SIGNIFICANCE: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.", + "authors": { + "abbreviation": "Vanessa S Rodrik-Outmezguine, Sarat Chandarlapaty, Nen C Pagano, ..., Neal Rosen", + "authorList": [ + { + "ForeName": "Vanessa", + "LastName": "Rodrik-Outmezguine", + "abbrevName": "Rodrik-Outmezguine VS", + "email": null, + "isCollectiveName": false, + "name": "Vanessa S Rodrik-Outmezguine", + "orcid": null + }, + { + "ForeName": "Sarat", + "LastName": "Chandarlapaty", + "abbrevName": "Chandarlapaty S", + "email": null, + "isCollectiveName": false, + "name": "Sarat Chandarlapaty", + "orcid": null + }, + { + "ForeName": "Nen", + "LastName": "Pagano", + "abbrevName": "Pagano NC", + "email": null, + "isCollectiveName": false, + "name": "Nen C Pagano", + "orcid": null + }, + { + "ForeName": "Poulikos", + "LastName": "Poulikakos", + "abbrevName": "Poulikakos PI", + "email": null, + "isCollectiveName": false, + "name": "Poulikos I Poulikakos", + "orcid": null + }, + { + "ForeName": "Maurizio", + "LastName": "Scaltriti", + "abbrevName": "Scaltriti M", + "email": null, + "isCollectiveName": false, + "name": "Maurizio Scaltriti", + "orcid": null + }, + { + "ForeName": "Elizabeth", + "LastName": "Moskatel", + "abbrevName": "Moskatel E", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth Moskatel", + "orcid": null + }, + { + "ForeName": "José", + "LastName": "Baselga", + "abbrevName": "Baselga J", + "email": null, + "isCollectiveName": false, + "name": "José Baselga", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Guichard", + "abbrevName": "Guichard S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Guichard", + "orcid": null + }, + { + "ForeName": "Neal", + "LastName": "Rosen", + "abbrevName": "Rosen N", + "email": null, + "isCollectiveName": false, + "name": "Neal Rosen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0085", + "pmid": "22140653", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling." + } + }, + { + "pmid": "12181443", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1030838400, + "timezone": "+00:00" + }, + "abstract": "The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.", + "authors": { + "abbreviation": "Linnea M Baudhuin, Kelly L Cristina, Jun Lu, Yan Xu", + "authorList": [ + { + "ForeName": "Linnea", + "LastName": "Baudhuin", + "abbrevName": "Baudhuin LM", + "email": null, + "isCollectiveName": false, + "name": "Linnea M Baudhuin", + "orcid": null + }, + { + "ForeName": "Kelly", + "LastName": "Cristina", + "abbrevName": "Cristina KL", + "email": null, + "isCollectiveName": false, + "name": "Kelly L Cristina", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lu", + "abbrevName": "Lu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lu", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Xu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1124/mol.62.3.660", + "pmid": "12181443", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Pharmacol 62 2002", + "title": "Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific." + } + } + ], + "secret": "998d53dc-8150-40b9-b59f-b5b54439e22d", + "type": "protein" + }, + { + "_creationTimestamp": { + "$reql_type$": "TIME", + "epoch_time": 1671052744.612, + "timezone": "+00:00" + }, + "_newestOpId": "f833a99a-54b3-4ce6-80e8-1fdf4d02e121", + "_ops": [], + "association": { + "charge": null, + "combinedOrganismIndex": 0, + "dbName": "NCBI Gene", + "dbPrefix": "ncbigene", + "dbXrefs": [ + { + "db": "MIM", + "id": "164730" + }, + { + "db": "HGNC", + "id": "HGNC:391" + }, + { + "db": "Ensembl", + "id": "ENSG00000142208" + } + ], + "defaultOrganismIndex": 2, + "distance": 0, + "esScore": 10.916169, + "formulae": null, + "id": "207", + "mass": null, + "monoisotopicMass": null, + "name": "AKT1", + "nameDistance": 0.19999999999999996, + "namespace": "ncbi", + "organism": "9606", + "organismIndex": 0, + "organismName": "Homo sapiens", + "overallDistance": 20, + "shortSynonyms": [ + "AKT1", + "AKT", + "PKB", + "PKB-ALPHA", + "PRKBA", + "RAC", + "AKT1m", + "proto-oncogene c-Akt", + "AKT serine/threonine kinase 1", + "v-akt murine thymoma viral oncogene homolog 1", + "v-akt murine thymoma viral oncogene-like protein 1" + ], + "synonyms": [ + "AKT", + "PKB", + "PKB-ALPHA", + "PRKBA", + "RAC", + "RAC-ALPHA", + "RAC-alpha serine/threonine-protein kinase", + "AKT1m", + "PKB alpha", + "RAC-PK-alpha", + "protein kinase B alpha", + "proto-oncogene c-Akt", + "rac protein kinase alpha", + "serine-threonine protein kinase", + "v-akt murine thymoma viral oncogene homolog 1", + "v-akt murine thymoma viral oncogene-like protein 1", + "AKT serine/threonine kinase 1" + ], + "type": "protein" + }, + "completed": true, + "description": "", + "id": "4081348e-20b8-4bf8-836f-695827a4f9a2", + "liveId": "2beeff33-6540-4a16-9d34-01dbe0e07eed", + "lock": null, + "locked": false, + "name": "AKT", + "position": { + "x": -246.42444519327938, + "y": -98.99404397931303 + }, + "relatedPapers": [ + { + "pmid": "22808163", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.", + "authors": { + "abbreviation": "Alan L Ho, Elgilda Musi, Grazia Ambrosini, ..., Gary K Schwartz", + "authorList": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "abbrevName": "Ho AL", + "email": "hoa@mskcc.org", + "isCollectiveName": false, + "name": "Alan L Ho", + "orcid": null + }, + { + "ForeName": "Elgilda", + "LastName": "Musi", + "abbrevName": "Musi E", + "email": null, + "isCollectiveName": false, + "name": "Elgilda Musi", + "orcid": null + }, + { + "ForeName": "Grazia", + "LastName": "Ambrosini", + "abbrevName": "Ambrosini G", + "email": null, + "isCollectiveName": false, + "name": "Grazia Ambrosini", + "orcid": null + }, + { + "ForeName": "Jayasree", + "LastName": "Nair", + "abbrevName": "Nair JS", + "email": null, + "isCollectiveName": false, + "name": "Jayasree S Nair", + "orcid": null + }, + { + "ForeName": "Shyamprasad", + "LastName": "Deraje Vasudeva", + "abbrevName": "Deraje Vasudeva S", + "email": null, + "isCollectiveName": false, + "name": "Shyamprasad Deraje Vasudeva", + "orcid": null + }, + { + "ForeName": "Elisa", + "LastName": "de Stanchina", + "abbrevName": "de Stanchina E", + "email": null, + "isCollectiveName": false, + "name": "Elisa de Stanchina", + "orcid": null + }, + { + "ForeName": "Gary", + "LastName": "Schwartz", + "abbrevName": "Schwartz GK", + "email": null, + "isCollectiveName": false, + "name": "Gary K Schwartz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "email": [ + "hoa@mskcc.org" + ], + "name": "Alan L Ho" + } + ] + }, + "doi": "10.1371/journal.pone.0040439", + "pmid": "22808163", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype." + } + }, + { + "pmid": "30688659", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.", + "authors": { + "abbreviation": "Wei Wang, Tao Shen, Bingning Dong, ..., Feng Yang", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Shen", + "abbrevName": "Shen T", + "email": null, + "isCollectiveName": false, + "name": "Tao Shen", + "orcid": null + }, + { + "ForeName": "Bingning", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bingning Dong", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Yanling", + "LastName": "Meng", + "abbrevName": "Meng Y", + "email": null, + "isCollectiveName": false, + "name": "Yanling Meng", + "orcid": null + }, + { + "ForeName": "Wolong", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wolong Zhou", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Shi", + "abbrevName": "Shi Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Shi", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Zhou", + "abbrevName": "Zhou H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhou", + "orcid": null + }, + { + "ForeName": "Yinjie", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinjie Zhang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moore", + "abbrevName": "Moore DD", + "email": null, + "isCollectiveName": false, + "name": "David D Moore", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI97712", + "pmid": "30688659", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Clin Invest 129 2019", + "title": "MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling." + } + }, + { + "pmid": "23991179", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin complex 1 and 2 (mTORC1/2) are overactive in colorectal carcinomas; however, the first generation of mTOR inhibitors such as rapamycin have failed to show clinical benefits in treating colorectal carcinoma in part due to their effects only on mTORC1. The second generation of mTOR inhibitors such as PP242 targets mTOR kinase; thus, they are capable of inhibiting both mTORC1 and mTORC2. To examine the therapeutic potential of the mTOR kinase inhibitors, we treated a panel of colorectal carcinoma cell lines with PP242. Western blotting showed that the PP242 inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT(S473)) was transient only in the first few hours of the PP242 treatment. Receptor tyrosine kinase arrays further revealed that PP242 treatment increased the phosphorylated epidermal growth factor receptor (EGFR) at Tyr 1068 (EGFR(T1068)). The parallel increase of AKT(S473) and EGFR(T1068) in the cells following PP242 treatment raised the possibility that EGFR phosphorylation might contribute to the PP242 incomplete inhibition of mTORC2. To test this notion, we showed that the combination of PP242 with erlotinib, an EGFR small molecule inhibitor, blocked both mTORC1 and mTORC2 kinase activity. In addition, we showed that the combination treatment inhibited colony formation, blocked cell growth and induced apoptotic cell death. A systemic administration of PP242 and erlotinib resulted in the progression suppression of colorectal carcinoma xenografts in mice. This study suggests that the combination of mTOR kinase and EGFR inhibitors may provide an effective treatment of colorectal carcinoma.", + "authors": { + "abbreviation": "Quan Wang, Feng Wei, Chunsheng Li, ..., Chunhai Hao", + "authorList": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": "wangquan-jlcc@hotmail.com", + "isCollectiveName": false, + "name": "Quan Wang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Wei", + "abbrevName": "Wei F", + "email": null, + "isCollectiveName": false, + "name": "Feng Wei", + "orcid": null + }, + { + "ForeName": "Chunsheng", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunsheng Li", + "orcid": null + }, + { + "ForeName": "Guoyue", + "LastName": "Lv", + "abbrevName": "Lv G", + "email": null, + "isCollectiveName": false, + "name": "Guoyue Lv", + "orcid": null + }, + { + "ForeName": "Guangyi", + "LastName": "Wang", + "abbrevName": "Wang G", + "email": null, + "isCollectiveName": false, + "name": "Guangyi Wang", + "orcid": null + }, + { + "ForeName": "Tongjun", + "LastName": "Liu", + "abbrevName": "Liu T", + "email": null, + "isCollectiveName": false, + "name": "Tongjun Liu", + "orcid": null + }, + { + "ForeName": "Anita", + "LastName": "Bellail", + "abbrevName": "Bellail AC", + "email": null, + "isCollectiveName": false, + "name": "Anita C Bellail", + "orcid": null + }, + { + "ForeName": "Chunhai", + "LastName": "Hao", + "abbrevName": "Hao C", + "email": null, + "isCollectiveName": false, + "name": "Chunhai Hao", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "email": [ + "wangquan-jlcc@hotmail.com" + ], + "name": "Quan Wang" + } + ] + }, + "doi": "10.1371/journal.pone.0073175", + "pmid": "23991179", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 8 2013", + "title": "Combination of mTOR and EGFR kinase inhibitors blocks mTORC1 and mTORC2 kinase activity and suppresses the progression of colorectal carcinoma." + } + }, + { + "pmid": "30285764", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1538352000, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin. METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells. RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells. CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.", + "authors": { + "abbreviation": "Masoud Razmara, Azita Monazzam, Britt Skogseid", + "authorList": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "abbrevName": "Razmara M", + "email": "Masoud.Razmara@medsci.uu.se", + "isCollectiveName": false, + "name": "Masoud Razmara", + "orcid": "0000-0002-1037-4810" + }, + { + "ForeName": "Azita", + "LastName": "Monazzam", + "abbrevName": "Monazzam A", + "email": null, + "isCollectiveName": false, + "name": "Azita Monazzam", + "orcid": null + }, + { + "ForeName": "Britt", + "LastName": "Skogseid", + "abbrevName": "Skogseid B", + "email": null, + "isCollectiveName": false, + "name": "Britt Skogseid", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "email": [ + "Masoud.Razmara@medsci.uu.se" + ], + "name": "Masoud Razmara" + } + ] + }, + "doi": "10.1186/s12964-018-0278-2", + "pmid": "30285764", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Commun Signal 16 2018", + "title": "Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration." + } + }, + { + "pmid": "19209957", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1234224000, + "timezone": "+00:00" + }, + "abstract": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.", + "authors": { + "abbreviation": "Morris E Feldman, Beth Apsel, Aino Uotila, ..., Kevan M Shokat", + "authorList": [ + { + "ForeName": "Morris", + "LastName": "Feldman", + "abbrevName": "Feldman ME", + "email": null, + "isCollectiveName": false, + "name": "Morris E Feldman", + "orcid": null + }, + { + "ForeName": "Beth", + "LastName": "Apsel", + "abbrevName": "Apsel B", + "email": null, + "isCollectiveName": false, + "name": "Beth Apsel", + "orcid": null + }, + { + "ForeName": "Aino", + "LastName": "Uotila", + "abbrevName": "Uotila A", + "email": null, + "isCollectiveName": false, + "name": "Aino Uotila", + "orcid": null + }, + { + "ForeName": "Robbie", + "LastName": "Loewith", + "abbrevName": "Loewith R", + "email": null, + "isCollectiveName": false, + "name": "Robbie Loewith", + "orcid": null + }, + { + "ForeName": "Zachary", + "LastName": "Knight", + "abbrevName": "Knight ZA", + "email": null, + "isCollectiveName": false, + "name": "Zachary A Knight", + "orcid": null + }, + { + "ForeName": "Davide", + "LastName": "Ruggero", + "abbrevName": "Ruggero D", + "email": null, + "isCollectiveName": false, + "name": "Davide Ruggero", + "orcid": null + }, + { + "ForeName": "Kevan", + "LastName": "Shokat", + "abbrevName": "Shokat KM", + "email": null, + "isCollectiveName": false, + "name": "Kevan M Shokat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.1000038", + "pmid": "19209957", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 7 2009", + "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." + } + }, + { + "pmid": "30542835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1569888000, + "timezone": "+00:00" + }, + "abstract": "Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt's two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1 with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.", + "authors": { + "abbreviation": "Blair P Curless, Nne E Uko, Diane F Matesic", + "authorList": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "abbrevName": "Curless BP", + "email": "Blair.curless@live.mercer.edu", + "isCollectiveName": false, + "name": "Blair P Curless", + "orcid": "0000-0003-3158-745X" + }, + { + "ForeName": "Nne", + "LastName": "Uko", + "abbrevName": "Uko NE", + "email": null, + "isCollectiveName": false, + "name": "Nne E Uko", + "orcid": null + }, + { + "ForeName": "Diane", + "LastName": "Matesic", + "abbrevName": "Matesic DF", + "email": null, + "isCollectiveName": false, + "name": "Diane F Matesic", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "email": [ + "Blair.curless@live.mercer.edu" + ], + "name": "Blair P Curless" + } + ] + }, + "doi": "10.1007/s10637-018-0705-7", + "pmid": "30542835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Invest New Drugs 37 2019", + "title": "Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells." + } + }, + { + "pmid": "22476852", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1343779200, + "timezone": "+00:00" + }, + "abstract": "Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.", + "authors": { + "abbreviation": "Haiyan Li, Jun Lin, Xiaokai Wang, ..., Xiaochun Bai", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Li", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lin", + "orcid": null + }, + { + "ForeName": "Xiaokai", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaokai Wang", + "orcid": null + }, + { + "ForeName": "Guangyu", + "LastName": "Yao", + "abbrevName": "Yao G", + "email": null, + "isCollectiveName": false, + "name": "Guangyu Yao", + "orcid": null + }, + { + "ForeName": "Liping", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Liping Wang", + "orcid": null + }, + { + "ForeName": "Hang", + "LastName": "Zheng", + "abbrevName": "Zheng H", + "email": null, + "isCollectiveName": false, + "name": "Hang Zheng", + "orcid": null + }, + { + "ForeName": "Cuilan", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuilan Yang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Jia", + "orcid": null + }, + { + "ForeName": "Anling", + "LastName": "Liu", + "abbrevName": "Liu A", + "email": null, + "isCollectiveName": false, + "name": "Anling Liu", + "orcid": null + }, + { + "ForeName": "Xiaochun", + "LastName": "Bai", + "abbrevName": "Bai X", + "email": null, + "isCollectiveName": false, + "name": "Xiaochun Bai", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s10549-012-2036-2", + "pmid": "22476852", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 134 2012", + "title": "Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer." + } + }, + { + "pmid": "24374738", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1401580800, + "timezone": "+00:00" + }, + "abstract": "To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.", + "authors": { + "abbreviation": "Victor Jeannot, Benoît Busser, Elisabeth Brambilla, ..., Amandine Hurbin", + "authorList": [ + { + "ForeName": "Victor", + "LastName": "Jeannot", + "abbrevName": "Jeannot V", + "email": null, + "isCollectiveName": false, + "name": "Victor Jeannot", + "orcid": null + }, + { + "ForeName": "Benoît", + "LastName": "Busser", + "abbrevName": "Busser B", + "email": null, + "isCollectiveName": false, + "name": "Benoît Busser", + "orcid": null + }, + { + "ForeName": "Elisabeth", + "LastName": "Brambilla", + "abbrevName": "Brambilla E", + "email": null, + "isCollectiveName": false, + "name": "Elisabeth Brambilla", + "orcid": null + }, + { + "ForeName": "Marie", + "LastName": "Wislez", + "abbrevName": "Wislez M", + "email": null, + "isCollectiveName": false, + "name": "Marie Wislez", + "orcid": null + }, + { + "ForeName": "Blaise", + "LastName": "Robin", + "abbrevName": "Robin B", + "email": null, + "isCollectiveName": false, + "name": "Blaise Robin", + "orcid": null + }, + { + "ForeName": "Jacques", + "LastName": "Cadranel", + "abbrevName": "Cadranel J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Cadranel", + "orcid": null + }, + { + "ForeName": "Jean-Luc", + "LastName": "Coll", + "abbrevName": "Coll JL", + "email": null, + "isCollectiveName": false, + "name": "Jean-Luc Coll", + "orcid": null + }, + { + "ForeName": "Amandine", + "LastName": "Hurbin", + "abbrevName": "Hurbin A", + "email": null, + "isCollectiveName": false, + "name": "Amandine Hurbin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28594", + "pmid": "24374738", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Cancer 134 2014", + "title": "The PI3K/AKT pathway promotes gefitinib resistance in mutant KRAS lung adenocarcinoma by a deacetylase-dependent mechanism." + } + }, + { + "pmid": "24966685", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1388534400, + "timezone": "+00:00" + }, + "abstract": "Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as \"231/Gem\"), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.", + "authors": { + "abbreviation": "Xiao Li Yang, Feng Juan Lin, Ya Jie Guo, ..., Zhou Luo Ou", + "authorList": [ + { + "ForeName": "Xiao", + "LastName": "Yang", + "abbrevName": "Yang XL", + "email": null, + "isCollectiveName": false, + "name": "Xiao Li Yang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Lin", + "abbrevName": "Lin FJ", + "email": null, + "isCollectiveName": false, + "name": "Feng Juan Lin", + "orcid": null + }, + { + "ForeName": "Ya", + "LastName": "Guo", + "abbrevName": "Guo YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jie Guo", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi Min Shao", + "orcid": null + }, + { + "ForeName": "Zhou", + "LastName": "Ou", + "abbrevName": "Ou ZL", + "email": null, + "isCollectiveName": false, + "name": "Zhou Luo Ou", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2147/OTT.S63145", + "pmid": "24966685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Onco Targets Ther 7 2014", + "title": "Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways." + } + }, + { + "pmid": "19661225", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1262304000, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: Activated B-Raf alone cannot induce melanoma but must cooperate with other signaling pathways. The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR)/p70S6K pathways are critical for tumorigenesis. The authors investigated the role of these pathways in uveal melanoma cells. METHODS: The effects of PI3K and mTOR activation and inhibition on the proliferation of human uveal melanoma cell lines expressing either activated (WT)B-Raf or (V600E)B-Raf were investigated. Interactions among PI3K, mTOR, and B-Raf/ERK were studied. RESULTS: Inhibition of PI3K deactivated P70S6 kinase, reduced cell proliferation by 71% to 84%, and increased apoptosis by a factor of 5.0 to 8.4 without reducing ERK1/2 activation, indicating that ERK plays no role in mediating PI3K in these processes. In contrast, rapamycin-induced inhibition of mTOR did not significantly affect cell proliferation because it simultaneously stimulated PI3K/Akt activation and cyclin D1 expression. Regardless of B-Raf mutation status, cotreatment with the PI3K inhibitor effectively sensitized all melanoma cell lines to the B-Raf or ERK1/2 inhibition-induced reduction of cell proliferation. B-Raf/ERK and PI3K signaling, but not mTOR signaling, converged to control cyclin D1 expression. Moreover, p70S6K required the activation of ERK1/2. These data demonstrate that PI3K/Akt and mTOR/P70S6K interact with B-Raf/ERK. CONCLUSIONS: Activated PI3K/Akt attenuates the inhibitory effects of rapamycin on cell proliferation and thus serves as a negative feedback mechanism. This finding suggests that rapamycin is unlikely to inhibit uveal melanoma growth. In contrast, targeting PI3K while inhibiting B-Raf/ERK may be a promising approach to reduce the proliferation of uveal melanoma cells.", + "authors": { + "abbreviation": "Narjes Babchia, Armelle Calipel, Frédéric Mouriaux, ..., Frédéric Mascarelli", + "authorList": [ + { + "ForeName": "Narjes", + "LastName": "Babchia", + "abbrevName": "Babchia N", + "email": null, + "isCollectiveName": false, + "name": "Narjes Babchia", + "orcid": null + }, + { + "ForeName": "Armelle", + "LastName": "Calipel", + "abbrevName": "Calipel A", + "email": null, + "isCollectiveName": false, + "name": "Armelle Calipel", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mouriaux", + "abbrevName": "Mouriaux F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mouriaux", + "orcid": null + }, + { + "ForeName": "Anne-Marie", + "LastName": "Faussat", + "abbrevName": "Faussat AM", + "email": null, + "isCollectiveName": false, + "name": "Anne-Marie Faussat", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mascarelli", + "abbrevName": "Mascarelli F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mascarelli", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1167/iovs.09-3974", + "pmid": "19661225", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Invest Ophthalmol Vis Sci 51 2010", + "title": "The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK." + } + }, + { + "pmid": "32630372", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1593043200, + "timezone": "+00:00" + }, + "abstract": "Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.", + "authors": { + "abbreviation": "Boris Y Shorning, Manisha S Dass, Matthew J Smalley, Helen B Pearson", + "authorList": [ + { + "ForeName": "Boris", + "LastName": "Shorning", + "abbrevName": "Shorning BY", + "email": null, + "isCollectiveName": false, + "name": "Boris Y Shorning", + "orcid": null + }, + { + "ForeName": "Manisha", + "LastName": "Dass", + "abbrevName": "Dass MS", + "email": null, + "isCollectiveName": false, + "name": "Manisha S Dass", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Smalley", + "abbrevName": "Smalley MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J Smalley", + "orcid": "0000-0001-9540-1146" + }, + { + "ForeName": "Helen", + "LastName": "Pearson", + "abbrevName": "Pearson HB", + "email": null, + "isCollectiveName": false, + "name": "Helen B Pearson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21124507", + "pmid": "32630372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling." + } + }, + { + "pmid": "30887599", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1561939200, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin-Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)-induced G1/S cell-cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF-induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal-regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c-Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP-1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate-bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage-independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage-independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR-Akt-p70S6K and mTOR-Akt-GSK3β-AP-1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2-Akt-p70S6k signaling pathway.", + "authors": { + "abbreviation": "Sun-Mi Yoo, Cheol-Jung Lee, Han Chang Kang, ..., Yong-Yeon Cho", + "authorList": [ + { + "ForeName": "Sun-Mi", + "LastName": "Yoo", + "abbrevName": "Yoo SM", + "email": null, + "isCollectiveName": false, + "name": "Sun-Mi Yoo", + "orcid": null + }, + { + "ForeName": "Cheol-Jung", + "LastName": "Lee", + "abbrevName": "Lee CJ", + "email": null, + "isCollectiveName": false, + "name": "Cheol-Jung Lee", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Han Chang Kang", + "orcid": null + }, + { + "ForeName": "Hye", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Hye Suk Lee", + "orcid": null + }, + { + "ForeName": "Joo", + "LastName": "Lee", + "abbrevName": "Lee JY", + "email": null, + "isCollectiveName": false, + "name": "Joo Young Lee", + "orcid": null + }, + { + "ForeName": "Kwang", + "LastName": "Kim", + "abbrevName": "Kim KD", + "email": null, + "isCollectiveName": false, + "name": "Kwang Dong Kim", + "orcid": null + }, + { + "ForeName": "Dae", + "LastName": "Kim", + "abbrevName": "Kim DJ", + "email": null, + "isCollectiveName": false, + "name": "Dae Joon Kim", + "orcid": "0000-0002-7977-9955" + }, + { + "ForeName": "Hyun-Jung", + "LastName": "An", + "abbrevName": "An HJ", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Jung An", + "orcid": null + }, + { + "ForeName": "Yong-Yeon", + "LastName": "Cho", + "abbrevName": "Cho YY", + "email": null, + "isCollectiveName": false, + "name": "Yong-Yeon Cho", + "orcid": "0000-0003-1107-2651" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23005", + "pmid": "30887599", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells." + } + }, + { + "pmid": "23272152", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "OBJECTIVE: Tetrameric α(2)-macroglobulin (α(2)M), a plasma panproteinase inhibitor, is activated upon interaction with a proteinase, and undergoes a major conformational change exposing a receptor recognition site in each of its subunits. Activated α(2)M (α(2)M*) binds to cancer cell surface GRP78 and triggers proliferative and antiapoptotic signaling. We have studied the role of α(2)M* in the regulation of mTORC1 and TORC2 signaling in the growth of human prostate cancer cells. METHODS: Employing immunoprecipitation techniques and Western blotting as well as kinase assays, activation of the mTORC1 and mTORC2 complexes, as well as down stream targets were studied. RNAi was also employed to silence expression of Raptor, Rictor, or GRP78 in parallel studies. RESULTS: Stimulation of cells with α(2)M* promotes phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt(T308), and Akt(S473) in a concentration and time-dependent manner. Rheb, Raptor, and Rictor also increased. α(2)M* treatment of cells elevated mTORC1 kinase activity as determined by kinase assays of mTOR or Raptor immunoprecipitates. mTORC1 activity was sensitive to LY294002 and rapamycin or transfection of cells with GRP78 dsRNA. Down regulation of Raptor expression by RNAi significantly reduced α(2)M*-induced S6-Kinase phosphorylation at T389 and kinase activity in Raptor immunoprecipitates. α(2)M*-treated cells demonstrate about a twofold increase in mTORC2 kinase activity as determined by kinase assay of Akt(S473) phosphorylation and levels of p-Akt(S473) in mTOR and Rictor immunoprecipitates. mTORC2 activity was sensitive to LY294002 and transfection of cells with GRP78 dsRNA, but insensitive to rapamycin. Down regulation of Rictor expression by RNAi significantly reduces α(2)M*-induced phosphorylation of Akt(S473) phosphorylation in Rictor immunoprecipitates. CONCLUSION: Binding of α(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0051735", + "pmid": "23272152", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 7 2012", + "title": "Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells." + } + }, + { + "pmid": "29095526", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "Long noncoding RNAs (lncRNAs) or microRNAs belong to the two most important noncoding RNAs and they are involved in a lot of cancers, including non-small-cell lung cancer (NSCLC). Therefore, currently, we focused on the biological and clinical significance of lncRNA nuclear enriched abundant transcript 1 (NEAT1) and hsa-mir-98-5p in NSCLC. It was observed that NEAT1 was upregulated while hsa-mir-98-5p was downregulated respectively in NSCLC cell lines compared to human normal lung epithelial BES-2B cells. Inhibition of NEAT1 can suppress the progression of NSCLC cells and hsa-mir-98-5p can reverse this phenomenon. Bioinformatics search was used to elucidate the correlation between NEAT1 and hsa-mir-98-5p. Additionally, a novel messenger RNA target of hsa-mir-98-5p, mitogen-activated protein kinase 6 (MAPK6), was predicted. Overexpression and knockdown studies were conducted to verify whether NEAT1 exhibits its biological functions through regulating hsa-mir-98-5p and MAPK6 in vitro. NEAT1 was able to increase MAPK6 expression and hsa-mir-98-5p mimics can inhibit MAPK6 via downregulating NEAT1 levels. We speculated that NEAT1 may act as a competing endogenous lncRNA to upregulate MAPK6 by attaching hsa-mir-98-5p in lung cancers. Taken these together, NEAT1/hsa-mir-98-5p/MAPK6 is involved in the development and progress in NSCLC. NEAT1 could be recommended as a prognostic biomarker and therapeutic indicator in NSCLC diagnosis and treatment.", + "authors": { + "abbreviation": "Feima Wu, Qiang Mo, Xiaoling Wan, ..., Haibo Hu", + "authorList": [ + { + "ForeName": "Feima", + "LastName": "Wu", + "abbrevName": "Wu F", + "email": null, + "isCollectiveName": false, + "name": "Feima Wu", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Mo", + "abbrevName": "Mo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Mo", + "orcid": null + }, + { + "ForeName": "Xiaoling", + "LastName": "Wan", + "abbrevName": "Wan X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoling Wan", + "orcid": null + }, + { + "ForeName": "Jialong", + "LastName": "Dan", + "abbrevName": "Dan J", + "email": null, + "isCollectiveName": false, + "name": "Jialong Dan", + "orcid": null + }, + { + "ForeName": "Haibo", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Haibo Hu", + "orcid": "0000-0003-1851-7756" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.26442", + "pmid": "29095526", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 120 2019", + "title": "NEAT1/hsa-mir-98-5p/MAPK6 axis is involved in non-small-cell lung cancer development." + } + }, + { + "pmid": "24112608", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1381363200, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. METHODS: A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. RESULTS: ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK. CONCLUSIONS: Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.", + "authors": { + "abbreviation": "Ju Gao, Minzhi Yin, Yiping Zhu, ..., Zhigui Ma", + "authorList": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": "ma_zg@yahoo.com", + "isCollectiveName": false, + "name": "Ju Gao", + "orcid": null + }, + { + "ForeName": "Minzhi", + "LastName": "Yin", + "abbrevName": "Yin M", + "email": null, + "isCollectiveName": false, + "name": "Minzhi Yin", + "orcid": null + }, + { + "ForeName": "Yiping", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yiping Zhu", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Gu", + "abbrevName": "Gu L", + "email": null, + "isCollectiveName": false, + "name": "Ling Gu", + "orcid": null + }, + { + "ForeName": "Yanle", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanle Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Li", + "orcid": null + }, + { + "ForeName": "Cangsong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Cangsong Jia", + "orcid": null + }, + { + "ForeName": "Zhigui", + "LastName": "Ma", + "abbrevName": "Ma Z", + "email": null, + "isCollectiveName": false, + "name": "Zhigui Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "email": [ + "ma_zg@yahoo.com" + ], + "name": "Ju Gao" + } + ] + }, + "doi": "10.1186/1471-2407-13-471", + "pmid": "24112608", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cancer 13 2013", + "title": "Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma." + } + }, + { + "pmid": "22145100", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1320105600, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. SIGNIFICANCE: This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.", + "authors": { + "abbreviation": "Kazuhiro Tanaka, Ivan Babic, David Nathanson, ..., Paul S Mischel", + "authorList": [ + { + "ForeName": "Kazuhiro", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Tanaka", + "orcid": null + }, + { + "ForeName": "Ivan", + "LastName": "Babic", + "abbrevName": "Babic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Babic", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Nathanson", + "abbrevName": "Nathanson D", + "email": null, + "isCollectiveName": false, + "name": "David Nathanson", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Akhavan", + "abbrevName": "Akhavan D", + "email": null, + "isCollectiveName": false, + "name": "David Akhavan", + "orcid": null + }, + { + "ForeName": "Deliang", + "LastName": "Guo", + "abbrevName": "Guo D", + "email": null, + "isCollectiveName": false, + "name": "Deliang Guo", + "orcid": null + }, + { + "ForeName": "Beatrice", + "LastName": "Gini", + "abbrevName": "Gini B", + "email": null, + "isCollectiveName": false, + "name": "Beatrice Gini", + "orcid": null + }, + { + "ForeName": "Julie", + "LastName": "Dang", + "abbrevName": "Dang J", + "email": null, + "isCollectiveName": false, + "name": "Julie Dang", + "orcid": null + }, + { + "ForeName": "Shaojun", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Shaojun Zhu", + "orcid": null + }, + { + "ForeName": "Huijun", + "LastName": "Yang", + "abbrevName": "Yang H", + "email": null, + "isCollectiveName": false, + "name": "Huijun Yang", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "De Jesus", + "abbrevName": "De Jesus J", + "email": null, + "isCollectiveName": false, + "name": "Jason De Jesus", + "orcid": null + }, + { + "ForeName": "Ali", + "LastName": "Amzajerdi", + "abbrevName": "Amzajerdi AN", + "email": null, + "isCollectiveName": false, + "name": "Ali Nael Amzajerdi", + "orcid": null + }, + { + "ForeName": "Yinan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinan Zhang", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Dibble", + "abbrevName": "Dibble CC", + "email": null, + "isCollectiveName": false, + "name": "Christian C Dibble", + "orcid": null + }, + { + "ForeName": "Hancai", + "LastName": "Dan", + "abbrevName": "Dan H", + "email": null, + "isCollectiveName": false, + "name": "Hancai Dan", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Rinkenbaugh", + "abbrevName": "Rinkenbaugh A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Rinkenbaugh", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Yong", + "abbrevName": "Yong WH", + "email": null, + "isCollectiveName": false, + "name": "William H Yong", + "orcid": null + }, + { + "ForeName": "Harry", + "LastName": "Vinters", + "abbrevName": "Vinters HV", + "email": null, + "isCollectiveName": false, + "name": "Harry V Vinters", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Gera", + "abbrevName": "Gera JF", + "email": null, + "isCollectiveName": false, + "name": "Joseph F Gera", + "orcid": null + }, + { + "ForeName": "Webster", + "LastName": "Cavenee", + "abbrevName": "Cavenee WK", + "email": null, + "isCollectiveName": false, + "name": "Webster K Cavenee", + "orcid": null + }, + { + "ForeName": "Timothy", + "LastName": "Cloughesy", + "abbrevName": "Cloughesy TF", + "email": null, + "isCollectiveName": false, + "name": "Timothy F Cloughesy", + "orcid": null + }, + { + "ForeName": "Brendan", + "LastName": "Manning", + "abbrevName": "Manning BD", + "email": null, + "isCollectiveName": false, + "name": "Brendan D Manning", + "orcid": null + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Mischel", + "abbrevName": "Mischel PS", + "email": null, + "isCollectiveName": false, + "name": "Paul S Mischel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0124", + "pmid": "22145100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance." + } + }, + { + "pmid": "28666462", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1498780800, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear. METHODS: Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays. RESULTS: We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility. CONCLUSION: These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Michelle M Williams, Donna J Hicks, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams MM", + "email": null, + "isCollectiveName": false, + "name": "Michelle M Williams", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young CD", + "email": null, + "isCollectiveName": false, + "name": "Christian D Young", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov DD", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "Rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "Rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1186/s13058-017-0868-8", + "pmid": "28666462", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res 19 2017", + "title": "Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis." + } + }, + { + "pmid": "27197158", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1471219200, + "timezone": "+00:00" + }, + "abstract": "HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752-64. ©2016 AACR.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Donna J Hicks, Bayley Jones, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Monica", + "LastName": "Estrada", + "abbrevName": "Estrada MV", + "email": null, + "isCollectiveName": false, + "name": "Monica Valeria Estrada", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young C", + "email": null, + "isCollectiveName": false, + "name": "Christian Young", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Williams", + "orcid": null + }, + { + "ForeName": "Brent", + "LastName": "Rexer", + "abbrevName": "Rexer BN", + "email": null, + "isCollectiveName": false, + "name": "Brent N Rexer", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov dos D", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-3393", + "pmid": "27197158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers." + } + }, + { + "pmid": "22173835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1335830400, + "timezone": "+00:00" + }, + "abstract": "Ligation of cell surface-associated GRP78 by activated α(2) -macroglobulin triggers pro-proliferative cellular responses. In part, this results from activation of adenylyl cyclase leading to an increase in cAMP. We have previously employed the cAMP analog 8-CPT-2Me-cAMP to probe these responses. Here we show in 1-LN prostate cancer cells that 8-CPT-2Me-cAMP causes a dose-dependent increase in Epac1, p-Akt(T308) , p-Akt(S473) , but not p-CREB. By contrast, the PKA activator 6-Benz-cAMP caused a dose-dependent increase in p-CREB, but not Epac1. We measured mTORC2-dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells. 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt(S473) and Akt(S473) kinase activity in Rictor immunoprecipitates. By contrast, there was only a negligible effect on p-Akt(T308) in Rictor immunoprecipitates. Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of Akt at Ser(473) . These studies represent the first report that Epac1 mediates mTORC2-dependent phosphorylation of Akt(S473) . Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP-dependent p-Akt(S473) and p-Akt(S473) kinase activities, and both effects were rapamycin insensitive. This treatment caused a two to threefold increase in S6 Kinase and 4EBP1 phosphorylation, indices of mTORC1 activation. Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of S6 Kinase and 4EBP1. We further demonstrate that in 8-CPT-2Me-cAMP-treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1-induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a \"scaffold\" protein.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24018", + "pmid": "22173835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 113 2012", + "title": "Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex." + } + }, + { + "pmid": "22845486", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1349049600, + "timezone": "+00:00" + }, + "abstract": "The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.", + "authors": { + "abbreviation": "David Barrett, Valerie I Brown, Stephan A Grupp, David T Teachey", + "authorList": [ + { + "ForeName": "David", + "LastName": "Barrett", + "abbrevName": "Barrett D", + "email": null, + "isCollectiveName": false, + "name": "David Barrett", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Brown", + "abbrevName": "Brown VI", + "email": null, + "isCollectiveName": false, + "name": "Valerie I Brown", + "orcid": null + }, + { + "ForeName": "Stephan", + "LastName": "Grupp", + "abbrevName": "Grupp SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Grupp", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Teachey", + "abbrevName": "Teachey DT", + "email": null, + "isCollectiveName": false, + "name": "David T Teachey", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2165/11594740-000000000-00000", + "pmid": "22845486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Paediatr Drugs 14 2012", + "title": "Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies." + } + }, + { + "pmid": "19372546", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1238544000, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.", + "authors": { + "abbreviation": "Madlaina Breuleux, Matthieu Klopfenstein, Christine Stephan, ..., Heidi A Lane", + "authorList": [ + { + "ForeName": "Madlaina", + "LastName": "Breuleux", + "abbrevName": "Breuleux M", + "email": null, + "isCollectiveName": false, + "name": "Madlaina Breuleux", + "orcid": null + }, + { + "ForeName": "Matthieu", + "LastName": "Klopfenstein", + "abbrevName": "Klopfenstein M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Klopfenstein", + "orcid": null + }, + { + "ForeName": "Christine", + "LastName": "Stephan", + "abbrevName": "Stephan C", + "email": null, + "isCollectiveName": false, + "name": "Christine Stephan", + "orcid": null + }, + { + "ForeName": "Cheryl", + "LastName": "Doughty", + "abbrevName": "Doughty CA", + "email": null, + "isCollectiveName": false, + "name": "Cheryl A Doughty", + "orcid": null + }, + { + "ForeName": "Louise", + "LastName": "Barys", + "abbrevName": "Barys L", + "email": null, + "isCollectiveName": false, + "name": "Louise Barys", + "orcid": null + }, + { + "ForeName": "Saveur-Michel", + "LastName": "Maira", + "abbrevName": "Maira SM", + "email": null, + "isCollectiveName": false, + "name": "Saveur-Michel Maira", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Kwiatkowski", + "abbrevName": "Kwiatkowski D", + "email": null, + "isCollectiveName": false, + "name": "David Kwiatkowski", + "orcid": null + }, + { + "ForeName": "Heidi", + "LastName": "Lane", + "abbrevName": "Lane HA", + "email": null, + "isCollectiveName": false, + "name": "Heidi A Lane", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/1535-7163.MCT-08-0668", + "pmid": "19372546", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cancer Ther 8 2009", + "title": "Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition." + } + }, + { + "pmid": "29808317", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1533081600, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21/BTG2, that inhibits both growth and invasion of triple negative breast cancer cells via AKT1 activation by differential regulation of mTORc1 and mTORc2 activity. METHODS: Transduction of adenovirus carrying TIS21/BTG2 gene and transfection of short interfering RNAs were employed to regulate TIS21/BTG2 gene expression in various cell lines. Treatment of mTOR inhibitors and mTOR kinase assays can evaluate the role of mTORc in the regulation of AKT phosphorylation at S473 residue by TIS21/BTG2 in breast cancer cells. Open data and immunohistochemical analysis were performed to confirm the role of TIS21/BTG2 expression in various human breast cancer tissues. RESULTS: We observed that TIS21/BTG2 inhibited mTORc1 activity by reducing Raptor-mTOR interaction along with upregulation of tsc1 expression, which lead to significant reduction of p70S6K activation as opposed to AKT1S473, but not AKT2, phosphorylation via downregulating PHLPP2 (AKT1-specific phosphatase) in breast cancers. TIS21/BTG2-induced pAKTS473 required Rictor-bound mTOR kinase, indicating activation of mTORc2 by TIS21/BTG2 gene. Additionally, the TIS21/BTG2-induced pAKTS473 could reduce expression of NFAT1 (nuclear factor of activated T cells) and its target genes, which regulate cancer microenvironment. CONCLUSIONS: TIS21/BTG2 significantly lost in the infiltrating ductal carcinoma, but it can inhibit cancer growth via the TIS21/BTG2-tsc1/2-mTORc1-p70S6K axis and downregulate cancer progression via the TIS21/BTG2-mTORc2-AKT1-NFAT1-PHLPP2 pathway.", + "authors": { + "abbreviation": "Santhoshkumar Sundaramoorthy, Preethi Devanand, Min Sook Ryu, ..., In Kyoung Lim", + "authorList": [ + { + "ForeName": "Santhoshkumar", + "LastName": "Sundaramoorthy", + "abbrevName": "Sundaramoorthy S", + "email": null, + "isCollectiveName": false, + "name": "Santhoshkumar Sundaramoorthy", + "orcid": null + }, + { + "ForeName": "Preethi", + "LastName": "Devanand", + "abbrevName": "Devanand P", + "email": null, + "isCollectiveName": false, + "name": "Preethi Devanand", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ryu", + "abbrevName": "Ryu MS", + "email": null, + "isCollectiveName": false, + "name": "Min Sook Ryu", + "orcid": null + }, + { + "ForeName": "Kye", + "LastName": "Song", + "abbrevName": "Song KY", + "email": null, + "isCollectiveName": false, + "name": "Kye Yong Song", + "orcid": null + }, + { + "ForeName": "Dong", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong Young Noh", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Lim", + "abbrevName": "Lim IK", + "email": "iklim@ajou.ac.kr", + "isCollectiveName": false, + "name": "In Kyoung Lim", + "orcid": "0000-0002-2399-607X" + } + ], + "contacts": [ + { + "ForeName": "In", + "LastName": "Lim", + "email": [ + "iklim@ajou.ac.kr" + ], + "name": "In Kyoung Lim" + } + ] + }, + "doi": "10.1007/s00432-018-2677-6", + "pmid": "29808317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cancer Res Clin Oncol 144 2018", + "title": "TIS21/BTG2 inhibits breast cancer growth and progression by differential regulation of mTORc1 and mTORc2-AKT1-NFAT1-PHLPP2 signaling axis." + } + }, + { + "pmid": "23874880", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "AIMS: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic clinical benefits in advanced non-small cell lung cancer (NSCLC); however, resistance remains a serious problem in clinical practice. The present study analyzed mTOR-associated signaling-pathway differences between the EGFR TKI-sensitive and -resistant NSCLC cell lines and investigated the feasibility of targeting mTOR with specific mTOR inhibitor in EGFR TKI resistant NSCLC cells. METHODS: We selected four different types of EGFR TKI-sensitive and -resistant NSCLC cells: PC9, PC9GR, H1650 and H1975 cells as models to detect mTOR-associated signaling-pathway differences by western blot and Immunoprecipitation and evaluated the antiproliferative effect and cell cycle arrest of ku-0063794 by MTT method and flow cytometry. RESULTS: In the present study, we observed that mTORC2-associated Akt ser473-FOXO1 signaling pathway in a basal state was highly activated in resistant cells. In vitro mTORC1 and mTORC2 kinase activities assays showed that EGFR TKI-resistant NSCLC cell lines had higher mTORC2 kinase activity, whereas sensitive cells had higher mTORC1 kinase activity in the basal state. The ATP-competitive mTOR inhibitor ku-0063794 showed dramatic antiproliferative effects and G1-cell cycle arrest in both sensitive and resistant cells. Ku-0063794 at the IC50 concentration effectively inhibited both mTOR and p70S6K phosphorylation levels; the latter is an mTORC1 substrate and did not upregulate Akt ser473 phosphorylation which would be induced by rapamycin and resulted in partial inhibition of FOXO1 phosphorylation. We also observed that EGFR TKI-sensitive and -resistant clinical NSCLC tumor specimens had higher total and phosphorylated p70S6K expression levels. CONCLUSION: Our results indicate mTORC2-associated signaling-pathway was hyperactivated in EGFR TKI-resistant cells and targeting mTOR with specific mTOR inhibitors is likely a good strategy for patients with EGFR mutant NSCLC who develop EGFR TKI resistance; the potential specific roles of mTORC2 in EGFR TKI-resistant NSCLC cells were still unknown and should be further investigated.", + "authors": { + "abbreviation": "Shi-Jiang Fei, Xu-Chao Zhang, Song Dong, ..., Yi-Long Wu", + "authorList": [ + { + "ForeName": "Shi-Jiang", + "LastName": "Fei", + "abbrevName": "Fei SJ", + "email": null, + "isCollectiveName": false, + "name": "Shi-Jiang Fei", + "orcid": null + }, + { + "ForeName": "Xu-Chao", + "LastName": "Zhang", + "abbrevName": "Zhang XC", + "email": null, + "isCollectiveName": false, + "name": "Xu-Chao Zhang", + "orcid": null + }, + { + "ForeName": "Song", + "LastName": "Dong", + "abbrevName": "Dong S", + "email": null, + "isCollectiveName": false, + "name": "Song Dong", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Cheng", + "abbrevName": "Cheng H", + "email": null, + "isCollectiveName": false, + "name": "Hua Cheng", + "orcid": null + }, + { + "ForeName": "Yi-Fang", + "LastName": "Zhang", + "abbrevName": "Zhang YF", + "email": null, + "isCollectiveName": false, + "name": "Yi-Fang Zhang", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Huang", + "abbrevName": "Huang L", + "email": null, + "isCollectiveName": false, + "name": "Ling Huang", + "orcid": null + }, + { + "ForeName": "Hai-Yu", + "LastName": "Zhou", + "abbrevName": "Zhou HY", + "email": null, + "isCollectiveName": false, + "name": "Hai-Yu Zhou", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Xie", + "abbrevName": "Xie Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Xie", + "orcid": null + }, + { + "ForeName": "Zhi-Hong", + "LastName": "Chen", + "abbrevName": "Chen ZH", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Hong Chen", + "orcid": null + }, + { + "ForeName": "Yi-Long", + "LastName": "Wu", + "abbrevName": "Wu YL", + "email": null, + "isCollectiveName": false, + "name": "Yi-Long Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0069104", + "pmid": "23874880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells." + } + }, + { + "pmid": "22140653", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1312156800, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. SIGNIFICANCE: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.", + "authors": { + "abbreviation": "Vanessa S Rodrik-Outmezguine, Sarat Chandarlapaty, Nen C Pagano, ..., Neal Rosen", + "authorList": [ + { + "ForeName": "Vanessa", + "LastName": "Rodrik-Outmezguine", + "abbrevName": "Rodrik-Outmezguine VS", + "email": null, + "isCollectiveName": false, + "name": "Vanessa S Rodrik-Outmezguine", + "orcid": null + }, + { + "ForeName": "Sarat", + "LastName": "Chandarlapaty", + "abbrevName": "Chandarlapaty S", + "email": null, + "isCollectiveName": false, + "name": "Sarat Chandarlapaty", + "orcid": null + }, + { + "ForeName": "Nen", + "LastName": "Pagano", + "abbrevName": "Pagano NC", + "email": null, + "isCollectiveName": false, + "name": "Nen C Pagano", + "orcid": null + }, + { + "ForeName": "Poulikos", + "LastName": "Poulikakos", + "abbrevName": "Poulikakos PI", + "email": null, + "isCollectiveName": false, + "name": "Poulikos I Poulikakos", + "orcid": null + }, + { + "ForeName": "Maurizio", + "LastName": "Scaltriti", + "abbrevName": "Scaltriti M", + "email": null, + "isCollectiveName": false, + "name": "Maurizio Scaltriti", + "orcid": null + }, + { + "ForeName": "Elizabeth", + "LastName": "Moskatel", + "abbrevName": "Moskatel E", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth Moskatel", + "orcid": null + }, + { + "ForeName": "José", + "LastName": "Baselga", + "abbrevName": "Baselga J", + "email": null, + "isCollectiveName": false, + "name": "José Baselga", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Guichard", + "abbrevName": "Guichard S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Guichard", + "orcid": null + }, + { + "ForeName": "Neal", + "LastName": "Rosen", + "abbrevName": "Rosen N", + "email": null, + "isCollectiveName": false, + "name": "Neal Rosen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0085", + "pmid": "22140653", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling." + } + }, + { + "pmid": "24562770", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1396310400, + "timezone": "+00:00" + }, + "abstract": "Resistance of breast cancers to targeted hormone receptor (HR) or human epidermal growth factor receptor 2 (HER2) inhibitors often occurs through dysregulation of the phosphoinositide 3-kinase, protein kinase B/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Presently, no targeted therapies exist for breast cancers lacking HR and HER2 overexpression, many of which also exhibit PI3K/AKT/mTOR hyper-activation. Resistance of breast cancers to current therapeutics also results, in part, from aberrant epigenetic modifications including protein acetylation regulated by histone deacetylases (HDACs). We show that the investigational drug MLN0128, which inhibits both complexes of mTOR (mTORC1 and mTORC2), and the hydroxamic acid pan-HDAC inhibitor TSA synergistically inhibit the viability of a phenotypically diverse panel of five breast cancer cell lines (HR-/+, HER2-/+). The combination of MLN0128 and TSA induces apoptosis in most breast cancer cell lines tested, but not in the non-malignant MCF-10A mammary epithelial cells. In parallel, the MLN0128/TSA combination reduces phosphorylation of AKT at S473 more than single agents alone and more so in the 5 malignant breast cancer cell lines than in the non-malignant mammary epithelial cells. Examining polysome profiles from one of the most sensitive breast cancer cell lines (SKBR3), we demonstrate that this MLN0128/TSA treatment combination synergistically impairs polysome assembly in conjunction with enhanced inhibition of 4eBP1 phosphorylation at S65. Taken together, these data indicate that the synergistic growth inhibiting consequence of combining a mTORC1/C2 inhibitor like MLN0128 with a pan-HDAC inhibitor like TSA results from their mechanistic convergence onto the PI3K/AKT/mTOR pathway, profoundly inhibiting both AKT S473 and 4eBP1 S65 phosphorylation, reducing polysome formation and cancer cell viability.", + "authors": { + "abbreviation": "Kathleen A Wilson-Edell, Mariya A Yevtushenko, Daniel E Rothschild, ..., Christopher C Benz", + "authorList": [ + { + "ForeName": "Kathleen", + "LastName": "Wilson-Edell", + "abbrevName": "Wilson-Edell KA", + "email": null, + "isCollectiveName": false, + "name": "Kathleen A Wilson-Edell", + "orcid": null + }, + { + "ForeName": "Mariya", + "LastName": "Yevtushenko", + "abbrevName": "Yevtushenko MA", + "email": null, + "isCollectiveName": false, + "name": "Mariya A Yevtushenko", + "orcid": null + }, + { + "ForeName": "Daniel", + "LastName": "Rothschild", + "abbrevName": "Rothschild DE", + "email": null, + "isCollectiveName": false, + "name": "Daniel E Rothschild", + "orcid": null + }, + { + "ForeName": "Aric", + "LastName": "Rogers", + "abbrevName": "Rogers AN", + "email": null, + "isCollectiveName": false, + "name": "Aric N Rogers", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Benz", + "abbrevName": "Benz CC", + "email": "cbenz@buckinstitute.org", + "isCollectiveName": false, + "name": "Christopher C Benz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Christopher", + "LastName": "Benz", + "email": [ + "cbenz@buckinstitute.org" + ], + "name": "Christopher C Benz" + } + ] + }, + "doi": "10.1007/s10549-014-2877-y", + "pmid": "24562770", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 144 2014", + "title": "mTORC1/C2 and pan-HDAC inhibitors synergistically impair breast cancer growth by convergent AKT and polysome inhibiting mechanisms." + } + }, + { + "pmid": "32899862", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1599177600, + "timezone": "+00:00" + }, + "abstract": "Recently, we have reported that blockade/deletion of P2X7 receptor (P2X7R), an ATP-gated ion channel, exacerbates heat shock protein 25 (HSP25)-mediated astroglial autophagy (clasmatodendrosis) following kainic acid (KA) injection. In P2X7R knockout (KO) mice, prolonged astroglial HSP25 induction exerts 5' adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1-mediated autophagic pathway independent of mammalian target of rapamycin (mTOR) activity following KA injection. Sustained HSP25 expression also enhances AKT-serine (S) 473 phosphorylation leading to astroglial autophagy via glycogen synthase kinase-3β/bax interacting factor 1 signaling pathway. However, it is unanswered how P2X7R deletion induces AKT-S473 hyperphosphorylation during autophagic process in astrocytes. In the present study, we found that AKT-S473 phosphorylation was increased by enhancing activity of focal adhesion kinase (FAK), independent of mTOR complex (mTORC) 1 and 2 activities in isolated astrocytes of P2X7R knockout (KO) mice following KA injection. In addition, HSP25 overexpression in P2X7R KO mice acted as a chaperone of AKT, which retained AKT-S473 phosphorylation by inhibiting the pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1- and 2-binding to AKT. Therefore, our findings suggest that P2X7R may be a fine-tuner of AKT-S473 activity during astroglial autophagy by regulating FAK phosphorylation and HSP25-mediated inhibition of PHLPP1/2-AKT binding following KA treatment.", + "authors": { + "abbreviation": "Duk-Shin Lee, Ji-Eun Kim", + "authorList": [ + { + "ForeName": "Duk-Shin", + "LastName": "Lee", + "abbrevName": "Lee DS", + "email": null, + "isCollectiveName": false, + "name": "Duk-Shin Lee", + "orcid": null + }, + { + "ForeName": "Ji-Eun", + "LastName": "Kim", + "abbrevName": "Kim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Kim", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21186476", + "pmid": "32899862", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures." + } + }, + { + "pmid": "30642949", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1552608000, + "timezone": "+00:00" + }, + "abstract": "The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6lacZ ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6KD ) or conditional (Mapk6Δ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6lacZ mice but not in Mapk6KD or Mapk6Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6lacZ mutant mice.", + "authors": { + "abbreviation": "Mathilde Soulez, Marc K Saba-El-Leil, Benjamin Turgeon, ..., Sylvain Meloche", + "authorList": [ + { + "ForeName": "Mathilde", + "LastName": "Soulez", + "abbrevName": "Soulez M", + "email": null, + "isCollectiveName": false, + "name": "Mathilde Soulez", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Saba-El-Leil", + "abbrevName": "Saba-El-Leil MK", + "email": null, + "isCollectiveName": false, + "name": "Marc K Saba-El-Leil", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Turgeon", + "abbrevName": "Turgeon B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Turgeon", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Mathien", + "abbrevName": "Mathien S", + "email": null, + "isCollectiveName": false, + "name": "Simon Mathien", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Coulombe", + "orcid": null + }, + { + "ForeName": "Sonia", + "LastName": "Klinger", + "abbrevName": "Klinger S", + "email": null, + "isCollectiveName": false, + "name": "Sonia Klinger", + "orcid": null + }, + { + "ForeName": "Justine", + "LastName": "Rousseau", + "abbrevName": "Rousseau J", + "email": null, + "isCollectiveName": false, + "name": "Justine Rousseau", + "orcid": null + }, + { + "ForeName": "Kim", + "LastName": "Lévesque", + "abbrevName": "Lévesque K", + "email": null, + "isCollectiveName": false, + "name": "Kim Lévesque", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": "sylvain.meloche@umontreal.ca", + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "email": [ + "sylvain.meloche@umontreal.ca" + ], + "name": "Sylvain Meloche" + } + ] + }, + "doi": "10.1128/MCB.00527-18", + "pmid": "30642949", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Biol 39 2019", + "title": "Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models." + } + }, + { + "pmid": "12181443", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1030838400, + "timezone": "+00:00" + }, + "abstract": "The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.", + "authors": { + "abbreviation": "Linnea M Baudhuin, Kelly L Cristina, Jun Lu, Yan Xu", + "authorList": [ + { + "ForeName": "Linnea", + "LastName": "Baudhuin", + "abbrevName": "Baudhuin LM", + "email": null, + "isCollectiveName": false, + "name": "Linnea M Baudhuin", + "orcid": null + }, + { + "ForeName": "Kelly", + "LastName": "Cristina", + "abbrevName": "Cristina KL", + "email": null, + "isCollectiveName": false, + "name": "Kelly L Cristina", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lu", + "abbrevName": "Lu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lu", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Xu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1124/mol.62.3.660", + "pmid": "12181443", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Pharmacol 62 2002", + "title": "Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific." + } + }, + { + "pmid": "23802099", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review \"PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle\" we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty.", + "authors": { + "abbreviation": "Lakshmipathi Vadlakonda, Abhinandita Dash, Mukesh Pasupuleti, ..., Pallu Reddanna", + "authorList": [ + { + "ForeName": "Lakshmipathi", + "LastName": "Vadlakonda", + "abbrevName": "Vadlakonda L", + "email": null, + "isCollectiveName": false, + "name": "Lakshmipathi Vadlakonda", + "orcid": null + }, + { + "ForeName": "Abhinandita", + "LastName": "Dash", + "abbrevName": "Dash A", + "email": null, + "isCollectiveName": false, + "name": "Abhinandita Dash", + "orcid": null + }, + { + "ForeName": "Mukesh", + "LastName": "Pasupuleti", + "abbrevName": "Pasupuleti M", + "email": null, + "isCollectiveName": false, + "name": "Mukesh Pasupuleti", + "orcid": null + }, + { + "ForeName": "Kotha", + "LastName": "Anil Kumar", + "abbrevName": "Anil Kumar K", + "email": null, + "isCollectiveName": false, + "name": "Kotha Anil Kumar", + "orcid": null + }, + { + "ForeName": "Pallu", + "LastName": "Reddanna", + "abbrevName": "Reddanna P", + "email": null, + "isCollectiveName": false, + "name": "Pallu Reddanna", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3389/fonc.2013.00165", + "pmid": "23802099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Front Oncol 3 2013", + "title": "The Paradox of Akt-mTOR Interactions." + } + }, + { + "pmid": "33495824", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1614556800, + "timezone": "+00:00" + }, + "abstract": "Breast cancer is the worldwide leading cause of cancer‑related deaths among women. Increasing evidence has demonstrated that microRNAs (miRNAs) play critical roles in the carcinogenesis and progression of breast cancer. miR‑653‑5p was previously reported to be involved in cell proliferation and apoptosis. However, the role of miR‑653‑5p in the progression of breast cancer has not been studied. In the present study, it was found that overexpression of miR‑653‑5p significantly inhibited the proliferation, migration and invasion of breast cancer cells in vitro. Moreover, overexpression of miR‑653‑5p promoted cell apoptosis in breast cancer by regulating the Bcl‑2/Bax axis and caspase‑9 activation. Additionally, the epithelial‑mesenchymal transition and activation of the Akt/mammalian target of rapamycin signaling pathway were also inhibited by miR‑653‑5p. Furthermore, the data demonstrated that miR‑653‑5p directly targeted mitogen‑activated protein kinase 6 (MAPK6) and negatively regulated its expression in breast cancer cells. Upregulation of MAPK6 could overcome the inhibitory effects of miR‑653‑5p on cell proliferation and migration in breast cancer. In conclusion, this study suggested that miR‑653‑5p functions as a tumor suppressor by targeting MAPK6 in the progression of breast cancer, and it may be a potential target for breast cancer therapy.", + "authors": { + "abbreviation": "Mei Zhang, Hongwei Wang, Xiaomei Zhang, Fengping Liu", + "authorList": [ + { + "ForeName": "Mei", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Zhang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Wang", + "orcid": null + }, + { + "ForeName": "Xiaomei", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaomei Zhang", + "orcid": null + }, + { + "ForeName": "Fengping", + "LastName": "Liu", + "abbrevName": "Liu F", + "email": null, + "isCollectiveName": false, + "name": "Fengping Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3892/mmr.2021.11839", + "pmid": "33495824", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Med Rep 23 2021", + "title": "miR‑653‑5p suppresses the growth and migration of breast cancer cells by targeting MAPK6." + } + } + ], + "secret": "998d53dc-8150-40b9-b59f-b5b54439e22d", + "type": "protein" + }, + { + "_creationTimestamp": { + "$reql_type$": "TIME", + "epoch_time": 1671115308.621, + "timezone": "+00:00" + }, + "_newestOpId": "2583a864-bd59-4698-8ada-e0476f1e9cee", + "_ops": [], + "association": "phosphorylation", + "completed": true, + "description": "", + "entries": [ + { + "group": null, + "id": "598f8bef-f858-4dd0-b1c6-5168a8ae5349" + }, + { + "group": "positive", + "id": "4081348e-20b8-4bf8-836f-695827a4f9a2" + } + ], + "id": "01ef22cc-2a8e-46d4-9060-6bf1c273869b", + "liveId": "e24724d0-e502-4382-bfdf-3f6c4cfed96e", + "lock": null, + "locked": false, + "name": "", + "novel": true, + "position": { + "x": -691.2664263804326, + "y": -368.2212088426656 + }, + "relatedPapers": [ + { + "pmid": "22173835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1335830400, + "timezone": "+00:00" + }, + "abstract": "Ligation of cell surface-associated GRP78 by activated α(2) -macroglobulin triggers pro-proliferative cellular responses. In part, this results from activation of adenylyl cyclase leading to an increase in cAMP. We have previously employed the cAMP analog 8-CPT-2Me-cAMP to probe these responses. Here we show in 1-LN prostate cancer cells that 8-CPT-2Me-cAMP causes a dose-dependent increase in Epac1, p-Akt(T308) , p-Akt(S473) , but not p-CREB. By contrast, the PKA activator 6-Benz-cAMP caused a dose-dependent increase in p-CREB, but not Epac1. We measured mTORC2-dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells. 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt(S473) and Akt(S473) kinase activity in Rictor immunoprecipitates. By contrast, there was only a negligible effect on p-Akt(T308) in Rictor immunoprecipitates. Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of Akt at Ser(473) . These studies represent the first report that Epac1 mediates mTORC2-dependent phosphorylation of Akt(S473) . Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP-dependent p-Akt(S473) and p-Akt(S473) kinase activities, and both effects were rapamycin insensitive. This treatment caused a two to threefold increase in S6 Kinase and 4EBP1 phosphorylation, indices of mTORC1 activation. Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of S6 Kinase and 4EBP1. We further demonstrate that in 8-CPT-2Me-cAMP-treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1-induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a \"scaffold\" protein.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.24018", + "pmid": "22173835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 113 2012", + "title": "Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex." + } + }, + { + "pmid": "30688659", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.", + "authors": { + "abbreviation": "Wei Wang, Tao Shen, Bingning Dong, ..., Feng Yang", + "authorList": [ + { + "ForeName": "Wei", + "LastName": "Wang", + "abbrevName": "Wang W", + "email": null, + "isCollectiveName": false, + "name": "Wei Wang", + "orcid": null + }, + { + "ForeName": "Tao", + "LastName": "Shen", + "abbrevName": "Shen T", + "email": null, + "isCollectiveName": false, + "name": "Tao Shen", + "orcid": null + }, + { + "ForeName": "Bingning", + "LastName": "Dong", + "abbrevName": "Dong B", + "email": null, + "isCollectiveName": false, + "name": "Bingning Dong", + "orcid": null + }, + { + "ForeName": "Chad", + "LastName": "Creighton", + "abbrevName": "Creighton CJ", + "email": null, + "isCollectiveName": false, + "name": "Chad J Creighton", + "orcid": null + }, + { + "ForeName": "Yanling", + "LastName": "Meng", + "abbrevName": "Meng Y", + "email": null, + "isCollectiveName": false, + "name": "Yanling Meng", + "orcid": null + }, + { + "ForeName": "Wolong", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wolong Zhou", + "orcid": null + }, + { + "ForeName": "Qing", + "LastName": "Shi", + "abbrevName": "Shi Q", + "email": null, + "isCollectiveName": false, + "name": "Qing Shi", + "orcid": null + }, + { + "ForeName": "Hao", + "LastName": "Zhou", + "abbrevName": "Zhou H", + "email": null, + "isCollectiveName": false, + "name": "Hao Zhou", + "orcid": null + }, + { + "ForeName": "Yinjie", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinjie Zhang", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Moore", + "abbrevName": "Moore DD", + "email": null, + "isCollectiveName": false, + "name": "David D Moore", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Yang", + "abbrevName": "Yang F", + "email": null, + "isCollectiveName": false, + "name": "Feng Yang", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1172/JCI97712", + "pmid": "30688659", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + } + ], + "reference": "J Clin Invest 129 2019", + "title": "MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling." + } + }, + { + "pmid": "24374738", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1401580800, + "timezone": "+00:00" + }, + "abstract": "To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.", + "authors": { + "abbreviation": "Victor Jeannot, Benoît Busser, Elisabeth Brambilla, ..., Amandine Hurbin", + "authorList": [ + { + "ForeName": "Victor", + "LastName": "Jeannot", + "abbrevName": "Jeannot V", + "email": null, + "isCollectiveName": false, + "name": "Victor Jeannot", + "orcid": null + }, + { + "ForeName": "Benoît", + "LastName": "Busser", + "abbrevName": "Busser B", + "email": null, + "isCollectiveName": false, + "name": "Benoît Busser", + "orcid": null + }, + { + "ForeName": "Elisabeth", + "LastName": "Brambilla", + "abbrevName": "Brambilla E", + "email": null, + "isCollectiveName": false, + "name": "Elisabeth Brambilla", + "orcid": null + }, + { + "ForeName": "Marie", + "LastName": "Wislez", + "abbrevName": "Wislez M", + "email": null, + "isCollectiveName": false, + "name": "Marie Wislez", + "orcid": null + }, + { + "ForeName": "Blaise", + "LastName": "Robin", + "abbrevName": "Robin B", + "email": null, + "isCollectiveName": false, + "name": "Blaise Robin", + "orcid": null + }, + { + "ForeName": "Jacques", + "LastName": "Cadranel", + "abbrevName": "Cadranel J", + "email": null, + "isCollectiveName": false, + "name": "Jacques Cadranel", + "orcid": null + }, + { + "ForeName": "Jean-Luc", + "LastName": "Coll", + "abbrevName": "Coll JL", + "email": null, + "isCollectiveName": false, + "name": "Jean-Luc Coll", + "orcid": null + }, + { + "ForeName": "Amandine", + "LastName": "Hurbin", + "abbrevName": "Hurbin A", + "email": null, + "isCollectiveName": false, + "name": "Amandine Hurbin", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1002/ijc.28594", + "pmid": "24374738", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Int J Cancer 134 2014", + "title": "The PI3K/AKT pathway promotes gefitinib resistance in mutant KRAS lung adenocarcinoma by a deacetylase-dependent mechanism." + } + }, + { + "pmid": "28666462", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1498780800, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: The importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear. METHODS: Because Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays. RESULTS: We found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility. CONCLUSION: These findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Michelle M Williams, Donna J Hicks, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams MM", + "email": null, + "isCollectiveName": false, + "name": "Michelle M Williams", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young CD", + "email": null, + "isCollectiveName": false, + "name": "Christian D Young", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov DD", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "Rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "Rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1186/s13058-017-0868-8", + "pmid": "28666462", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Breast Cancer Res 19 2017", + "title": "Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis." + } + }, + { + "pmid": "12181443", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1030838400, + "timezone": "+00:00" + }, + "abstract": "The signaling pathways that lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) use to activate Akt in ovarian cancer cells are investigated here. We show for the first time, with the use of both pharmacological and genetic inhibitors, that the kinase activity and S473 phosphorylation of Akt induced by LPA and S1P requires both mitogen-activated protein (MAP) kinase kinase (MEK) and p38 MAP kinase, and MEK is likely to be upstream of p38, in HEY ovarian cancer cells. The requirement for both MEK and p38 is cell type- and stimulus-specific. Among 12 cell lines that we tested, 11 respond to LPA and S1P and all of the responsive cell lines require p38 but only nine of them require MEK. Among different stimuli tested, platelet-derived growth factor stimulates S473 phosphorylation of Akt in a MEK- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1-stimulated Akt S473 phosphorylation require p38 but not MEK. Insulin, on the other hand, stimulates Akt S473 phosphorylation independent of both MEK and p38 in HEY cells. T308 phosphorylation stimulated by LPA/S1P requires MEK but not p38 activation. MEK and p38 activation were sufficient for Akt S473 but not T308 phosphorylation in HEY cells. In contrast to S1P and PDGF, LPA requires Rho for Akt S473 phosphorylation, and Rho is upstream of phosphatidylinositol 3-kinase (PI3-K). LPA/S1P-induced Akt activation may be involved in cell survival, because LPA and S1P treatment in HEY ovarian cancer cells results in a decrease in paclitaxel-induced caspase-3 activity in a PI3-K/MEK/p38-dependent manner.", + "authors": { + "abbreviation": "Linnea M Baudhuin, Kelly L Cristina, Jun Lu, Yan Xu", + "authorList": [ + { + "ForeName": "Linnea", + "LastName": "Baudhuin", + "abbrevName": "Baudhuin LM", + "email": null, + "isCollectiveName": false, + "name": "Linnea M Baudhuin", + "orcid": null + }, + { + "ForeName": "Kelly", + "LastName": "Cristina", + "abbrevName": "Cristina KL", + "email": null, + "isCollectiveName": false, + "name": "Kelly L Cristina", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lu", + "abbrevName": "Lu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lu", + "orcid": null + }, + { + "ForeName": "Yan", + "LastName": "Xu", + "abbrevName": "Xu Y", + "email": null, + "isCollectiveName": false, + "name": "Yan Xu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1124/mol.62.3.660", + "pmid": "12181443", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D013486", + "value": "Research Support, U.S. Gov't, Non-P.H.S." + }, + { + "UI": "D013487", + "value": "Research Support, U.S. Gov't, P.H.S." + } + ], + "reference": "Mol Pharmacol 62 2002", + "title": "Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific." + } + }, + { + "pmid": "29095526", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1551398400, + "timezone": "+00:00" + }, + "abstract": "Long noncoding RNAs (lncRNAs) or microRNAs belong to the two most important noncoding RNAs and they are involved in a lot of cancers, including non-small-cell lung cancer (NSCLC). Therefore, currently, we focused on the biological and clinical significance of lncRNA nuclear enriched abundant transcript 1 (NEAT1) and hsa-mir-98-5p in NSCLC. It was observed that NEAT1 was upregulated while hsa-mir-98-5p was downregulated respectively in NSCLC cell lines compared to human normal lung epithelial BES-2B cells. Inhibition of NEAT1 can suppress the progression of NSCLC cells and hsa-mir-98-5p can reverse this phenomenon. Bioinformatics search was used to elucidate the correlation between NEAT1 and hsa-mir-98-5p. Additionally, a novel messenger RNA target of hsa-mir-98-5p, mitogen-activated protein kinase 6 (MAPK6), was predicted. Overexpression and knockdown studies were conducted to verify whether NEAT1 exhibits its biological functions through regulating hsa-mir-98-5p and MAPK6 in vitro. NEAT1 was able to increase MAPK6 expression and hsa-mir-98-5p mimics can inhibit MAPK6 via downregulating NEAT1 levels. We speculated that NEAT1 may act as a competing endogenous lncRNA to upregulate MAPK6 by attaching hsa-mir-98-5p in lung cancers. Taken these together, NEAT1/hsa-mir-98-5p/MAPK6 is involved in the development and progress in NSCLC. NEAT1 could be recommended as a prognostic biomarker and therapeutic indicator in NSCLC diagnosis and treatment.", + "authors": { + "abbreviation": "Feima Wu, Qiang Mo, Xiaoling Wan, ..., Haibo Hu", + "authorList": [ + { + "ForeName": "Feima", + "LastName": "Wu", + "abbrevName": "Wu F", + "email": null, + "isCollectiveName": false, + "name": "Feima Wu", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Mo", + "abbrevName": "Mo Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Mo", + "orcid": null + }, + { + "ForeName": "Xiaoling", + "LastName": "Wan", + "abbrevName": "Wan X", + "email": null, + "isCollectiveName": false, + "name": "Xiaoling Wan", + "orcid": null + }, + { + "ForeName": "Jialong", + "LastName": "Dan", + "abbrevName": "Dan J", + "email": null, + "isCollectiveName": false, + "name": "Jialong Dan", + "orcid": null + }, + { + "ForeName": "Haibo", + "LastName": "Hu", + "abbrevName": "Hu H", + "email": null, + "isCollectiveName": false, + "name": "Haibo Hu", + "orcid": "0000-0003-1851-7756" + } + ], + "contacts": [] + }, + "doi": "10.1002/jcb.26442", + "pmid": "29095526", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cell Biochem 120 2019", + "title": "NEAT1/hsa-mir-98-5p/MAPK6 axis is involved in non-small-cell lung cancer development." + } + }, + { + "pmid": "30542835", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1569888000, + "timezone": "+00:00" + }, + "abstract": "Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt's two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1 with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.", + "authors": { + "abbreviation": "Blair P Curless, Nne E Uko, Diane F Matesic", + "authorList": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "abbrevName": "Curless BP", + "email": "Blair.curless@live.mercer.edu", + "isCollectiveName": false, + "name": "Blair P Curless", + "orcid": "0000-0003-3158-745X" + }, + { + "ForeName": "Nne", + "LastName": "Uko", + "abbrevName": "Uko NE", + "email": null, + "isCollectiveName": false, + "name": "Nne E Uko", + "orcid": null + }, + { + "ForeName": "Diane", + "LastName": "Matesic", + "abbrevName": "Matesic DF", + "email": null, + "isCollectiveName": false, + "name": "Diane F Matesic", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Blair", + "LastName": "Curless", + "email": [ + "Blair.curless@live.mercer.edu" + ], + "name": "Blair P Curless" + } + ] + }, + "doi": "10.1007/s10637-018-0705-7", + "pmid": "30542835", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Invest New Drugs 37 2019", + "title": "Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells." + } + }, + { + "pmid": "22845486", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1349049600, + "timezone": "+00:00" + }, + "abstract": "The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.", + "authors": { + "abbreviation": "David Barrett, Valerie I Brown, Stephan A Grupp, David T Teachey", + "authorList": [ + { + "ForeName": "David", + "LastName": "Barrett", + "abbrevName": "Barrett D", + "email": null, + "isCollectiveName": false, + "name": "David Barrett", + "orcid": null + }, + { + "ForeName": "Valerie", + "LastName": "Brown", + "abbrevName": "Brown VI", + "email": null, + "isCollectiveName": false, + "name": "Valerie I Brown", + "orcid": null + }, + { + "ForeName": "Stephan", + "LastName": "Grupp", + "abbrevName": "Grupp SA", + "email": null, + "isCollectiveName": false, + "name": "Stephan A Grupp", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Teachey", + "abbrevName": "Teachey DT", + "email": null, + "isCollectiveName": false, + "name": "David T Teachey", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2165/11594740-000000000-00000", + "pmid": "22845486", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Paediatr Drugs 14 2012", + "title": "Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies." + } + }, + { + "pmid": "30642949", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1552608000, + "timezone": "+00:00" + }, + "abstract": "The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6lacZ ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6KD ) or conditional (Mapk6Δ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6lacZ mice but not in Mapk6KD or Mapk6Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6lacZ mutant mice.", + "authors": { + "abbreviation": "Mathilde Soulez, Marc K Saba-El-Leil, Benjamin Turgeon, ..., Sylvain Meloche", + "authorList": [ + { + "ForeName": "Mathilde", + "LastName": "Soulez", + "abbrevName": "Soulez M", + "email": null, + "isCollectiveName": false, + "name": "Mathilde Soulez", + "orcid": null + }, + { + "ForeName": "Marc", + "LastName": "Saba-El-Leil", + "abbrevName": "Saba-El-Leil MK", + "email": null, + "isCollectiveName": false, + "name": "Marc K Saba-El-Leil", + "orcid": null + }, + { + "ForeName": "Benjamin", + "LastName": "Turgeon", + "abbrevName": "Turgeon B", + "email": null, + "isCollectiveName": false, + "name": "Benjamin Turgeon", + "orcid": null + }, + { + "ForeName": "Simon", + "LastName": "Mathien", + "abbrevName": "Mathien S", + "email": null, + "isCollectiveName": false, + "name": "Simon Mathien", + "orcid": null + }, + { + "ForeName": "Philippe", + "LastName": "Coulombe", + "abbrevName": "Coulombe P", + "email": null, + "isCollectiveName": false, + "name": "Philippe Coulombe", + "orcid": null + }, + { + "ForeName": "Sonia", + "LastName": "Klinger", + "abbrevName": "Klinger S", + "email": null, + "isCollectiveName": false, + "name": "Sonia Klinger", + "orcid": null + }, + { + "ForeName": "Justine", + "LastName": "Rousseau", + "abbrevName": "Rousseau J", + "email": null, + "isCollectiveName": false, + "name": "Justine Rousseau", + "orcid": null + }, + { + "ForeName": "Kim", + "LastName": "Lévesque", + "abbrevName": "Lévesque K", + "email": null, + "isCollectiveName": false, + "name": "Kim Lévesque", + "orcid": null + }, + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "abbrevName": "Meloche S", + "email": "sylvain.meloche@umontreal.ca", + "isCollectiveName": false, + "name": "Sylvain Meloche", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Sylvain", + "LastName": "Meloche", + "email": [ + "sylvain.meloche@umontreal.ca" + ], + "name": "Sylvain Meloche" + } + ] + }, + "doi": "10.1128/MCB.00527-18", + "pmid": "30642949", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Cell Biol 39 2019", + "title": "Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models." + } + }, + { + "pmid": "23991179", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin complex 1 and 2 (mTORC1/2) are overactive in colorectal carcinomas; however, the first generation of mTOR inhibitors such as rapamycin have failed to show clinical benefits in treating colorectal carcinoma in part due to their effects only on mTORC1. The second generation of mTOR inhibitors such as PP242 targets mTOR kinase; thus, they are capable of inhibiting both mTORC1 and mTORC2. To examine the therapeutic potential of the mTOR kinase inhibitors, we treated a panel of colorectal carcinoma cell lines with PP242. Western blotting showed that the PP242 inhibition of mTORC2-mediated AKT phosphorylation at Ser 473 (AKT(S473)) was transient only in the first few hours of the PP242 treatment. Receptor tyrosine kinase arrays further revealed that PP242 treatment increased the phosphorylated epidermal growth factor receptor (EGFR) at Tyr 1068 (EGFR(T1068)). The parallel increase of AKT(S473) and EGFR(T1068) in the cells following PP242 treatment raised the possibility that EGFR phosphorylation might contribute to the PP242 incomplete inhibition of mTORC2. To test this notion, we showed that the combination of PP242 with erlotinib, an EGFR small molecule inhibitor, blocked both mTORC1 and mTORC2 kinase activity. In addition, we showed that the combination treatment inhibited colony formation, blocked cell growth and induced apoptotic cell death. A systemic administration of PP242 and erlotinib resulted in the progression suppression of colorectal carcinoma xenografts in mice. This study suggests that the combination of mTOR kinase and EGFR inhibitors may provide an effective treatment of colorectal carcinoma.", + "authors": { + "abbreviation": "Quan Wang, Feng Wei, Chunsheng Li, ..., Chunhai Hao", + "authorList": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "abbrevName": "Wang Q", + "email": "wangquan-jlcc@hotmail.com", + "isCollectiveName": false, + "name": "Quan Wang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Wei", + "abbrevName": "Wei F", + "email": null, + "isCollectiveName": false, + "name": "Feng Wei", + "orcid": null + }, + { + "ForeName": "Chunsheng", + "LastName": "Li", + "abbrevName": "Li C", + "email": null, + "isCollectiveName": false, + "name": "Chunsheng Li", + "orcid": null + }, + { + "ForeName": "Guoyue", + "LastName": "Lv", + "abbrevName": "Lv G", + "email": null, + "isCollectiveName": false, + "name": "Guoyue Lv", + "orcid": null + }, + { + "ForeName": "Guangyi", + "LastName": "Wang", + "abbrevName": "Wang G", + "email": null, + "isCollectiveName": false, + "name": "Guangyi Wang", + "orcid": null + }, + { + "ForeName": "Tongjun", + "LastName": "Liu", + "abbrevName": "Liu T", + "email": null, + "isCollectiveName": false, + "name": "Tongjun Liu", + "orcid": null + }, + { + "ForeName": "Anita", + "LastName": "Bellail", + "abbrevName": "Bellail AC", + "email": null, + "isCollectiveName": false, + "name": "Anita C Bellail", + "orcid": null + }, + { + "ForeName": "Chunhai", + "LastName": "Hao", + "abbrevName": "Hao C", + "email": null, + "isCollectiveName": false, + "name": "Chunhai Hao", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Quan", + "LastName": "Wang", + "email": [ + "wangquan-jlcc@hotmail.com" + ], + "name": "Quan Wang" + } + ] + }, + "doi": "10.1371/journal.pone.0073175", + "pmid": "23991179", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + } + ], + "reference": "PLoS One 8 2013", + "title": "Combination of mTOR and EGFR kinase inhibitors blocks mTORC1 and mTORC2 kinase activity and suppresses the progression of colorectal carcinoma." + } + }, + { + "pmid": "32899862", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1599177600, + "timezone": "+00:00" + }, + "abstract": "Recently, we have reported that blockade/deletion of P2X7 receptor (P2X7R), an ATP-gated ion channel, exacerbates heat shock protein 25 (HSP25)-mediated astroglial autophagy (clasmatodendrosis) following kainic acid (KA) injection. In P2X7R knockout (KO) mice, prolonged astroglial HSP25 induction exerts 5' adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1-mediated autophagic pathway independent of mammalian target of rapamycin (mTOR) activity following KA injection. Sustained HSP25 expression also enhances AKT-serine (S) 473 phosphorylation leading to astroglial autophagy via glycogen synthase kinase-3β/bax interacting factor 1 signaling pathway. However, it is unanswered how P2X7R deletion induces AKT-S473 hyperphosphorylation during autophagic process in astrocytes. In the present study, we found that AKT-S473 phosphorylation was increased by enhancing activity of focal adhesion kinase (FAK), independent of mTOR complex (mTORC) 1 and 2 activities in isolated astrocytes of P2X7R knockout (KO) mice following KA injection. In addition, HSP25 overexpression in P2X7R KO mice acted as a chaperone of AKT, which retained AKT-S473 phosphorylation by inhibiting the pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1- and 2-binding to AKT. Therefore, our findings suggest that P2X7R may be a fine-tuner of AKT-S473 activity during astroglial autophagy by regulating FAK phosphorylation and HSP25-mediated inhibition of PHLPP1/2-AKT binding following KA treatment.", + "authors": { + "abbreviation": "Duk-Shin Lee, Ji-Eun Kim", + "authorList": [ + { + "ForeName": "Duk-Shin", + "LastName": "Lee", + "abbrevName": "Lee DS", + "email": null, + "isCollectiveName": false, + "name": "Duk-Shin Lee", + "orcid": null + }, + { + "ForeName": "Ji-Eun", + "LastName": "Kim", + "abbrevName": "Kim JE", + "email": null, + "isCollectiveName": false, + "name": "Ji-Eun Kim", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21186476", + "pmid": "32899862", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures." + } + }, + { + "pmid": "29808317", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1533081600, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21/BTG2, that inhibits both growth and invasion of triple negative breast cancer cells via AKT1 activation by differential regulation of mTORc1 and mTORc2 activity. METHODS: Transduction of adenovirus carrying TIS21/BTG2 gene and transfection of short interfering RNAs were employed to regulate TIS21/BTG2 gene expression in various cell lines. Treatment of mTOR inhibitors and mTOR kinase assays can evaluate the role of mTORc in the regulation of AKT phosphorylation at S473 residue by TIS21/BTG2 in breast cancer cells. Open data and immunohistochemical analysis were performed to confirm the role of TIS21/BTG2 expression in various human breast cancer tissues. RESULTS: We observed that TIS21/BTG2 inhibited mTORc1 activity by reducing Raptor-mTOR interaction along with upregulation of tsc1 expression, which lead to significant reduction of p70S6K activation as opposed to AKT1S473, but not AKT2, phosphorylation via downregulating PHLPP2 (AKT1-specific phosphatase) in breast cancers. TIS21/BTG2-induced pAKTS473 required Rictor-bound mTOR kinase, indicating activation of mTORc2 by TIS21/BTG2 gene. Additionally, the TIS21/BTG2-induced pAKTS473 could reduce expression of NFAT1 (nuclear factor of activated T cells) and its target genes, which regulate cancer microenvironment. CONCLUSIONS: TIS21/BTG2 significantly lost in the infiltrating ductal carcinoma, but it can inhibit cancer growth via the TIS21/BTG2-tsc1/2-mTORc1-p70S6K axis and downregulate cancer progression via the TIS21/BTG2-mTORc2-AKT1-NFAT1-PHLPP2 pathway.", + "authors": { + "abbreviation": "Santhoshkumar Sundaramoorthy, Preethi Devanand, Min Sook Ryu, ..., In Kyoung Lim", + "authorList": [ + { + "ForeName": "Santhoshkumar", + "LastName": "Sundaramoorthy", + "abbrevName": "Sundaramoorthy S", + "email": null, + "isCollectiveName": false, + "name": "Santhoshkumar Sundaramoorthy", + "orcid": null + }, + { + "ForeName": "Preethi", + "LastName": "Devanand", + "abbrevName": "Devanand P", + "email": null, + "isCollectiveName": false, + "name": "Preethi Devanand", + "orcid": null + }, + { + "ForeName": "Min", + "LastName": "Ryu", + "abbrevName": "Ryu MS", + "email": null, + "isCollectiveName": false, + "name": "Min Sook Ryu", + "orcid": null + }, + { + "ForeName": "Kye", + "LastName": "Song", + "abbrevName": "Song KY", + "email": null, + "isCollectiveName": false, + "name": "Kye Yong Song", + "orcid": null + }, + { + "ForeName": "Dong", + "LastName": "Noh", + "abbrevName": "Noh DY", + "email": null, + "isCollectiveName": false, + "name": "Dong Young Noh", + "orcid": null + }, + { + "ForeName": "In", + "LastName": "Lim", + "abbrevName": "Lim IK", + "email": "iklim@ajou.ac.kr", + "isCollectiveName": false, + "name": "In Kyoung Lim", + "orcid": "0000-0002-2399-607X" + } + ], + "contacts": [ + { + "ForeName": "In", + "LastName": "Lim", + "email": [ + "iklim@ajou.ac.kr" + ], + "name": "In Kyoung Lim" + } + ] + }, + "doi": "10.1007/s00432-018-2677-6", + "pmid": "29808317", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "J Cancer Res Clin Oncol 144 2018", + "title": "TIS21/BTG2 inhibits breast cancer growth and progression by differential regulation of mTORc1 and mTORc2-AKT1-NFAT1-PHLPP2 signaling axis." + } + }, + { + "pmid": "32630372", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1593043200, + "timezone": "+00:00" + }, + "abstract": "Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.", + "authors": { + "abbreviation": "Boris Y Shorning, Manisha S Dass, Matthew J Smalley, Helen B Pearson", + "authorList": [ + { + "ForeName": "Boris", + "LastName": "Shorning", + "abbrevName": "Shorning BY", + "email": null, + "isCollectiveName": false, + "name": "Boris Y Shorning", + "orcid": null + }, + { + "ForeName": "Manisha", + "LastName": "Dass", + "abbrevName": "Dass MS", + "email": null, + "isCollectiveName": false, + "name": "Manisha S Dass", + "orcid": null + }, + { + "ForeName": "Matthew", + "LastName": "Smalley", + "abbrevName": "Smalley MJ", + "email": null, + "isCollectiveName": false, + "name": "Matthew J Smalley", + "orcid": "0000-0001-9540-1146" + }, + { + "ForeName": "Helen", + "LastName": "Pearson", + "abbrevName": "Pearson HB", + "email": null, + "isCollectiveName": false, + "name": "Helen B Pearson", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3390/ijms21124507", + "pmid": "32630372", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D016454", + "value": "Review" + } + ], + "reference": "Int J Mol Sci 21 2020", + "title": "The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling." + } + }, + { + "pmid": "30285764", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1538352000, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin. METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells. RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells. CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.", + "authors": { + "abbreviation": "Masoud Razmara, Azita Monazzam, Britt Skogseid", + "authorList": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "abbrevName": "Razmara M", + "email": "Masoud.Razmara@medsci.uu.se", + "isCollectiveName": false, + "name": "Masoud Razmara", + "orcid": "0000-0002-1037-4810" + }, + { + "ForeName": "Azita", + "LastName": "Monazzam", + "abbrevName": "Monazzam A", + "email": null, + "isCollectiveName": false, + "name": "Azita Monazzam", + "orcid": null + }, + { + "ForeName": "Britt", + "LastName": "Skogseid", + "abbrevName": "Skogseid B", + "email": null, + "isCollectiveName": false, + "name": "Britt Skogseid", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Masoud", + "LastName": "Razmara", + "email": [ + "Masoud.Razmara@medsci.uu.se" + ], + "name": "Masoud Razmara" + } + ] + }, + "doi": "10.1186/s12964-018-0278-2", + "pmid": "30285764", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cell Commun Signal 16 2018", + "title": "Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration." + } + }, + { + "pmid": "19209957", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1234224000, + "timezone": "+00:00" + }, + "abstract": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.", + "authors": { + "abbreviation": "Morris E Feldman, Beth Apsel, Aino Uotila, ..., Kevan M Shokat", + "authorList": [ + { + "ForeName": "Morris", + "LastName": "Feldman", + "abbrevName": "Feldman ME", + "email": null, + "isCollectiveName": false, + "name": "Morris E Feldman", + "orcid": null + }, + { + "ForeName": "Beth", + "LastName": "Apsel", + "abbrevName": "Apsel B", + "email": null, + "isCollectiveName": false, + "name": "Beth Apsel", + "orcid": null + }, + { + "ForeName": "Aino", + "LastName": "Uotila", + "abbrevName": "Uotila A", + "email": null, + "isCollectiveName": false, + "name": "Aino Uotila", + "orcid": null + }, + { + "ForeName": "Robbie", + "LastName": "Loewith", + "abbrevName": "Loewith R", + "email": null, + "isCollectiveName": false, + "name": "Robbie Loewith", + "orcid": null + }, + { + "ForeName": "Zachary", + "LastName": "Knight", + "abbrevName": "Knight ZA", + "email": null, + "isCollectiveName": false, + "name": "Zachary A Knight", + "orcid": null + }, + { + "ForeName": "Davide", + "LastName": "Ruggero", + "abbrevName": "Ruggero D", + "email": null, + "isCollectiveName": false, + "name": "Davide Ruggero", + "orcid": null + }, + { + "ForeName": "Kevan", + "LastName": "Shokat", + "abbrevName": "Shokat KM", + "email": null, + "isCollectiveName": false, + "name": "Kevan M Shokat", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pbio.1000038", + "pmid": "19209957", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS Biol 7 2009", + "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." + } + }, + { + "pmid": "19661225", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1262304000, + "timezone": "+00:00" + }, + "abstract": "PURPOSE: Activated B-Raf alone cannot induce melanoma but must cooperate with other signaling pathways. The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR)/p70S6K pathways are critical for tumorigenesis. The authors investigated the role of these pathways in uveal melanoma cells. METHODS: The effects of PI3K and mTOR activation and inhibition on the proliferation of human uveal melanoma cell lines expressing either activated (WT)B-Raf or (V600E)B-Raf were investigated. Interactions among PI3K, mTOR, and B-Raf/ERK were studied. RESULTS: Inhibition of PI3K deactivated P70S6 kinase, reduced cell proliferation by 71% to 84%, and increased apoptosis by a factor of 5.0 to 8.4 without reducing ERK1/2 activation, indicating that ERK plays no role in mediating PI3K in these processes. In contrast, rapamycin-induced inhibition of mTOR did not significantly affect cell proliferation because it simultaneously stimulated PI3K/Akt activation and cyclin D1 expression. Regardless of B-Raf mutation status, cotreatment with the PI3K inhibitor effectively sensitized all melanoma cell lines to the B-Raf or ERK1/2 inhibition-induced reduction of cell proliferation. B-Raf/ERK and PI3K signaling, but not mTOR signaling, converged to control cyclin D1 expression. Moreover, p70S6K required the activation of ERK1/2. These data demonstrate that PI3K/Akt and mTOR/P70S6K interact with B-Raf/ERK. CONCLUSIONS: Activated PI3K/Akt attenuates the inhibitory effects of rapamycin on cell proliferation and thus serves as a negative feedback mechanism. This finding suggests that rapamycin is unlikely to inhibit uveal melanoma growth. In contrast, targeting PI3K while inhibiting B-Raf/ERK may be a promising approach to reduce the proliferation of uveal melanoma cells.", + "authors": { + "abbreviation": "Narjes Babchia, Armelle Calipel, Frédéric Mouriaux, ..., Frédéric Mascarelli", + "authorList": [ + { + "ForeName": "Narjes", + "LastName": "Babchia", + "abbrevName": "Babchia N", + "email": null, + "isCollectiveName": false, + "name": "Narjes Babchia", + "orcid": null + }, + { + "ForeName": "Armelle", + "LastName": "Calipel", + "abbrevName": "Calipel A", + "email": null, + "isCollectiveName": false, + "name": "Armelle Calipel", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mouriaux", + "abbrevName": "Mouriaux F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mouriaux", + "orcid": null + }, + { + "ForeName": "Anne-Marie", + "LastName": "Faussat", + "abbrevName": "Faussat AM", + "email": null, + "isCollectiveName": false, + "name": "Anne-Marie Faussat", + "orcid": null + }, + { + "ForeName": "Frédéric", + "LastName": "Mascarelli", + "abbrevName": "Mascarelli F", + "email": null, + "isCollectiveName": false, + "name": "Frédéric Mascarelli", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1167/iovs.09-3974", + "pmid": "19661225", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Invest Ophthalmol Vis Sci 51 2010", + "title": "The PI3K/Akt and mTOR/P70S6K signaling pathways in human uveal melanoma cells: interaction with B-Raf/ERK." + } + }, + { + "pmid": "22140653", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1312156800, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. SIGNIFICANCE: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.", + "authors": { + "abbreviation": "Vanessa S Rodrik-Outmezguine, Sarat Chandarlapaty, Nen C Pagano, ..., Neal Rosen", + "authorList": [ + { + "ForeName": "Vanessa", + "LastName": "Rodrik-Outmezguine", + "abbrevName": "Rodrik-Outmezguine VS", + "email": null, + "isCollectiveName": false, + "name": "Vanessa S Rodrik-Outmezguine", + "orcid": null + }, + { + "ForeName": "Sarat", + "LastName": "Chandarlapaty", + "abbrevName": "Chandarlapaty S", + "email": null, + "isCollectiveName": false, + "name": "Sarat Chandarlapaty", + "orcid": null + }, + { + "ForeName": "Nen", + "LastName": "Pagano", + "abbrevName": "Pagano NC", + "email": null, + "isCollectiveName": false, + "name": "Nen C Pagano", + "orcid": null + }, + { + "ForeName": "Poulikos", + "LastName": "Poulikakos", + "abbrevName": "Poulikakos PI", + "email": null, + "isCollectiveName": false, + "name": "Poulikos I Poulikakos", + "orcid": null + }, + { + "ForeName": "Maurizio", + "LastName": "Scaltriti", + "abbrevName": "Scaltriti M", + "email": null, + "isCollectiveName": false, + "name": "Maurizio Scaltriti", + "orcid": null + }, + { + "ForeName": "Elizabeth", + "LastName": "Moskatel", + "abbrevName": "Moskatel E", + "email": null, + "isCollectiveName": false, + "name": "Elizabeth Moskatel", + "orcid": null + }, + { + "ForeName": "José", + "LastName": "Baselga", + "abbrevName": "Baselga J", + "email": null, + "isCollectiveName": false, + "name": "José Baselga", + "orcid": null + }, + { + "ForeName": "Sylvie", + "LastName": "Guichard", + "abbrevName": "Guichard S", + "email": null, + "isCollectiveName": false, + "name": "Sylvie Guichard", + "orcid": null + }, + { + "ForeName": "Neal", + "LastName": "Rosen", + "abbrevName": "Rosen N", + "email": null, + "isCollectiveName": false, + "name": "Neal Rosen", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0085", + "pmid": "22140653", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling." + } + }, + { + "pmid": "33495824", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1614556800, + "timezone": "+00:00" + }, + "abstract": "Breast cancer is the worldwide leading cause of cancer‑related deaths among women. Increasing evidence has demonstrated that microRNAs (miRNAs) play critical roles in the carcinogenesis and progression of breast cancer. miR‑653‑5p was previously reported to be involved in cell proliferation and apoptosis. However, the role of miR‑653‑5p in the progression of breast cancer has not been studied. In the present study, it was found that overexpression of miR‑653‑5p significantly inhibited the proliferation, migration and invasion of breast cancer cells in vitro. Moreover, overexpression of miR‑653‑5p promoted cell apoptosis in breast cancer by regulating the Bcl‑2/Bax axis and caspase‑9 activation. Additionally, the epithelial‑mesenchymal transition and activation of the Akt/mammalian target of rapamycin signaling pathway were also inhibited by miR‑653‑5p. Furthermore, the data demonstrated that miR‑653‑5p directly targeted mitogen‑activated protein kinase 6 (MAPK6) and negatively regulated its expression in breast cancer cells. Upregulation of MAPK6 could overcome the inhibitory effects of miR‑653‑5p on cell proliferation and migration in breast cancer. In conclusion, this study suggested that miR‑653‑5p functions as a tumor suppressor by targeting MAPK6 in the progression of breast cancer, and it may be a potential target for breast cancer therapy.", + "authors": { + "abbreviation": "Mei Zhang, Hongwei Wang, Xiaomei Zhang, Fengping Liu", + "authorList": [ + { + "ForeName": "Mei", + "LastName": "Zhang", + "abbrevName": "Zhang M", + "email": null, + "isCollectiveName": false, + "name": "Mei Zhang", + "orcid": null + }, + { + "ForeName": "Hongwei", + "LastName": "Wang", + "abbrevName": "Wang H", + "email": null, + "isCollectiveName": false, + "name": "Hongwei Wang", + "orcid": null + }, + { + "ForeName": "Xiaomei", + "LastName": "Zhang", + "abbrevName": "Zhang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaomei Zhang", + "orcid": null + }, + { + "ForeName": "Fengping", + "LastName": "Liu", + "abbrevName": "Liu F", + "email": null, + "isCollectiveName": false, + "name": "Fengping Liu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3892/mmr.2021.11839", + "pmid": "33495824", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Med Rep 23 2021", + "title": "miR‑653‑5p suppresses the growth and migration of breast cancer cells by targeting MAPK6." + } + }, + { + "pmid": "22808163", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.", + "authors": { + "abbreviation": "Alan L Ho, Elgilda Musi, Grazia Ambrosini, ..., Gary K Schwartz", + "authorList": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "abbrevName": "Ho AL", + "email": "hoa@mskcc.org", + "isCollectiveName": false, + "name": "Alan L Ho", + "orcid": null + }, + { + "ForeName": "Elgilda", + "LastName": "Musi", + "abbrevName": "Musi E", + "email": null, + "isCollectiveName": false, + "name": "Elgilda Musi", + "orcid": null + }, + { + "ForeName": "Grazia", + "LastName": "Ambrosini", + "abbrevName": "Ambrosini G", + "email": null, + "isCollectiveName": false, + "name": "Grazia Ambrosini", + "orcid": null + }, + { + "ForeName": "Jayasree", + "LastName": "Nair", + "abbrevName": "Nair JS", + "email": null, + "isCollectiveName": false, + "name": "Jayasree S Nair", + "orcid": null + }, + { + "ForeName": "Shyamprasad", + "LastName": "Deraje Vasudeva", + "abbrevName": "Deraje Vasudeva S", + "email": null, + "isCollectiveName": false, + "name": "Shyamprasad Deraje Vasudeva", + "orcid": null + }, + { + "ForeName": "Elisa", + "LastName": "de Stanchina", + "abbrevName": "de Stanchina E", + "email": null, + "isCollectiveName": false, + "name": "Elisa de Stanchina", + "orcid": null + }, + { + "ForeName": "Gary", + "LastName": "Schwartz", + "abbrevName": "Schwartz GK", + "email": null, + "isCollectiveName": false, + "name": "Gary K Schwartz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Alan", + "LastName": "Ho", + "email": [ + "hoa@mskcc.org" + ], + "name": "Alan L Ho" + } + ] + }, + "doi": "10.1371/journal.pone.0040439", + "pmid": "22808163", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 7 2012", + "title": "Impact of combined mTOR and MEK inhibition in uveal melanoma is driven by tumor genotype." + } + }, + { + "pmid": "22476852", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1343779200, + "timezone": "+00:00" + }, + "abstract": "Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.", + "authors": { + "abbreviation": "Haiyan Li, Jun Lin, Xiaokai Wang, ..., Xiaochun Bai", + "authorList": [ + { + "ForeName": "Haiyan", + "LastName": "Li", + "abbrevName": "Li H", + "email": null, + "isCollectiveName": false, + "name": "Haiyan Li", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Lin", + "abbrevName": "Lin J", + "email": null, + "isCollectiveName": false, + "name": "Jun Lin", + "orcid": null + }, + { + "ForeName": "Xiaokai", + "LastName": "Wang", + "abbrevName": "Wang X", + "email": null, + "isCollectiveName": false, + "name": "Xiaokai Wang", + "orcid": null + }, + { + "ForeName": "Guangyu", + "LastName": "Yao", + "abbrevName": "Yao G", + "email": null, + "isCollectiveName": false, + "name": "Guangyu Yao", + "orcid": null + }, + { + "ForeName": "Liping", + "LastName": "Wang", + "abbrevName": "Wang L", + "email": null, + "isCollectiveName": false, + "name": "Liping Wang", + "orcid": null + }, + { + "ForeName": "Hang", + "LastName": "Zheng", + "abbrevName": "Zheng H", + "email": null, + "isCollectiveName": false, + "name": "Hang Zheng", + "orcid": null + }, + { + "ForeName": "Cuilan", + "LastName": "Yang", + "abbrevName": "Yang C", + "email": null, + "isCollectiveName": false, + "name": "Cuilan Yang", + "orcid": null + }, + { + "ForeName": "Chunhong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Chunhong Jia", + "orcid": null + }, + { + "ForeName": "Anling", + "LastName": "Liu", + "abbrevName": "Liu A", + "email": null, + "isCollectiveName": false, + "name": "Anling Liu", + "orcid": null + }, + { + "ForeName": "Xiaochun", + "LastName": "Bai", + "abbrevName": "Bai X", + "email": null, + "isCollectiveName": false, + "name": "Xiaochun Bai", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1007/s10549-012-2036-2", + "pmid": "22476852", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 134 2012", + "title": "Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer." + } + }, + { + "pmid": "24112608", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1381363200, + "timezone": "+00:00" + }, + "abstract": "BACKGROUND: Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. METHODS: A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK + ALCL cell line and the NPM-ALK transformed BaF3 cells. RESULTS: ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70 kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK + ALCL occurred more commonly in younger patients, and ALK + ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK + ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK. CONCLUSIONS: Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK + ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.", + "authors": { + "abbreviation": "Ju Gao, Minzhi Yin, Yiping Zhu, ..., Zhigui Ma", + "authorList": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "abbrevName": "Gao J", + "email": "ma_zg@yahoo.com", + "isCollectiveName": false, + "name": "Ju Gao", + "orcid": null + }, + { + "ForeName": "Minzhi", + "LastName": "Yin", + "abbrevName": "Yin M", + "email": null, + "isCollectiveName": false, + "name": "Minzhi Yin", + "orcid": null + }, + { + "ForeName": "Yiping", + "LastName": "Zhu", + "abbrevName": "Zhu Y", + "email": null, + "isCollectiveName": false, + "name": "Yiping Zhu", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Gu", + "abbrevName": "Gu L", + "email": null, + "isCollectiveName": false, + "name": "Ling Gu", + "orcid": null + }, + { + "ForeName": "Yanle", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yanle Zhang", + "orcid": null + }, + { + "ForeName": "Qiang", + "LastName": "Li", + "abbrevName": "Li Q", + "email": null, + "isCollectiveName": false, + "name": "Qiang Li", + "orcid": null + }, + { + "ForeName": "Cangsong", + "LastName": "Jia", + "abbrevName": "Jia C", + "email": null, + "isCollectiveName": false, + "name": "Cangsong Jia", + "orcid": null + }, + { + "ForeName": "Zhigui", + "LastName": "Ma", + "abbrevName": "Ma Z", + "email": null, + "isCollectiveName": false, + "name": "Zhigui Ma", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Ju", + "LastName": "Gao", + "email": [ + "ma_zg@yahoo.com" + ], + "name": "Ju Gao" + } + ] + }, + "doi": "10.1186/1471-2407-13-471", + "pmid": "24112608", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "BMC Cancer 13 2013", + "title": "Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma." + } + }, + { + "pmid": "22145100", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1320105600, + "timezone": "+00:00" + }, + "abstract": "UNLABELLED: Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. SIGNIFICANCE: This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.", + "authors": { + "abbreviation": "Kazuhiro Tanaka, Ivan Babic, David Nathanson, ..., Paul S Mischel", + "authorList": [ + { + "ForeName": "Kazuhiro", + "LastName": "Tanaka", + "abbrevName": "Tanaka K", + "email": null, + "isCollectiveName": false, + "name": "Kazuhiro Tanaka", + "orcid": null + }, + { + "ForeName": "Ivan", + "LastName": "Babic", + "abbrevName": "Babic I", + "email": null, + "isCollectiveName": false, + "name": "Ivan Babic", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Nathanson", + "abbrevName": "Nathanson D", + "email": null, + "isCollectiveName": false, + "name": "David Nathanson", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Akhavan", + "abbrevName": "Akhavan D", + "email": null, + "isCollectiveName": false, + "name": "David Akhavan", + "orcid": null + }, + { + "ForeName": "Deliang", + "LastName": "Guo", + "abbrevName": "Guo D", + "email": null, + "isCollectiveName": false, + "name": "Deliang Guo", + "orcid": null + }, + { + "ForeName": "Beatrice", + "LastName": "Gini", + "abbrevName": "Gini B", + "email": null, + "isCollectiveName": false, + "name": "Beatrice Gini", + "orcid": null + }, + { + "ForeName": "Julie", + "LastName": "Dang", + "abbrevName": "Dang J", + "email": null, + "isCollectiveName": false, + "name": "Julie Dang", + "orcid": null + }, + { + "ForeName": "Shaojun", + "LastName": "Zhu", + "abbrevName": "Zhu S", + "email": null, + "isCollectiveName": false, + "name": "Shaojun Zhu", + "orcid": null + }, + { + "ForeName": "Huijun", + "LastName": "Yang", + "abbrevName": "Yang H", + "email": null, + "isCollectiveName": false, + "name": "Huijun Yang", + "orcid": null + }, + { + "ForeName": "Jason", + "LastName": "De Jesus", + "abbrevName": "De Jesus J", + "email": null, + "isCollectiveName": false, + "name": "Jason De Jesus", + "orcid": null + }, + { + "ForeName": "Ali", + "LastName": "Amzajerdi", + "abbrevName": "Amzajerdi AN", + "email": null, + "isCollectiveName": false, + "name": "Ali Nael Amzajerdi", + "orcid": null + }, + { + "ForeName": "Yinan", + "LastName": "Zhang", + "abbrevName": "Zhang Y", + "email": null, + "isCollectiveName": false, + "name": "Yinan Zhang", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Dibble", + "abbrevName": "Dibble CC", + "email": null, + "isCollectiveName": false, + "name": "Christian C Dibble", + "orcid": null + }, + { + "ForeName": "Hancai", + "LastName": "Dan", + "abbrevName": "Dan H", + "email": null, + "isCollectiveName": false, + "name": "Hancai Dan", + "orcid": null + }, + { + "ForeName": "Amanda", + "LastName": "Rinkenbaugh", + "abbrevName": "Rinkenbaugh A", + "email": null, + "isCollectiveName": false, + "name": "Amanda Rinkenbaugh", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Yong", + "abbrevName": "Yong WH", + "email": null, + "isCollectiveName": false, + "name": "William H Yong", + "orcid": null + }, + { + "ForeName": "Harry", + "LastName": "Vinters", + "abbrevName": "Vinters HV", + "email": null, + "isCollectiveName": false, + "name": "Harry V Vinters", + "orcid": null + }, + { + "ForeName": "Joseph", + "LastName": "Gera", + "abbrevName": "Gera JF", + "email": null, + "isCollectiveName": false, + "name": "Joseph F Gera", + "orcid": null + }, + { + "ForeName": "Webster", + "LastName": "Cavenee", + "abbrevName": "Cavenee WK", + "email": null, + "isCollectiveName": false, + "name": "Webster K Cavenee", + "orcid": null + }, + { + "ForeName": "Timothy", + "LastName": "Cloughesy", + "abbrevName": "Cloughesy TF", + "email": null, + "isCollectiveName": false, + "name": "Timothy F Cloughesy", + "orcid": null + }, + { + "ForeName": "Brendan", + "LastName": "Manning", + "abbrevName": "Manning BD", + "email": null, + "isCollectiveName": false, + "name": "Brendan D Manning", + "orcid": null + }, + { + "ForeName": "Albert", + "LastName": "Baldwin", + "abbrevName": "Baldwin AS", + "email": null, + "isCollectiveName": false, + "name": "Albert S Baldwin", + "orcid": null + }, + { + "ForeName": "Paul", + "LastName": "Mischel", + "abbrevName": "Mischel PS", + "email": null, + "isCollectiveName": false, + "name": "Paul S Mischel", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/2159-8290.CD-11-0124", + "pmid": "22145100", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Cancer Discov 1 2011", + "title": "Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance." + } + }, + { + "pmid": "24562770", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1396310400, + "timezone": "+00:00" + }, + "abstract": "Resistance of breast cancers to targeted hormone receptor (HR) or human epidermal growth factor receptor 2 (HER2) inhibitors often occurs through dysregulation of the phosphoinositide 3-kinase, protein kinase B/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Presently, no targeted therapies exist for breast cancers lacking HR and HER2 overexpression, many of which also exhibit PI3K/AKT/mTOR hyper-activation. Resistance of breast cancers to current therapeutics also results, in part, from aberrant epigenetic modifications including protein acetylation regulated by histone deacetylases (HDACs). We show that the investigational drug MLN0128, which inhibits both complexes of mTOR (mTORC1 and mTORC2), and the hydroxamic acid pan-HDAC inhibitor TSA synergistically inhibit the viability of a phenotypically diverse panel of five breast cancer cell lines (HR-/+, HER2-/+). The combination of MLN0128 and TSA induces apoptosis in most breast cancer cell lines tested, but not in the non-malignant MCF-10A mammary epithelial cells. In parallel, the MLN0128/TSA combination reduces phosphorylation of AKT at S473 more than single agents alone and more so in the 5 malignant breast cancer cell lines than in the non-malignant mammary epithelial cells. Examining polysome profiles from one of the most sensitive breast cancer cell lines (SKBR3), we demonstrate that this MLN0128/TSA treatment combination synergistically impairs polysome assembly in conjunction with enhanced inhibition of 4eBP1 phosphorylation at S65. Taken together, these data indicate that the synergistic growth inhibiting consequence of combining a mTORC1/C2 inhibitor like MLN0128 with a pan-HDAC inhibitor like TSA results from their mechanistic convergence onto the PI3K/AKT/mTOR pathway, profoundly inhibiting both AKT S473 and 4eBP1 S65 phosphorylation, reducing polysome formation and cancer cell viability.", + "authors": { + "abbreviation": "Kathleen A Wilson-Edell, Mariya A Yevtushenko, Daniel E Rothschild, ..., Christopher C Benz", + "authorList": [ + { + "ForeName": "Kathleen", + "LastName": "Wilson-Edell", + "abbrevName": "Wilson-Edell KA", + "email": null, + "isCollectiveName": false, + "name": "Kathleen A Wilson-Edell", + "orcid": null + }, + { + "ForeName": "Mariya", + "LastName": "Yevtushenko", + "abbrevName": "Yevtushenko MA", + "email": null, + "isCollectiveName": false, + "name": "Mariya A Yevtushenko", + "orcid": null + }, + { + "ForeName": "Daniel", + "LastName": "Rothschild", + "abbrevName": "Rothschild DE", + "email": null, + "isCollectiveName": false, + "name": "Daniel E Rothschild", + "orcid": null + }, + { + "ForeName": "Aric", + "LastName": "Rogers", + "abbrevName": "Rogers AN", + "email": null, + "isCollectiveName": false, + "name": "Aric N Rogers", + "orcid": null + }, + { + "ForeName": "Christopher", + "LastName": "Benz", + "abbrevName": "Benz CC", + "email": "cbenz@buckinstitute.org", + "isCollectiveName": false, + "name": "Christopher C Benz", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Christopher", + "LastName": "Benz", + "email": [ + "cbenz@buckinstitute.org" + ], + "name": "Christopher C Benz" + } + ] + }, + "doi": "10.1007/s10549-014-2877-y", + "pmid": "24562770", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D052061", + "value": "Research Support, N.I.H., Extramural" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Breast Cancer Res Treat 144 2014", + "title": "mTORC1/C2 and pan-HDAC inhibitors synergistically impair breast cancer growth by convergent AKT and polysome inhibiting mechanisms." + } + }, + { + "pmid": "19372546", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1238544000, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.", + "authors": { + "abbreviation": "Madlaina Breuleux, Matthieu Klopfenstein, Christine Stephan, ..., Heidi A Lane", + "authorList": [ + { + "ForeName": "Madlaina", + "LastName": "Breuleux", + "abbrevName": "Breuleux M", + "email": null, + "isCollectiveName": false, + "name": "Madlaina Breuleux", + "orcid": null + }, + { + "ForeName": "Matthieu", + "LastName": "Klopfenstein", + "abbrevName": "Klopfenstein M", + "email": null, + "isCollectiveName": false, + "name": "Matthieu Klopfenstein", + "orcid": null + }, + { + "ForeName": "Christine", + "LastName": "Stephan", + "abbrevName": "Stephan C", + "email": null, + "isCollectiveName": false, + "name": "Christine Stephan", + "orcid": null + }, + { + "ForeName": "Cheryl", + "LastName": "Doughty", + "abbrevName": "Doughty CA", + "email": null, + "isCollectiveName": false, + "name": "Cheryl A Doughty", + "orcid": null + }, + { + "ForeName": "Louise", + "LastName": "Barys", + "abbrevName": "Barys L", + "email": null, + "isCollectiveName": false, + "name": "Louise Barys", + "orcid": null + }, + { + "ForeName": "Saveur-Michel", + "LastName": "Maira", + "abbrevName": "Maira SM", + "email": null, + "isCollectiveName": false, + "name": "Saveur-Michel Maira", + "orcid": null + }, + { + "ForeName": "David", + "LastName": "Kwiatkowski", + "abbrevName": "Kwiatkowski D", + "email": null, + "isCollectiveName": false, + "name": "David Kwiatkowski", + "orcid": null + }, + { + "ForeName": "Heidi", + "LastName": "Lane", + "abbrevName": "Lane HA", + "email": null, + "isCollectiveName": false, + "name": "Heidi A Lane", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1158/1535-7163.MCT-08-0668", + "pmid": "19372546", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Mol Cancer Ther 8 2009", + "title": "Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition." + } + }, + { + "pmid": "23874880", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "AIMS: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic clinical benefits in advanced non-small cell lung cancer (NSCLC); however, resistance remains a serious problem in clinical practice. The present study analyzed mTOR-associated signaling-pathway differences between the EGFR TKI-sensitive and -resistant NSCLC cell lines and investigated the feasibility of targeting mTOR with specific mTOR inhibitor in EGFR TKI resistant NSCLC cells. METHODS: We selected four different types of EGFR TKI-sensitive and -resistant NSCLC cells: PC9, PC9GR, H1650 and H1975 cells as models to detect mTOR-associated signaling-pathway differences by western blot and Immunoprecipitation and evaluated the antiproliferative effect and cell cycle arrest of ku-0063794 by MTT method and flow cytometry. RESULTS: In the present study, we observed that mTORC2-associated Akt ser473-FOXO1 signaling pathway in a basal state was highly activated in resistant cells. In vitro mTORC1 and mTORC2 kinase activities assays showed that EGFR TKI-resistant NSCLC cell lines had higher mTORC2 kinase activity, whereas sensitive cells had higher mTORC1 kinase activity in the basal state. The ATP-competitive mTOR inhibitor ku-0063794 showed dramatic antiproliferative effects and G1-cell cycle arrest in both sensitive and resistant cells. Ku-0063794 at the IC50 concentration effectively inhibited both mTOR and p70S6K phosphorylation levels; the latter is an mTORC1 substrate and did not upregulate Akt ser473 phosphorylation which would be induced by rapamycin and resulted in partial inhibition of FOXO1 phosphorylation. We also observed that EGFR TKI-sensitive and -resistant clinical NSCLC tumor specimens had higher total and phosphorylated p70S6K expression levels. CONCLUSION: Our results indicate mTORC2-associated signaling-pathway was hyperactivated in EGFR TKI-resistant cells and targeting mTOR with specific mTOR inhibitors is likely a good strategy for patients with EGFR mutant NSCLC who develop EGFR TKI resistance; the potential specific roles of mTORC2 in EGFR TKI-resistant NSCLC cells were still unknown and should be further investigated.", + "authors": { + "abbreviation": "Shi-Jiang Fei, Xu-Chao Zhang, Song Dong, ..., Yi-Long Wu", + "authorList": [ + { + "ForeName": "Shi-Jiang", + "LastName": "Fei", + "abbrevName": "Fei SJ", + "email": null, + "isCollectiveName": false, + "name": "Shi-Jiang Fei", + "orcid": null + }, + { + "ForeName": "Xu-Chao", + "LastName": "Zhang", + "abbrevName": "Zhang XC", + "email": null, + "isCollectiveName": false, + "name": "Xu-Chao Zhang", + "orcid": null + }, + { + "ForeName": "Song", + "LastName": "Dong", + "abbrevName": "Dong S", + "email": null, + "isCollectiveName": false, + "name": "Song Dong", + "orcid": null + }, + { + "ForeName": "Hua", + "LastName": "Cheng", + "abbrevName": "Cheng H", + "email": null, + "isCollectiveName": false, + "name": "Hua Cheng", + "orcid": null + }, + { + "ForeName": "Yi-Fang", + "LastName": "Zhang", + "abbrevName": "Zhang YF", + "email": null, + "isCollectiveName": false, + "name": "Yi-Fang Zhang", + "orcid": null + }, + { + "ForeName": "Ling", + "LastName": "Huang", + "abbrevName": "Huang L", + "email": null, + "isCollectiveName": false, + "name": "Ling Huang", + "orcid": null + }, + { + "ForeName": "Hai-Yu", + "LastName": "Zhou", + "abbrevName": "Zhou HY", + "email": null, + "isCollectiveName": false, + "name": "Hai-Yu Zhou", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Xie", + "abbrevName": "Xie Z", + "email": null, + "isCollectiveName": false, + "name": "Zhi Xie", + "orcid": null + }, + { + "ForeName": "Zhi-Hong", + "LastName": "Chen", + "abbrevName": "Chen ZH", + "email": null, + "isCollectiveName": false, + "name": "Zhi-Hong Chen", + "orcid": null + }, + { + "ForeName": "Yi-Long", + "LastName": "Wu", + "abbrevName": "Wu YL", + "email": null, + "isCollectiveName": false, + "name": "Yi-Long Wu", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0069104", + "pmid": "23874880", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "PLoS One 8 2013", + "title": "Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells." + } + }, + { + "pmid": "30887599", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1561939200, + "timezone": "+00:00" + }, + "abstract": "Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin-Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)-induced G1/S cell-cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF-induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal-regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c-Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP-1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate-bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage-independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage-independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR-Akt-p70S6K and mTOR-Akt-GSK3β-AP-1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2-Akt-p70S6k signaling pathway.", + "authors": { + "abbreviation": "Sun-Mi Yoo, Cheol-Jung Lee, Han Chang Kang, ..., Yong-Yeon Cho", + "authorList": [ + { + "ForeName": "Sun-Mi", + "LastName": "Yoo", + "abbrevName": "Yoo SM", + "email": null, + "isCollectiveName": false, + "name": "Sun-Mi Yoo", + "orcid": null + }, + { + "ForeName": "Cheol-Jung", + "LastName": "Lee", + "abbrevName": "Lee CJ", + "email": null, + "isCollectiveName": false, + "name": "Cheol-Jung Lee", + "orcid": null + }, + { + "ForeName": "Han", + "LastName": "Kang", + "abbrevName": "Kang HC", + "email": null, + "isCollectiveName": false, + "name": "Han Chang Kang", + "orcid": null + }, + { + "ForeName": "Hye", + "LastName": "Lee", + "abbrevName": "Lee HS", + "email": null, + "isCollectiveName": false, + "name": "Hye Suk Lee", + "orcid": null + }, + { + "ForeName": "Joo", + "LastName": "Lee", + "abbrevName": "Lee JY", + "email": null, + "isCollectiveName": false, + "name": "Joo Young Lee", + "orcid": null + }, + { + "ForeName": "Kwang", + "LastName": "Kim", + "abbrevName": "Kim KD", + "email": null, + "isCollectiveName": false, + "name": "Kwang Dong Kim", + "orcid": null + }, + { + "ForeName": "Dae", + "LastName": "Kim", + "abbrevName": "Kim DJ", + "email": null, + "isCollectiveName": false, + "name": "Dae Joon Kim", + "orcid": "0000-0002-7977-9955" + }, + { + "ForeName": "Hyun-Jung", + "LastName": "An", + "abbrevName": "An HJ", + "email": null, + "isCollectiveName": false, + "name": "Hyun-Jung An", + "orcid": null + }, + { + "ForeName": "Yong-Yeon", + "LastName": "Cho", + "abbrevName": "Cho YY", + "email": null, + "isCollectiveName": false, + "name": "Yong-Yeon Cho", + "orcid": "0000-0003-1107-2651" + } + ], + "contacts": [] + }, + "doi": "10.1002/mc.23005", + "pmid": "30887599", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "reference": "Mol Carcinog 58 2019", + "title": "Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells." + } + }, + { + "pmid": "23272152", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1325376000, + "timezone": "+00:00" + }, + "abstract": "OBJECTIVE: Tetrameric α(2)-macroglobulin (α(2)M), a plasma panproteinase inhibitor, is activated upon interaction with a proteinase, and undergoes a major conformational change exposing a receptor recognition site in each of its subunits. Activated α(2)M (α(2)M*) binds to cancer cell surface GRP78 and triggers proliferative and antiapoptotic signaling. We have studied the role of α(2)M* in the regulation of mTORC1 and TORC2 signaling in the growth of human prostate cancer cells. METHODS: Employing immunoprecipitation techniques and Western blotting as well as kinase assays, activation of the mTORC1 and mTORC2 complexes, as well as down stream targets were studied. RNAi was also employed to silence expression of Raptor, Rictor, or GRP78 in parallel studies. RESULTS: Stimulation of cells with α(2)M* promotes phosphorylation of mTOR, TSC2, S6-Kinase, 4EBP, Akt(T308), and Akt(S473) in a concentration and time-dependent manner. Rheb, Raptor, and Rictor also increased. α(2)M* treatment of cells elevated mTORC1 kinase activity as determined by kinase assays of mTOR or Raptor immunoprecipitates. mTORC1 activity was sensitive to LY294002 and rapamycin or transfection of cells with GRP78 dsRNA. Down regulation of Raptor expression by RNAi significantly reduced α(2)M*-induced S6-Kinase phosphorylation at T389 and kinase activity in Raptor immunoprecipitates. α(2)M*-treated cells demonstrate about a twofold increase in mTORC2 kinase activity as determined by kinase assay of Akt(S473) phosphorylation and levels of p-Akt(S473) in mTOR and Rictor immunoprecipitates. mTORC2 activity was sensitive to LY294002 and transfection of cells with GRP78 dsRNA, but insensitive to rapamycin. Down regulation of Rictor expression by RNAi significantly reduces α(2)M*-induced phosphorylation of Akt(S473) phosphorylation in Rictor immunoprecipitates. CONCLUSION: Binding of α(2)M* to prostate cancer cell surface GRP78 upregulates mTORC1 and mTORC2 activation and promotes protein synthesis in the prostate cancer cells.", + "authors": { + "abbreviation": "Uma K Misra, Salvatore V Pizzo", + "authorList": [ + { + "ForeName": "Uma", + "LastName": "Misra", + "abbrevName": "Misra UK", + "email": null, + "isCollectiveName": false, + "name": "Uma K Misra", + "orcid": null + }, + { + "ForeName": "Salvatore", + "LastName": "Pizzo", + "abbrevName": "Pizzo SV", + "email": null, + "isCollectiveName": false, + "name": "Salvatore V Pizzo", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.1371/journal.pone.0051735", + "pmid": "23272152", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "PLoS One 7 2012", + "title": "Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells." + } + }, + { + "pmid": "24966685", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1388534400, + "timezone": "+00:00" + }, + "abstract": "Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as \"231/Gem\"), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.", + "authors": { + "abbreviation": "Xiao Li Yang, Feng Juan Lin, Ya Jie Guo, ..., Zhou Luo Ou", + "authorList": [ + { + "ForeName": "Xiao", + "LastName": "Yang", + "abbrevName": "Yang XL", + "email": null, + "isCollectiveName": false, + "name": "Xiao Li Yang", + "orcid": null + }, + { + "ForeName": "Feng", + "LastName": "Lin", + "abbrevName": "Lin FJ", + "email": null, + "isCollectiveName": false, + "name": "Feng Juan Lin", + "orcid": null + }, + { + "ForeName": "Ya", + "LastName": "Guo", + "abbrevName": "Guo YJ", + "email": null, + "isCollectiveName": false, + "name": "Ya Jie Guo", + "orcid": null + }, + { + "ForeName": "Zhi", + "LastName": "Shao", + "abbrevName": "Shao ZM", + "email": null, + "isCollectiveName": false, + "name": "Zhi Min Shao", + "orcid": null + }, + { + "ForeName": "Zhou", + "LastName": "Ou", + "abbrevName": "Ou ZL", + "email": null, + "isCollectiveName": false, + "name": "Zhou Luo Ou", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.2147/OTT.S63145", + "pmid": "24966685", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Onco Targets Ther 7 2014", + "title": "Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways." + } + }, + { + "pmid": "23802099", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1356998400, + "timezone": "+00:00" + }, + "abstract": "The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review \"PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle\" we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells. We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP:AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes. Depletion of energy leads to inactivation of mTORC1, activation of AMPK, FoxO, and promotes constitution of mTORC2 that leads to phosphorylation of Akt S473. Akt can also be activated independent of PI3K; this appears to have an advantage under situations like dietary restrictions, where insulin/insulin growth factor signaling could be a casualty.", + "authors": { + "abbreviation": "Lakshmipathi Vadlakonda, Abhinandita Dash, Mukesh Pasupuleti, ..., Pallu Reddanna", + "authorList": [ + { + "ForeName": "Lakshmipathi", + "LastName": "Vadlakonda", + "abbrevName": "Vadlakonda L", + "email": null, + "isCollectiveName": false, + "name": "Lakshmipathi Vadlakonda", + "orcid": null + }, + { + "ForeName": "Abhinandita", + "LastName": "Dash", + "abbrevName": "Dash A", + "email": null, + "isCollectiveName": false, + "name": "Abhinandita Dash", + "orcid": null + }, + { + "ForeName": "Mukesh", + "LastName": "Pasupuleti", + "abbrevName": "Pasupuleti M", + "email": null, + "isCollectiveName": false, + "name": "Mukesh Pasupuleti", + "orcid": null + }, + { + "ForeName": "Kotha", + "LastName": "Anil Kumar", + "abbrevName": "Anil Kumar K", + "email": null, + "isCollectiveName": false, + "name": "Kotha Anil Kumar", + "orcid": null + }, + { + "ForeName": "Pallu", + "LastName": "Reddanna", + "abbrevName": "Reddanna P", + "email": null, + "isCollectiveName": false, + "name": "Pallu Reddanna", + "orcid": null + } + ], + "contacts": [] + }, + "doi": "10.3389/fonc.2013.00165", + "pmid": "23802099", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Front Oncol 3 2013", + "title": "The Paradox of Akt-mTOR Interactions." + } + }, + { + "pmid": "27197158", + "pubmed": { + "ISODate": { + "$reql_type$": "TIME", + "epoch_time": 1471219200, + "timezone": "+00:00" + }, + "abstract": "HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752-64. ©2016 AACR.", + "authors": { + "abbreviation": "Meghan Morrison Joly, Donna J Hicks, Bayley Jones, ..., Rebecca S Cook", + "authorList": [ + { + "ForeName": "Meghan", + "LastName": "Morrison Joly", + "abbrevName": "Morrison Joly M", + "email": null, + "isCollectiveName": false, + "name": "Meghan Morrison Joly", + "orcid": null + }, + { + "ForeName": "Donna", + "LastName": "Hicks", + "abbrevName": "Hicks DJ", + "email": null, + "isCollectiveName": false, + "name": "Donna J Hicks", + "orcid": null + }, + { + "ForeName": "Bayley", + "LastName": "Jones", + "abbrevName": "Jones B", + "email": null, + "isCollectiveName": false, + "name": "Bayley Jones", + "orcid": null + }, + { + "ForeName": "Violeta", + "LastName": "Sanchez", + "abbrevName": "Sanchez V", + "email": null, + "isCollectiveName": false, + "name": "Violeta Sanchez", + "orcid": null + }, + { + "ForeName": "Monica", + "LastName": "Estrada", + "abbrevName": "Estrada MV", + "email": null, + "isCollectiveName": false, + "name": "Monica Valeria Estrada", + "orcid": null + }, + { + "ForeName": "Christian", + "LastName": "Young", + "abbrevName": "Young C", + "email": null, + "isCollectiveName": false, + "name": "Christian Young", + "orcid": null + }, + { + "ForeName": "Michelle", + "LastName": "Williams", + "abbrevName": "Williams M", + "email": null, + "isCollectiveName": false, + "name": "Michelle Williams", + "orcid": null + }, + { + "ForeName": "Brent", + "LastName": "Rexer", + "abbrevName": "Rexer BN", + "email": null, + "isCollectiveName": false, + "name": "Brent N Rexer", + "orcid": null + }, + { + "ForeName": "Dos", + "LastName": "Sarbassov", + "abbrevName": "Sarbassov dos D", + "email": null, + "isCollectiveName": false, + "name": "Dos D Sarbassov", + "orcid": null + }, + { + "ForeName": "William", + "LastName": "Muller", + "abbrevName": "Muller WJ", + "email": null, + "isCollectiveName": false, + "name": "William J Muller", + "orcid": null + }, + { + "ForeName": "Dana", + "LastName": "Brantley-Sieders", + "abbrevName": "Brantley-Sieders D", + "email": null, + "isCollectiveName": false, + "name": "Dana Brantley-Sieders", + "orcid": null + }, + { + "ForeName": "Rebecca", + "LastName": "Cook", + "abbrevName": "Cook RS", + "email": "rebecca.cook@vanderbilt.edu", + "isCollectiveName": false, + "name": "Rebecca S Cook", + "orcid": null + } + ], + "contacts": [ + { + "ForeName": "Rebecca", + "LastName": "Cook", + "email": [ + "rebecca.cook@vanderbilt.edu" + ], + "name": "Rebecca S Cook" + } + ] + }, + "doi": "10.1158/0008-5472.CAN-15-3393", + "pmid": "27197158", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + } + ], + "reference": "Cancer Res 76 2016", + "title": "Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers." + } + } + ], + "secret": "998d53dc-8150-40b9-b59f-b5b54439e22d", + "type": "phosphorylation" + } + ] +} \ No newline at end of file diff --git a/neo4j-test/example.js b/neo4j-test/example.js deleted file mode 100644 index 1f4319a1a..000000000 --- a/neo4j-test/example.js +++ /dev/null @@ -1,29 +0,0 @@ -describe('Example set of tests', function () { - before(function () { - - }); - - after(function () { - - }); - - beforeEach(function () { - - }); - - afterEach(function () { - - }); - - it('does something', function () { - - }); - - it('does something else', function () { - - }); - - it('does something completely different', function () { - - }); -}); \ No newline at end of file diff --git a/neo4j-test/fixtures.js b/neo4j-test/fixtures.js new file mode 100644 index 000000000..70d9131b6 --- /dev/null +++ b/neo4j-test/fixtures.js @@ -0,0 +1,128 @@ +import r from 'rethinkdb'; +import _ from 'lodash'; +import path from 'path'; +import { writeFile } from 'fs/promises'; + +// ****** Customized variables ********** +// Document ID list to retrieve +const DOC_IDS = [ + 'df9348dc-2126-45ff-a379-138b5589bcc8', + '8a33f76c-802e-4df2-8f1e-0a94ab3fc735' +]; +const FILENAME = 'doct_tests_1.json'; + +/** + * makeFixture + * + * Use this file to create text fixtures + * + * Customize: + * - DOC_IDS: The list of Document IDs you want to retrieve + * - FILENAME: The name of the output file + * + * Run + * node -r esm neo4j-test/fixtures.js + * + * Output + * File JSON with schema { document: [...], element: [...] } + */ +async function makeFixture () { + + let conn; + let db; + + const dbName = 'factoid'; + const dbTables = ['document', 'element']; + + try { + // Connect to db + conn = await r.connect({ host: 'localhost', db: dbName }); + db = r.db(dbName); + let loadTable = name => ({ rethink: r, conn, db, table: db.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + const { docDb, eleDb } = await loadTables(); + + let document = await getDocs( DOC_IDS, docDb ); + let element = await getElts( DOC_IDS, docDb, eleDb ); + + return { + document, + element + }; + + } catch (err) { + console.error(`Error: ${err}`); + throw err; + + } finally { + await conn.close(); + + } +} + +async function getElts( ids, docDb, eleDb ){ + const redactElt = elt => _.assign( {}, elt, { + secret: 'read-only', + _ops: [] + }); + + // Retrieve records + let q = docDb.table + .getAll( r.args( ids ) ) + .map( function( document ){ + return document.merge({ entries: document( 'entries' )( 'id' ) }); + }) + .merge( function( document ) { + return { + elements: eleDb.table + .getAll( r.args( document( 'entries' ) ) ) + .coerceTo( 'array' ) + }; + }) + .map(function(val){ + return val('elements'); + }); + + const cursor = await q.run( docDb.conn ); + const raw = _.flatten( await cursor.toArray() ); + const elts = raw.map( redactElt ); + + return elts; +} + +async function getDocs( ids, { conn, table } ){ + const redactDoc = doc => _.assign( {}, doc, { + secret: 'read-only', + _ops: [], + correspondence: { + authorEmail: [], + emails: [] + }, + provided: { + authorEmail: 'user@email.org', + authorName: 'John Doe', + name: 'John Doe', + paperId: 'Some paper id' + }, + tweet: null + }); + + // Retrieve records + let q = table.getAll( r.args( ids ) ); + const cursor = await q.run( conn ); + const raw = await cursor.toArray(); + + // Process records + const docs = raw.map( redactDoc ); + return docs; +} + +async function writeData(data){ + const OUT_FILE = path.join(__dirname, FILENAME); + const formatJSON = d => JSON.stringify(d, null, 2); + await writeFile(OUT_FILE, formatJSON(data)); +} + +// Run this +makeFixture().then( writeData ); + diff --git a/neo4j-test/search-tests.js b/neo4j-test/search-tests.js new file mode 100644 index 000000000..056b39aef --- /dev/null +++ b/neo4j-test/search-tests.js @@ -0,0 +1,130 @@ +import { expect } from 'chai'; +import rdbFix from 'rethinkdb-fixtures'; +import r from 'rethinkdb'; +import _ from 'lodash'; + +import { loadDoc } from '../src/server/routes/api/document/index.js'; +import { initDriver, closeDriver } from '../src/neo4j/neo4j-driver.js'; +import { neighbourhood, getInteractions, getNeighbouringNodes } from '../src/neo4j/neo4j-functions.js'; +import { addDocumentToNeo4j } from '../src/neo4j/neo4j-document.js'; +import { deleteAllNodesAndEdges } from '../src/neo4j/test-functions.js'; + +import goult1 from './document/doct_tests_1.json'; +import goult2 from './document/doct_tests_2.json'; +import goult3 from './document/doct_tests_3.json'; +import goult4 from './document/doct_tests_4.json'; +import goult5 from './document/doct_tests_5.json'; + +let rdbConn; +let dbFix; +let testDb; +const dbName = 'factoid-neo4j-test'; +const dbTables = ['document', 'element']; + +describe('04. Tests for search functions', function () { + + before('Create a Neo4j driver instance and connect to server. Connect to RDB', async function () { + await initDriver(); + + rdbConn = await r.connect({ host: 'localhost', db: dbName }); + const exists = await r.dbList().contains(dbName).run(rdbConn); + if (!exists) { + await r.dbCreate(dbName).run(rdbConn); + } + testDb = r.db(dbName); + dbFix = rdbFix({ + db: dbName, + clear: true + }); + }); + + before('Wipe Neo4j database. Then add all 5 test docs to Neo4j', async function () { + await deleteAllNodesAndEdges(); + + let loadTable = name => ({ rethink: r, conn: rdbConn, db: testDb, table: testDb.table(name) }); + let loadTables = () => Promise.all(dbTables.map(loadTable)).then(dbInfos => ({ docDb: dbInfos[0], eleDb: dbInfos[1] })); + + let docs = [goult1, goult2, goult3, goult4, goult5]; + + for (const goultDoc of docs) { + const { document } = await dbFix.Insert(goultDoc); + const { docDb, eleDb } = await loadTables(); + const loadDocs = ({ id, secret }) => loadDoc({ docDb, eleDb, id, secret }); + let fixtureDocs = await Promise.all(document.map(loadDocs)); + + let myDoc = fixtureDocs[0]; + await addDocumentToNeo4j(myDoc); + } + }); + + after('Wipe RDB. Close Neo4j driver and RDB connection.', async function () { + await dbFix.Delete(dbTables); + await closeDriver(); + await rdbConn.close(); + }); + + it('Search for MAPK6', async function () { + let mapk6 = 'ncbigene:5597'; + expect(await neighbourhood(mapk6)).to.be.null; + expect(await getInteractions(mapk6)).to.be.null; + expect(await getNeighbouringNodes(mapk6)).to.be.null; + }); + + it('Search for KANK1', async function () { + let kank1 = 'ncbigene:23189'; + expect(await neighbourhood(kank1)).to.not.be.null; + let edges = await getInteractions(kank1); + expect(edges.length).equal(3); + expect(_.find(edges, { id: 'd7b2a15d-43bf-4494-815b-a77e08cea59c', doi: '10.1083/jcb.202005214' })).to.be.not.undefined; + expect(_.find(edges, { id: 'e56263d8-d5b6-4812-bc2f-8d905a66f0f9', doi: '10.7554/eLife.18124' })).to.be.not.undefined; + expect(_.find(edges, { id: '5a374667-a51d-4aa3-bf93-526fe203b04e', doi: '10.7554/eLife.18124' })).to.be.not.undefined; + + let nodes = await getNeighbouringNodes(kank1); + expect(nodes.length).equal(3); + expect(_.find(nodes, { id: 'ncbigene:59274', name: 'TLNRD1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:7094', name: 'TLN1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:83660', name: 'TLN2' })).to.be.not.undefined; + }); + + it('Search for TLN1', async function () { + let tln1 = 'ncbigene:7094'; + expect(await neighbourhood(tln1)).to.not.be.null; + let edges = await getInteractions(tln1); + expect(edges.length).equal(6); + expect(_.find(edges, { id: '028e7366-9779-4466-96ea-18a45bfe3f38', doi: '10.1016/j.str.2016.04.016' })).to.be.not.undefined; + expect(_.find(edges, { id: '80a4d403-8bc1-4ddb-a4f9-5227e87ef6fa', doi: '10.1016/j.str.2016.04.016' })).to.be.not.undefined; + expect(_.find(edges, { id: 'e56263d8-d5b6-4812-bc2f-8d905a66f0f9', doi: '10.7554/eLife.18124' })).to.be.not.undefined; + expect(_.find(edges, { id: '013b7e2a-7240-4668-b628-2653c60f47e9', doi: '10.7554/eLife.18124' })).to.be.not.undefined; + expect(_.find(edges, { id: '3e7c85db-c2a3-4a1f-b96e-6d187c6ab93b', doi: '10.1016/j.jbc.2021.100837' })).to.be.not.undefined; + expect(_.find(edges, { id: 'e39d0a06-5b02-44e3-9c36-27cc1f9ac08c', doi: '10.1016/j.jbc.2021.100837' })).to.be.not.undefined; + + let nodes = await getNeighbouringNodes(tln1); + expect(nodes.length).equal(5); + expect(_.find(nodes, { id: 'ncbigene:5829', name: 'PXN' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:983', name: 'CDK1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:10395', name: 'DLC1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:23189', name: 'KANK1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:25959', name: 'KANK2' })).to.be.not.undefined; + }); + + it('Search for TLNRD1', async function () { + let tlnrd1 = 'ncbigene:59274'; + expect(await neighbourhood(tlnrd1)).to.not.be.null; + let edges = await getInteractions(tlnrd1); + expect(edges.length).equal(5); + expect(_.find(edges, { id: 'd5d9fbcc-a1d9-4026-b1d3-d4a97faff36b', doi: '10.1083/jcb.202005214' })).to.be.not.undefined; + expect(_.find(edges, { id: '13ab91d1-ee5f-46ca-a1ea-82ce72a938f4', doi: '10.1083/jcb.202005214' })).to.be.not.undefined; + expect(_.find(edges, { id: 'd7b2a15d-43bf-4494-815b-a77e08cea59c', doi: '10.1083/jcb.202005214' })).to.be.not.undefined; + expect(_.find(edges, { id: 'eec84ebe-eece-4143-b406-cd99cdbe2e43', doi: '10.1083/jcb.202005214' })).to.be.not.undefined; + expect(_.find(edges, { id: 'e59c16c4-11e8-4755-8e2f-f88fe4a73b30', doi: '10.1083/jcb.202005214' })).to.be.not.undefined; + + let nodes = await getNeighbouringNodes(tlnrd1); + expect(nodes.length).equal(5); + expect(_.find(nodes, { id: 'ncbigene:59274', name: 'TLNRD1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:23189', name: 'KANK1' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:60', name: 'ACTB' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:54518', name: 'APBB1IP' })).to.be.not.undefined; + expect(_.find(nodes, { id: 'ncbigene:65059', name: 'RAPH1' })).to.be.not.undefined; + }); + +}); \ No newline at end of file diff --git a/package-lock.json b/package-lock.json index 1f9b410d1..f0dc1d699 100644 --- a/package-lock.json +++ b/package-lock.json @@ -1,12 +1,12 @@ { "name": "factoid", - "version": "0.22.1", + "version": "0.23.0", "lockfileVersion": 2, "requires": true, "packages": { "": { "name": "factoid", - "version": "0.22.1", + "version": "0.23.0", "license": "MIT", "dependencies": { "@appsignal/express": "^0.5.1", @@ -105,6 +105,7 @@ "postcss-cssnext": "^3.1.0", "postcss-import": "^10.0.0", "postcss-url": "^7.3.2", + "rethinkdb-fixtures": "^0.1.1", "rimraf": "^2.6.2", "stylelint": "^8.4.0", "stylelint-config-standard": "^17.0.0", @@ -14395,6 +14396,18 @@ "node": ">= 0.10.0" } }, + "node_modules/rethinkdb-fixtures": { + "version": "0.1.1", + "resolved": "https://registry.npmjs.org/rethinkdb-fixtures/-/rethinkdb-fixtures-0.1.1.tgz", + "integrity": "sha512-yCOlv5v+4TJF8E2tNjjC27A2W+DMPzF+zurJhio5/Fciyso2SdmDv8n0/MgPoi2e+JwUcVXGISGouf1eEt2EcQ==", + "dev": true, + "dependencies": { + "bluebird": "^3.4.6", + "glob": "^7.0.6", + "lodash": "^4.15.0", + "rethinkdb": "^2.3.3" + } + }, "node_modules/rethinkdb/node_modules/bluebird": { "version": "2.11.0", "resolved": "https://registry.npmjs.org/bluebird/-/bluebird-2.11.0.tgz", @@ -31042,6 +31055,18 @@ } } }, + "rethinkdb-fixtures": { + "version": "0.1.1", + "resolved": "https://registry.npmjs.org/rethinkdb-fixtures/-/rethinkdb-fixtures-0.1.1.tgz", + "integrity": "sha512-yCOlv5v+4TJF8E2tNjjC27A2W+DMPzF+zurJhio5/Fciyso2SdmDv8n0/MgPoi2e+JwUcVXGISGouf1eEt2EcQ==", + "dev": true, + "requires": { + "bluebird": "^3.4.6", + "glob": "^7.0.6", + "lodash": "^4.15.0", + "rethinkdb": "^2.3.3" + } + }, "rgb": { "version": "0.1.0", "resolved": "https://registry.npmjs.org/rgb/-/rgb-0.1.0.tgz", diff --git a/package.json b/package.json index 3442b8815..3dfd159d6 100644 --- a/package.json +++ b/package.json @@ -128,6 +128,7 @@ "postcss-cssnext": "^3.1.0", "postcss-import": "^10.0.0", "postcss-url": "^7.3.2", + "rethinkdb-fixtures": "^0.1.1", "rimraf": "^2.6.2", "stylelint": "^8.4.0", "stylelint-config-standard": "^17.0.0", @@ -137,5 +138,5 @@ "engines": { "node": ">=16.19.0" }, - "version": "0.22.1" + "version": "0.23.0" } diff --git a/src/config.js b/src/config.js index d2614c4b1..69f0bb982 100644 --- a/src/config.js +++ b/src/config.js @@ -110,6 +110,7 @@ export const EMAIL_ADDRESS_ADMIN = env('EMAIL_ADDRESS_ADMIN', 'pc@biofactoid.com // Sharing export const DOCUMENT_IMAGE_CACHE_SIZE = env('DOCUMENT_IMAGE_CACHE_SIZE', 500); +export const DOCUMENT_IMAGE_PLL_LIMIT = env('DOCUMENT_IMAGE_PLL_LIMIT', 1); export const DOCUMENT_IMAGE_WIDTH = env('DOCUMENT_IMAGE_WIDTH', 2400); export const DOCUMENT_IMAGE_HEIGHT = env('DOCUMENT_IMAGE_HEIGHT', 1200); export const DOCUMENT_IMAGE_PADDING = env('DOCUMENT_IMAGE_PADDING', 50); diff --git a/src/model/document/document.js b/src/model/document/document.js index c94c6df6e..d561d6a28 100644 --- a/src/model/document/document.js +++ b/src/model/document/document.js @@ -19,6 +19,7 @@ const DEFAULTS = Object.freeze({ }); const METADATA_FIELDS = ['provided', 'correspondence', 'status', 'verified', 'authorProfiles', 'caption' ]; +const DESERIAL_METADATA_FIELDS = _.concat(METADATA_FIELDS, ['article']); const READONLY_METADATA_FIELDS = _.difference( METADATA_FIELDS, ['provided', 'correspondence'] ); const DOCUMENT_STATUS_FIELDS = Object.freeze({ INITIATED: 'initiated', @@ -607,7 +608,7 @@ class Document { let orgIds = json.organisms || []; let addOrganism = id => this.toggleOrganism( id, true ); let addOrganisms = () => Promise.all( orgIds.map( addOrganism ) ); - let updateMetadataEtc = () => this.syncher.update( _.pick(json, METADATA_FIELDS) ); + let updateMetadataEtc = () => this.syncher.update( _.pick(json, DESERIAL_METADATA_FIELDS) ); return Promise.all([ updateMetadataEtc(), diff --git a/src/neo4j/.env b/src/neo4j/.env index 96205fc08..be24e69b4 100644 --- a/src/neo4j/.env +++ b/src/neo4j/.env @@ -1 +1,2 @@ -GRAPHDB_IMAGE_TAG=5.4.0 \ No newline at end of file +GRAPHDB_IMAGE_TAG=5.4.0 +RETHINKDB_IMAGE_TAG=latest diff --git a/src/neo4j/docker-compose.yml b/src/neo4j/docker-compose.yml index 3d7df97f7..ef3e73c7b 100644 --- a/src/neo4j/docker-compose.yml +++ b/src/neo4j/docker-compose.yml @@ -1,5 +1,5 @@ version: "3.8" -services: +services: graphdb: image: neo4j:${GRAPHDB_IMAGE_TAG:-latest} restart: unless-stopped @@ -18,11 +18,24 @@ services: NEO4J_PLUGINS: '["apoc"]' networks: - graphdb-config-network + db: + image: pathwaycommons/rethinkdb-docker:${RETHINKDB_IMAGE_TAG:-latest} + restart: unless-stopped + container_name: db + ports: + - "8080:8080" + - "28015:28015" + - "29015:29015" + volumes: + - db-data:/data + networks: + - graphdb-config-network volumes: graphdb-data: graphdb-plugins: - + db-data: + networks: graphdb-config-network: driver: bridge \ No newline at end of file diff --git a/src/neo4j/get-doc-functions.js b/src/neo4j/get-doc-functions.js index 875f65331..9f86b3dc6 100644 --- a/src/neo4j/get-doc-functions.js +++ b/src/neo4j/get-doc-functions.js @@ -1,28 +1,86 @@ -async function loadDoc(data, docSocket, eleSocket) { - const { id, secret } = data; +import db from '../server/db.js'; +import _ from 'lodash'; +import fetch from 'node-fetch'; +import Document from '../model/document'; - const doc = new Document({ - socket: docSocket, - factoryOptions: { socket: eleSocket }, - data: { id, secret } - }); +// Goal: Be able to read in a document or list of documents and get +// 1) the id of the document (ex. 'a896d611-affe-4b45-a5e1-9bc560ffceab') +// 2) the pmid +// 3) the doi +// 4) the article title +// These four items will be a property of each edge - await doc.load(); - await doc.sync(true); +// For each Node/Gene element, get +// 1) dbPrefix (ex. 'ncbigene') +// 2) the id from that database, (ex. '207') +// 3) a name (ex. 'MAPK6') - return doc; +// For each Edge/Interaction element, get +// 1) element id (ex. '01ef22cc-2a8e-46d4-9060-6bf1c273869b') +// 2) type (ex. 'phosphorylation') +// 3) source id (gene the edge is pointing away from) +// 4) target id (gene the edge is pointing to) +// Note: In final product, source and target id should be in the form of 'ncbigene:207' or similar + +export function newDoc({ docDb, eleDb, id, secret, provided }) { + return new Document(_.assign({}, docDb, { + factoryOptions: eleDb, + data: _.assign({}, { id, secret, provided }) + })); +} + +export async function createDoc({ docDb, eleDb, id, secret, provided }) { + let doc = newDoc({ docDb, eleDb, id, secret, provided }); + + return doc.create().then(() => doc); +} + +export async function deleteDoc(doc) { + let clearRows = (db, secret) => db.table.filter({ secret }).delete().run(db.conn); + const { docDb, eleDb } = await loadTables(); + const elements = doc.elements(); + + // delete doc + const docSecret = doc.secret(); + await clearRows(docDb, docSecret); + + // delete elements + const eleSecrets = elements.map(e => e.secret()); + await Promise.all(eleSecrets.map(s => clearRows(eleDb, s))); +} + +let loadDoc = ({ docDb, eleDb, id, secret }) => { + let doc = newDoc({ docDb, eleDb, id, secret }); + + return doc.load().then(() => doc); +}; + +let tables = ['document', 'element']; + +let loadTable = name => db.accessTable(name); + +export async function loadTables() { + return Promise.all(tables.map(loadTable)).then(dbInfos => ({ + docDb: dbInfos[0], + eleDb: dbInfos[1] + })); } -async function toDocs(docJSONs, docSocket, eleSocket) { - const docPromises = docJSONs.map(async docJSON => await loadDoc(docJSON, docSocket, eleSocket)); +async function toDocs(docJSONs) { + const getID = docJSON => docJSON.id; + const { docDb, eleDb } = await loadTables(); + const docPromises = docJSONs.map(getID).map(async id => await loadDoc({ docDb, eleDb, id })); return Promise.all(docPromises); } -async function getAllDocs() {// eslint-disable-line no-unused-vars - const url = 'https://biofactoid.org/api/document/a896d611-affe-4b45-a5e1-9bc560ffceab'; +export async function getAllDocs() { + // todo eventually replace with rethinkdb query because http requests are inefficient + const url = 'http://localhost:3000/api/document/'; // my machine + // const url = 'https://biofactoid.org/api/document/a896d611-affe-4b45-a5e1-9bc560ffceab'; + // const url = 'https://biofactoid.org/api/document/'; const res = await fetch(`${url}`); const docJSONs = await res.json(); - return await toDocs(docJSONs, this.docSocket, this.eleSocket); + return await toDocs(docJSONs); } \ No newline at end of file diff --git a/src/neo4j/index.js b/src/neo4j/index.js new file mode 100644 index 000000000..fb5fa74f7 --- /dev/null +++ b/src/neo4j/index.js @@ -0,0 +1,2 @@ +export { addDocumentToNeo4j } from './neo4j-document'; +export { addNode, addEdge, neighbourhood } from './neo4j-functions'; \ No newline at end of file diff --git a/src/neo4j/neo4j-document.js b/src/neo4j/neo4j-document.js new file mode 100644 index 000000000..b3de64e1d --- /dev/null +++ b/src/neo4j/neo4j-document.js @@ -0,0 +1,168 @@ +import { addNode, addEdge } from './neo4j-functions'; + +/** + * @param { Document } doc : document model instance + * @param { String } id : UUID of an entity element in doc + * @returns string in the form of dbname:id (ex. 'ncbigene:207') if entity element + * if found, 'node not found' otherwise + */ +export function convertUUIDtoId(doc, id) { + let node = doc.get(id); + if (node) { + return `${node.association().dbPrefix}:${node.association().id}`; + } + return 'node not found'; +} + +function makeComponent(complex, doc) { + const component = []; + for (const entry of complex.elements()) { + component.push(convertUUIDtoId(doc, entry.id())); + } + return component; +} + +/** + * addDocumentToNeo4j takes a Document as a parameter and creates the associated nodes + * and edges in a Neo4j database + * @param { Document } doc : a document model instance + * @returns + */ +export async function addDocumentToNeo4j(doc) { + + // Step 1: Sort each element in a document into one of two categories + // a. Node/Gene + // b. Edge/Interaction + let arrNodes = []; + let arrEdges = []; + let docElements = doc.elements(); + for (const e of docElements) { + if (e.isEntity() && !e.isComplex()) { + let nodeInfo = { + id: `${e.association().dbPrefix}:${e.association().id}`, + name: e.association().name + }; + arrNodes.push(nodeInfo); + } else if (e.isEntity && e.isComplex()) { + const complex = e; + const component = makeComponent(complex, doc); + for (let i = 0; i < complex.elements().length; i++) { + for (let j = i + 1; j < complex.elements().length; j++) { + const sourceUUId = complex.elements()[i].id(); + const targetUUId = complex.elements()[j].id(); + const edgeInfo = { + id: complex.id(), + type: 'binding', + component: component, + sourceId: convertUUIDtoId(doc, sourceUUId), + targetId: convertUUIDtoId(doc, targetUUId), + sourceComplex: '', + targetComplex: '' + }; + arrEdges.push(edgeInfo); + } + } + } else { + let sourceUUId; + let targetUUId; + if (e.association().getSource()) { + sourceUUId = e.association().getSource().id(); + targetUUId = e.association().getTarget().id(); + } else { // if getSource() is null, this interaction is undirected + sourceUUId = e.elements()[0].id(); + targetUUId = e.elements()[1].id(); + } + + let source = doc.get(sourceUUId); + let target = doc.get(targetUUId); + + if (!source.isComplex() && !target.isComplex()) { + const edgeInfo = { + id: e.id(), + type: e.type(), + component: [], + sourceId: convertUUIDtoId(doc, sourceUUId), + targetId: convertUUIDtoId(doc, targetUUId), + sourceComplex: '', + targetComplex: '' + }; + arrEdges.push(edgeInfo); + } else if (source.isComplex() && !target.isComplex()) { + // sourceUUID is a complex and targetUUID is a noncomplex + const sourceComplex = doc.get(sourceUUId); + + for (let i = 0; i < sourceComplex.elements().length; i++) { + const complexElementSourceUUId = sourceComplex.elements()[i].id(); + const edgeInfo = { + id: e.id(), + type: e.type(), + component: [], + sourceId: convertUUIDtoId(doc, complexElementSourceUUId), + targetId: convertUUIDtoId(doc, targetUUId), + sourceComplex: sourceComplex.id(), + targetComplex: '' + }; + arrEdges.push(edgeInfo); + } + } else if (!source.isComplex() && target.isComplex()) { + // sourceUUID is a noncomplex and targetUUID is a complex + const targetComplex = doc.get(targetUUId); + + for (let i = 0; i < targetComplex.elements().length; i++) { + const complexElementTargetUUId = targetComplex.elements()[i].id(); + const edgeInfo = { + id: e.id(), + type: e.type(), + component: [], + sourceId: convertUUIDtoId(doc, sourceUUId), + targetId: convertUUIDtoId(doc, complexElementTargetUUId), + sourceComplex: '', + targetComplex: targetComplex.id() + }; + arrEdges.push(edgeInfo); + } + } else { + // sourceUUID is a complex and targetUUID is a complex + const sourceComplex = doc.get(sourceUUId); + const targetComplex = doc.get(targetUUId); + + for (let i = 0; i < sourceComplex.elements().length; i++) { + for (let j = 0; j < targetComplex.elements().length; j++) { + const complexElementSourceUUId = sourceComplex.elements()[i].id(); + const targetElementSourceUUId = targetComplex.elements()[j].id(); + const edgeInfo = { + id: e.id(), + type: e.type(), + component: [], + sourceId: convertUUIDtoId(doc, complexElementSourceUUId), + targetId: convertUUIDtoId(doc, targetElementSourceUUId), + sourceComplex: sourceComplex.id(), + targetComplex: targetComplex.id() + }; + arrEdges.push(edgeInfo); + } + } + } + } + } + + let docCitations = { + xref: doc.id(), + doi: doc.citation().doi ? doc.citation().doi : 'not found', + pmid: doc.citation().pmid ? doc.citation().pmid : 'not found', + articleTitle: doc.citation().title ? doc.citation().title : 'not found' + }; + + // Step 2: Make all the nodes + for (const node of arrNodes) { + await addNode(node.id, node.name); + } + + // Step 3: Make all the edges + for (const edge of arrEdges) { + await addEdge(edge.id, edge.type, edge.component, edge.sourceId, edge.targetId, edge.sourceComplex, edge.targetComplex, + docCitations.xref, docCitations.doi, docCitations.pmid, docCitations.articleTitle); + } + + return; +} diff --git a/src/neo4j/neo4j-functions.js b/src/neo4j/neo4j-functions.js index ad3f53a4f..f634c709b 100644 --- a/src/neo4j/neo4j-functions.js +++ b/src/neo4j/neo4j-functions.js @@ -1,43 +1,57 @@ -import neo4j from 'neo4j-driver'; -import { giveInfoByGeneId, makeNodeQuery, makeRelationshipQuery } from './query-strings'; -import { closeDriver, getDriver, initDriver } from './neo4j-driver'; +import { giveConnectedInfoByGeneId, makeNodeQuery, makeEdgeQuery, giveConnectedInfoByGeneIdNoComplexes } from './query-strings'; +import { getDriver } from './neo4j-driver'; +import _ from 'lodash'; +/** + * @param { String } id in the form of "dbName:dbId", ex: "ncbigene:207" + * @param { String } name + * @returns + */ export async function addNode(id, name) { - initDriver(); const driver = getDriver(); let session; try { session = driver.session({ database: "neo4j" }); - // eslint-disable-next-line no-unused-vars - let result = await session.executeWrite(tx => { + await session.executeWrite(tx => { return tx.run(makeNodeQuery, { id: id.toLowerCase(), name: name }); }); } catch (error) { - console.error(error); throw error; } finally { await session.close(); - closeDriver(); } return; } -export async function addEdge(id, type, sourceId, targetId, xref, doi, pmid, articleTitle) { - initDriver(); +/** + * @param { String } id interaction element's UUID (NOT document id) + * @param { String } type + * @param { String } sourceId in the form of "dbName:dbId", ex: "ncbigene:207" + * @param { String } targetId in the form of "dbName:dbId", ex: "ncbigene:207" + * @param { String } participantTypes 'noncomplex-to-noncomplex', 'complex-to-noncomplex', etc + * @param { String } xref document UUID + * @param { String } doi + * @param { String } pmid + * @param { String } articleTitle + * @returns + */ +export async function addEdge(id, type, component, sourceId, targetId, sourceComplex, targetComplex, xref, doi, pmid, articleTitle) { const driver = getDriver(); let session; try { session = driver.session({ database: "neo4j" }); - // eslint-disable-next-line no-unused-vars - let result = await session.executeWrite(tx => { - return tx.run(makeRelationshipQuery, { + await session.executeWrite(tx => { + return tx.run(makeEdgeQuery, { id: id.toLowerCase(), type: type, + component: component, sourceId: sourceId.toLowerCase(), targetId: targetId.toLowerCase(), + sourceComplex: sourceComplex.toLowerCase(), + targetComplex: targetComplex.toLowerCase(), xref: xref.toLowerCase(), doi: doi, pmid: pmid, @@ -45,38 +59,85 @@ export async function addEdge(id, type, sourceId, targetId, xref, doi, pmid, art }); }); } catch (error) { - console.error(error); throw error; } finally { await session.close(); - closeDriver(); } return; } -export async function searchByGeneId(id) { - initDriver(); +/** + * @param { String } id in the form of "dbName:dbId", ex: "ncbigene:207" + * @returns An object with 2 fields: relationships (array) and neighbouring nodes (array) or null + */ +export async function neighbourhood(id) { const driver = getDriver(); let session; + let record; try { session = driver.session({ database: "neo4j" }); let result = await session.executeRead(tx => { - return tx.run(giveInfoByGeneId, { id: id }); + return tx.run(giveConnectedInfoByGeneId, { id: id }); }); - let nodes = result.records.map(row => { - return row.get('m'); - }); - let edges = result.records.map(row => { - return row.get('r'); + if (result.records.length > 0) { + record = result.records; + } else { + record = null; + } + } catch (error) { + throw error; + } finally { + await session.close(); + } + return record; +} + +/** + * @param { String } id in the form of "dbName:dbId", ex: "ncbigene:207" + * @returns an array of nodes that are neighbours to the specified gene + */ +export async function getNeighbouringNodes(id) { + let record = await neighbourhood(id); + if (record) { + return _.uniqBy(record.map(row => { + return row.get('m').properties; + }), node => node.id); + } + return null; +} + +/** + * @param {*} id in the form of "dbName:dbId", ex: "ncbigene:207" + * @returns an array of relationships leading away from/leading to the specified gene + */ +export async function getInteractions(id) { + let record = await neighbourhood(id); + if (record) { + return _.uniqBy(record.map(row => { + return row.get('r').properties; + }), edge => edge.id); + } + return null; +} + +export async function neighbourhoodWithoutComplexes(id) { + const driver = getDriver(); + let session; + let record; + try { + session = driver.session({ database: "neo4j" }); + let result = await session.executeRead(tx => { + return tx.run(giveConnectedInfoByGeneIdNoComplexes, { id: id }); }); - console.log(nodes); - console.log(edges); + if (result.records.length > 0) { + record = result.records; + } else { + record = null; + } } catch (error) { - console.error(error); throw error; } finally { await session.close(); - closeDriver(); } - return; + return record; } \ No newline at end of file diff --git a/src/neo4j/query-strings.js b/src/neo4j/query-strings.js index 03de2fa86..0873ad7fd 100644 --- a/src/neo4j/query-strings.js +++ b/src/neo4j/query-strings.js @@ -1,20 +1,52 @@ export const makeNodeQuery = - `MERGE (gene:Gene {id: $id}) - ON CREATE SET gene.name = $name`; + `MERGE (n:Entity {id: $id}) + ON CREATE SET n.name = $name`; -export const makeRelationshipQuery = - `MATCH (x:Gene {id: $sourceId}) - MATCH (y:Gene {id: $targetId}) +export const makeEdgeQuery = + `MATCH (x:Entity {id: $sourceId}) + MATCH (y:Entity {id: $targetId}) MERGE (x)-[r:INTERACTION {id: $id}]->(y) ON CREATE SET r.type = $type, + r.component = $component, + r.sourceId = $sourceId, + r.targetId = $targetId, + r.sourceComplex = $sourceComplex, + r.targetComplex = $targetComplex, r.xref = $xref, r.doi = $doi, r.pmid = $pmid, r.articleTitle = $articleTitle`; -export const giveInfoByGeneId = - `MATCH (n:Gene {id: $id})<-[r]-(m) +export const giveConnectedInfoByGeneId = + `MATCH (n:Entity {id: $id})<-[r]-(m) RETURN n, r, m UNION - MATCH (n:Gene {id: $id})-[r]->(m) - RETURN n, r, m`; \ No newline at end of file + MATCH (n:Entity {id: $id})-[r]->(m) + RETURN n, r, m`; + +export const giveConnectedInfoByGeneIdNoComplexes = + `MATCH (n:Entity {id: $id})<-[r]-(m) + WHERE r.component = [] AND r.sourceComplex = '' AND r.targetComplex = '' + RETURN n, r, m + UNION + MATCH (n:Entity {id: $id})-[r]->(m) + WHERE r.component = [] AND r.sourceComplex = '' AND r.targetComplex = '' + RETURN n, r, m`; + +export const returnGene = + `MATCH (n {id: $id}) + RETURN n`; + +export const returnEdgeById = + `MATCH(n)-[r {id: $id}]->(m) + RETURN r`; + +export const returnEdgeByIdAndEndpoints = + `MATCH(n {id: $sourceId})-[r {id: $complexId}]->(m {id: $targetId}) + RETURN r`; + +export const deleteAll = `MATCH (n) DETACH DELETE n`; + +export const numNodes = `MATCH (n) RETURN COUNT(*) as count`; + +export const numEdges = `MATCH (n)-[r]->(m) RETURN COUNT(r) as count`; \ No newline at end of file diff --git a/src/neo4j/starting-neo4j.js b/src/neo4j/starting-neo4j.js deleted file mode 100644 index bdad7b663..000000000 --- a/src/neo4j/starting-neo4j.js +++ /dev/null @@ -1,102 +0,0 @@ -import neo4j from 'neo4j-driver'; -import { giveInfoByGeneId, makeNodeQuery, makeRelationshipQuery } from './query-strings'; -import { nodeData, relationshipData } from './graph-data'; - -const driver = neo4j.driver('bolt://localhost:7687'); - -// makes the MAPK6 node. Successful -export async function makeMAPK6Test() { - let session; - try { - session = driver.session({ database: "neo4j" }); - let result = await session.executeWrite(tx => { - return tx.run(makeNodeQuery, nodeData[0]); - }); - console.log("Gene Node created:", result.records[0].get('gene.name')); - } catch (error) { - console.error(error); - throw error; - } finally { - await session.close(); - driver.close(); - } - return; -} - -// makes both the MAPK6 node and the AKT node, then terminates. Successful -export async function makeGeneNodeTest() { - for (let i = 0; i < nodeData.length; i++) { - let session; - try { - session = driver.session({ database: "neo4j" }); - let result = await session.executeWrite(tx => { - return tx.run(makeNodeQuery, nodeData[i]); - }); - console.log("Gene Node created: ", result.records); - } catch (error) { - console.error(error); - throw error; - } finally { - await session.close(); - } - } - driver.close(); - console.log("Loop ends!"); - return; -} - -// makes the MAPK6 node, AKT node and the relationship between them. Successful -export async function test() { - let session; - try { - session = driver.session({ database: "neo4j" }); - const tx = session.beginTransaction(); - try { - // Step 1: Make the nodes - for (let i = 0; i < nodeData.length; i++) { - let result = await tx.run(makeNodeQuery, nodeData[i]); - console.log("Gene Node created: ", result.records); - } - - // Step 2: Make the relationship - tx.run(makeRelationshipQuery, relationshipData[0]); - console.log ("Relationship made!"); - - await tx.commit(); - } catch(error) { - await tx.rollback(); - console.error(error); - throw error; - } - } catch(error) { - console.error(error); - throw error; - } finally { - await session.close(); - } - driver.close(); - return; -} - -// this test reads the database. Use case of: user gives "ncbigene:207" and -// the database returns all nodes and relationships connected to it -export async function read1() { - let session; - try { - session = driver.session({ database: "neo4j" }); - let result = await session.executeRead(tx => { - return tx.run(giveInfoByGeneId, { id: 'ncbigene:207' }); - }); - let names = result.records.map(row => { - return row.get('m'); - }); - console.log(names); - } catch (error) { - console.error(error); - throw error; - } finally { - await session.close(); - driver.close(); - } - return; -} \ No newline at end of file diff --git a/src/neo4j/test-functions.js b/src/neo4j/test-functions.js new file mode 100644 index 000000000..519a45c52 --- /dev/null +++ b/src/neo4j/test-functions.js @@ -0,0 +1,129 @@ +import { numNodes, numEdges, deleteAll, returnEdgeById, returnEdgeByIdAndEndpoints, returnGene } from './query-strings'; +import { getDriver } from './neo4j-driver'; + +export async function getNode(id) { + const driver = getDriver(); + let session; + let node; + try { + session = driver.session({ database: "neo4j" }); + let result = await session.executeRead(tx => { + return tx.run(returnGene, { id: id }); + }); + if (result.records.length > 0) { + node = result.records[0].get('n'); + } else { + node = null; + } + } catch (error) { + throw error; + } finally { + await session.close(); + } + return node; +} + +export async function getGeneName(id) { + let node = await getNode(id); + if (node) { + return node.properties.name; + } + return null; +} + +export async function getEdge(id) { + const driver = getDriver(); + let session; + let edge; + try { + session = driver.session({ database: 'neo4j' }); + let result = await session.executeRead(tx => { + return tx.run(returnEdgeById, { id: id }); + }); + if (result.records.length > 0) { + edge = result.records[0].get('r'); + } else { + edge = null; + } + } catch (error) { + throw error; + } finally { + await session.close(); + } + return edge; +} + +export async function getEdgeByIdAndEndpoints(sourceId, targetId, complexId) { + const driver = getDriver(); + let session; + let edge; + try { + session = driver.session({ database: 'neo4j' }); + let result = await session.executeRead(tx => { + return tx.run(returnEdgeByIdAndEndpoints, + { sourceId: sourceId, targetId: targetId, complexId: complexId }); + }); + if (result.records.length > 0) { + edge = result.records[0].get('r'); + } else { + edge = null; + } + } catch (error) { + throw error; + } finally { + await session.close(); + } + return edge; +} + +export async function deleteAllNodesAndEdges() { + const driver = getDriver(); + let session; + try { + session = driver.session({ database: "neo4j" }); + await session.executeWrite(tx => { + return tx.run(deleteAll); + }); + } catch (error) { + throw error; + } finally { + await session.close(); + } + return; +} + +export async function getNumNodes() { + const driver = getDriver(); + let session; + let num; + try { + session = driver.session({ database: "neo4j" }); + let result = await session.executeRead(tx => { + return tx.run(numNodes); + }); + num = result.records[0].get(0).toNumber(); + } catch (error) { + throw error; + } finally { + await session.close(); + } + return num; +} + +export async function getNumEdges() { + const driver = getDriver(); + let session; + let num; + try { + session = driver.session({ database: "neo4j" }); + let result = await session.executeRead(tx => { + return tx.run(numEdges); + }); + num = result.records[0].get(0).toNumber(); + } catch (error) { + throw error; + } finally { + await session.close(); + } + return num; +} \ No newline at end of file diff --git a/src/neo4j/test-temp-run.js b/src/neo4j/test-temp-run.js deleted file mode 100644 index 3d86b96e4..000000000 --- a/src/neo4j/test-temp-run.js +++ /dev/null @@ -1,31 +0,0 @@ -import { addNode, addEdge, searchByGeneId } from './neo4j-functions'; - -async function testingFunctions() { - console.log("Begin test"); - // Add MAPK6 Node - await addNode('ncbigene:5597', 'MAPK6'); - - // Add AKT Node - await addNode('ncbigene:207', 'AKT'); - - // Add Interaction - await addEdge( - '01ef22cc-2a8e-46d4-9060-6bf1c273869b', - 'phosphorylation', - 'ncbigene:5597', - 'ncbigene:207', - 'a896d611-affe-4b45-a5e1-9bc560ffceab', - '10.1126/sciadv.abi6439', - '34767444', - 'MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.' - ); - - // Search for MAPK6 - await searchByGeneId("ncbigene:5597"); - // Search for AKT - await searchByGeneId("ncbigene:207"); - - console.log("End test"); -} - -testingFunctions(); \ No newline at end of file diff --git a/src/server/routes/api/document/index.js b/src/server/routes/api/document/index.js index 6f3e3ad42..3fa754511 100644 --- a/src/server/routes/api/document/index.js +++ b/src/server/routes/api/document/index.js @@ -11,6 +11,7 @@ import emailRegex from 'email-regex'; import url from 'url'; import { URLSearchParams } from 'url'; import NodeCache from 'node-cache'; +import pLimit from './p-limit'; import { tryPromise, makeStaticStylesheet, makeCyEles, truncateString } from '../../../../util'; import { msgFactory, updateCorrespondence, EmailError } from '../../../email'; @@ -54,9 +55,12 @@ import { BASE_URL, BIOPAX_DOWNLOADS_PATH, BIOPAX_IDMAP_DOWNLOADS_PATH, ORCID_PUBLIC_API_BASE_URL, - DOI_LINK_BASE_URL + DOI_LINK_BASE_URL, + DOCUMENT_IMAGE_PLL_LIMIT } from '../../../../config'; + + import { ENTITY_TYPE } from '../../../../model/element/entity-type'; import { eLink, elink2UidList } from './pubmed/linkPubmed'; import { fetchPubmed } from './pubmed/fetchPubmed'; @@ -224,7 +228,7 @@ const mapToUniprotIds = biopaxTemplate => { if ( dbPrefix !== 'ncbigene' ){ return Promise.resolve(); } - + const UNIPROT_DB_PREFIX = 'uniprot'; const opts = { id: [ @@ -1407,6 +1411,12 @@ const getDocumentImageBuffer = doc => { ); }; +const imgLimit = pLimit(DOCUMENT_IMAGE_PLL_LIMIT); + +const getDocumentImageBufferRatedLimited = doc => { + return imgLimit(() => getDocumentImageBuffer(doc)); +}; + const imageCache = new LRUCache({ max: DOCUMENT_IMAGE_CACHE_SIZE }); @@ -1441,26 +1451,32 @@ http.get('/(:id).png', function( req, res, next ){ res.setHeader('content-type', 'image/png'); - const fillCache = async (doc, lastEditedDate) => { - const img = await getDocumentImageBuffer(doc); - const cache = { img, lastEditedDate }; + const calcTtl = doc => { + const now = Date.now(); + const lastEditedDate = doc.lastEditedDate(); + return now - lastEditedDate; + }; + + const fillCache = async doc => { + const img = await getDocumentImageBufferRatedLimited(doc); + const cache = { img }; + const ttl = calcTtl(doc); - imageCache.set(id, cache); + imageCache.set(id, cache, {ttl}); return cache; }; const main = async () => { try { - const doc = await getDoc(id); - const lastEditedDate = '' + doc.lastEditedDate(); - const cache = imageCache.get(id); - const canUseCache = imageCache.has(id) && cache.lastEditedDate === lastEditedDate; + const canUseCache = imageCache.has(id); if( canUseCache ){ + const cache = imageCache.get(id); res.send(cache.img); } else { - const cache = await fillCache(doc, lastEditedDate); + const doc = await getDoc(id); + const cache = await fillCache(doc); res.send(cache.img); } diff --git a/src/server/routes/api/document/p-limit.js b/src/server/routes/api/document/p-limit.js new file mode 100644 index 000000000..9766dc0dc --- /dev/null +++ b/src/server/routes/api/document/p-limit.js @@ -0,0 +1,151 @@ +/** + * This file is jury-rigged. It's the entire transitive code of 'p-limit'. + * + * - p-limit does not support CJS. + * - esm does not support p-limit. + * - This could be resolved in future by upgrading the entire project to use built-in ESM + * in new versions of node. However, all the imports would need to be changed. It would + * be a major project. + */ + + + + + + + + +/* +How it works: +`this.#head` is an instance of `Node` which keeps track of its current value and nests another instance of `Node` that keeps the value that comes after it. When a value is provided to `.enqueue()`, the code needs to iterate through `this.#head`, going deeper and deeper to find the last value. However, iterating through every single item is slow. This problem is solved by saving a reference to the last value as `this.#tail` so that it can reference it to add a new value. +*/ + +class Node { + value; + next; + + constructor(value) { + this.value = value; + } +} + +class Queue { + #head; + #tail; + #size; + + constructor() { + this.clear(); + } + + enqueue(value) { + const node = new Node(value); + + if (this.#head) { + this.#tail.next = node; + this.#tail = node; + } else { + this.#head = node; + this.#tail = node; + } + + this.#size++; + } + + dequeue() { + const current = this.#head; + if (!current) { + return; + } + + this.#head = this.#head.next; + this.#size--; + return current.value; + } + + clear() { + this.#head = undefined; + this.#tail = undefined; + this.#size = 0; + } + + get size() { + return this.#size; + } + + * [Symbol.iterator]() { + let current = this.#head; + + while (current) { + yield current.value; + current = current.next; + } + } +} + +export default function pLimit(concurrency) { + if (!((Number.isInteger(concurrency) || concurrency === Number.POSITIVE_INFINITY) && concurrency > 0)) { + throw new TypeError('Expected `concurrency` to be a number from 1 and up'); + } + + const queue = new Queue(); + let activeCount = 0; + + const next = () => { + activeCount--; + + if (queue.size > 0) { + queue.dequeue()(); + } + }; + + const run = async (fn, resolve, args) => { + activeCount++; + + const result = (async () => fn(...args))(); + + resolve(result); + + try { + await result; + } catch {} + + next(); + }; + + const enqueue = (fn, resolve, args) => { + queue.enqueue(run.bind(undefined, fn, resolve, args)); + + (async () => { + // This function needs to wait until the next microtask before comparing + // `activeCount` to `concurrency`, because `activeCount` is updated asynchronously + // when the run function is dequeued and called. The comparison in the if-statement + // needs to happen asynchronously as well to get an up-to-date value for `activeCount`. + await Promise.resolve(); + + if (activeCount < concurrency && queue.size > 0) { + queue.dequeue()(); + } + })(); + }; + + const generator = (fn, ...args) => new Promise(resolve => { + enqueue(fn, resolve, args); + }); + + Object.defineProperties(generator, { + activeCount: { + get: () => activeCount, + }, + pendingCount: { + get: () => queue.size, + }, + clearQueue: { + value: () => { + queue.clear(); + }, + }, + }); + + return generator; +} diff --git a/test/data/document.json b/test/data/document.json new file mode 100644 index 000000000..111fc2f70 --- /dev/null +++ b/test/data/document.json @@ -0,0 +1,1218 @@ +{ + "organisms": [ + 9606, + 10090, + "9606" + ], + "elements": [], + "publicUrl": "/document/5df17c41-acb7-4c42-a37b-fe323688bc64", + "privateUrl": "/document/5df17c41-acb7-4c42-a37b-fe323688bc64", + "citation": { + "title": "SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism.", + "authors": { + "abbreviation": "Tianshi Wang, Ying Cao, Quan Zheng, ..., Jinke Cheng", + "contacts": [ + { + "name": "Tianshi Wang", + "email": [ + "tianshi777@shsmu.edu.cn" + ], + "ForeName": "Tianshi", + "LastName": "Wang" + }, + { + "name": "Jinke Cheng", + "email": [ + "jkcheng@shsmu.edu.cn" + ], + "ForeName": "Jinke", + "LastName": "Cheng" + } + ], + "authorList": [ + { + "name": "Tianshi Wang", + "ForeName": "Tianshi", + "LastName": "Wang", + "email": "tianshi777@shsmu.edu.cn", + "abbrevName": "Wang T", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Ying Cao", + "ForeName": "Ying", + "LastName": "Cao", + "email": null, + "abbrevName": "Cao Y", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Quan Zheng", + "ForeName": "Quan", + "LastName": "Zheng", + "email": null, + "abbrevName": "Zheng Q", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jun Tu", + "ForeName": "Jun", + "LastName": "Tu", + "email": null, + "abbrevName": "Tu J", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Wei Zhou", + "ForeName": "Wei", + "LastName": "Zhou", + "email": null, + "abbrevName": "Zhou W", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jianli He", + "ForeName": "Jianli", + "LastName": "He", + "email": null, + "abbrevName": "He J", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jie Zhong", + "ForeName": "Jie", + "LastName": "Zhong", + "email": null, + "abbrevName": "Zhong J", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Yalan Chen", + "ForeName": "Yalan", + "LastName": "Chen", + "email": null, + "abbrevName": "Chen Y", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jiqiu Wang", + "ForeName": "Jiqiu", + "LastName": "Wang", + "email": null, + "abbrevName": "Wang J", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Rong Cai", + "ForeName": "Rong", + "LastName": "Cai", + "email": null, + "abbrevName": "Cai R", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Yong Zuo", + "ForeName": "Yong", + "LastName": "Zuo", + "email": null, + "abbrevName": "Zuo Y", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Bo Wei", + "ForeName": "Bo", + "LastName": "Wei", + "email": null, + "abbrevName": "Wei B", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Qiuju Fan", + "ForeName": "Qiuju", + "LastName": "Fan", + "email": null, + "abbrevName": "Fan Q", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jie Yang", + "ForeName": "Jie", + "LastName": "Yang", + "email": null, + "abbrevName": "Yang J", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Yicheng Wu", + "ForeName": "Yicheng", + "LastName": "Wu", + "email": null, + "abbrevName": "Wu Y", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jing Yi", + "ForeName": "Jing", + "LastName": "Yi", + "email": null, + "abbrevName": "Yi J", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Dali Li", + "ForeName": "Dali", + "LastName": "Li", + "email": null, + "abbrevName": "Li D", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Mingyao Liu", + "ForeName": "Mingyao", + "LastName": "Liu", + "email": null, + "abbrevName": "Liu M", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Chuangui Wang", + "ForeName": "Chuangui", + "LastName": "Wang", + "email": null, + "abbrevName": "Wang C", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Aiwu Zhou", + "ForeName": "Aiwu", + "LastName": "Zhou", + "email": null, + "abbrevName": "Zhou A", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Yu Li", + "ForeName": "Yu", + "LastName": "Li", + "email": null, + "abbrevName": "Li Y", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Xuefeng Wu", + "ForeName": "Xuefeng", + "LastName": "Wu", + "email": null, + "abbrevName": "Wu X", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Wen Yang", + "ForeName": "Wen", + "LastName": "Yang", + "email": null, + "abbrevName": "Yang W", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Y Eugene Chin", + "ForeName": "Y", + "LastName": "Chin", + "email": null, + "abbrevName": "Chin YE", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Guoqiang Chen", + "ForeName": "Guoqiang", + "LastName": "Chen", + "email": null, + "abbrevName": "Chen G", + "isCollectiveName": false, + "orcid": null + }, + { + "name": "Jinke Cheng", + "ForeName": "Jinke", + "LastName": "Cheng", + "email": "jkcheng@shsmu.edu.cn", + "abbrevName": "Cheng J", + "isCollectiveName": false, + "orcid": null + } + ] + }, + "reference": "Mol Cell 75 2019", + "abstract": "Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.", + "pmid": "31302001", + "doi": "10.1016/j.molcel.2019.06.008", + "pubTypes": [ + { + "UI": "D016428", + "value": "Journal Article" + }, + { + "UI": "D013485", + "value": "Research Support, Non-U.S. Gov't" + } + ], + "ISODate": "2019-08-22T00:00:00.000Z" + }, + "text": "senp1 activates sirt3.", + "createdDate": "2019-09-05T14:29:27.000Z", + "lastEditedDate": "2019-09-06T01:21:01.000Z", + "status": "public", + "verified": true, + "authorProfiles": [ + { + "ForeName": "Tianshi", + "LastName": "Wang", + "abbrevName": "Wang T", + "email": "tianshi777@shsmu.edu.cn", + "isCollectiveName": false, + "name": "Tianshi Wang", + "orcid": null + }, + { + "ForeName": "Ying", + "LastName": "Cao", + "abbrevName": "Cao Y", + "email": null, + "isCollectiveName": false, + "name": "Ying Cao", + "orcid": null + }, + { + "ForeName": "Quan", + "LastName": "Zheng", + "abbrevName": "Zheng Q", + "email": null, + "isCollectiveName": false, + "name": "Quan Zheng", + "orcid": null + }, + { + "ForeName": "Jun", + "LastName": "Tu", + "abbrevName": "Tu J", + "email": null, + "isCollectiveName": false, + "name": "Jun Tu", + "orcid": null + }, + { + "ForeName": "Wei", + "LastName": "Zhou", + "abbrevName": "Zhou W", + "email": null, + "isCollectiveName": false, + "name": "Wei Zhou", + "orcid": null + }, + { + "ForeName": "Jianli", + "LastName": "He", + "abbrevName": "He J", + "email": null, + "isCollectiveName": false, + "name": "Jianli He", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Zhong", + "abbrevName": "Zhong J", + "email": null, + "isCollectiveName": false, + "name": "Jie Zhong", + "orcid": null + }, + { + "ForeName": "Yalan", + "LastName": "Chen", + "abbrevName": "Chen Y", + "email": null, + "isCollectiveName": false, + "name": "Yalan Chen", + "orcid": null + }, + { + "ForeName": "Jiqiu", + "LastName": "Wang", + "abbrevName": "Wang J", + "email": null, + "isCollectiveName": false, + "name": "Jiqiu Wang", + "orcid": "0000-0002-9383-7656" + }, + { + "ForeName": "Rong", + "LastName": "Cai", + "abbrevName": "Cai R", + "email": null, + "isCollectiveName": false, + "name": "Rong Cai", + "orcid": null + }, + { + "ForeName": "Yong", + "LastName": "Zuo", + "abbrevName": "Zuo Y", + "email": null, + "isCollectiveName": false, + "name": "Yong Zuo", + "orcid": null + }, + { + "ForeName": "Bo", + "LastName": "Wei", + "abbrevName": "Wei B", + "email": null, + "isCollectiveName": false, + "name": "Bo Wei", + "orcid": null + }, + { + "ForeName": "Qiuju", + "LastName": "Fan", + "abbrevName": "Fan Q", + "email": null, + "isCollectiveName": false, + "name": "Qiuju Fan", + "orcid": null + }, + { + "ForeName": "Jie", + "LastName": "Yang", + "abbrevName": "Yang J", + "email": null, + "isCollectiveName": false, + "name": "Jie Yang", + "orcid": null + }, + { + "ForeName": "Yicheng", + "LastName": "Wu", + "abbrevName": "Wu Y", + "email": null, + "isCollectiveName": false, + "name": "Yicheng Wu", + "orcid": null + }, + { + "ForeName": "Jing", + "LastName": "Yi", + "abbrevName": "Yi J", + "email": null, + "isCollectiveName": false, + "name": "Jing Yi", + "orcid": null + }, + { + "ForeName": "Dali", + "LastName": "Li", + "abbrevName": "Li D", + "email": null, + "isCollectiveName": false, + "name": "Dali Li", + "orcid": "0000-0002-0046-8493" + }, + { + "ForeName": "Mingyao", + "LastName": "Liu", + "abbrevName": "Liu M", + "email": null, + "isCollectiveName": false, + "name": "Mingyao Liu", + "orcid": null + }, + { + "ForeName": "Chuangui", + "LastName": "Wang", + "abbrevName": "Wang C", + "email": null, + "isCollectiveName": false, + "name": "Chuangui Wang", + "orcid": null + }, + { + "ForeName": "Aiwu", + "LastName": "Zhou", + "abbrevName": "Zhou A", + "email": null, + "isCollectiveName": false, + "name": "Aiwu Zhou", + "orcid": null + }, + { + "ForeName": "Yu", + "LastName": "Li", + "abbrevName": "Li Y", + "email": null, + "isCollectiveName": false, + "name": "Yu Li", + "orcid": null + }, + { + "ForeName": "Xuefeng", + "LastName": "Wu", + "abbrevName": "Wu X", + "email": null, + "isCollectiveName": false, + "name": "Xuefeng Wu", + "orcid": null + }, + { + "ForeName": "Wen", + "LastName": "Yang", + "abbrevName": "Yang W", + "email": null, + "isCollectiveName": false, + "name": "Wen Yang", + "orcid": null + }, + { + "ForeName": "Y", + "LastName": "Chin", + "abbrevName": "Chin YE", + "email": null, + "isCollectiveName": false, + "name": "Y Eugene Chin", + "orcid": null + }, + { + "ForeName": "Guoqiang", + "LastName": "Chen", + "abbrevName": "Chen G", + "email": null, + "isCollectiveName": false, + "name": "Guoqiang Chen", + "orcid": null + }, + { + "ForeName": "Jinke", + "LastName": "Cheng", + "abbrevName": "Cheng J", + "email": "jkcheng@shsmu.edu.cn", + "isCollectiveName": false, + "name": "Jinke Cheng", + "orcid": null + } + ], + "article": { + "MedlineCitation": { + "Article": { + "Abstract": "Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.", + "ArticleTitle": "SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism.", + "AuthorList": [ + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: tianshi777@shsmu.edu.cn.", + "email": [ + "tianshi777@shsmu.edu.cn" + ] + } + ], + "CollectiveName": null, + "ForeName": "Tianshi", + "Identifier": [], + "Initials": "T", + "LastName": "Wang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Ying", + "Identifier": [], + "Initials": "Y", + "LastName": "Cao" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Quan", + "Identifier": [], + "Initials": "Q", + "LastName": "Zheng" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jun", + "Identifier": [], + "Initials": "J", + "LastName": "Tu" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Wei", + "Identifier": [], + "Initials": "W", + "LastName": "Zhou" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jianli", + "Identifier": [], + "Initials": "J", + "LastName": "He" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jie", + "Identifier": [], + "Initials": "J", + "LastName": "Zhong" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Yalan", + "Identifier": [], + "Initials": "Y", + "LastName": "Chen" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Jiqiu", + "Identifier": [], + "Initials": "J", + "LastName": "Wang" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.", + "email": null + } + ], + "CollectiveName": null, + "ForeName": "Rong", + "Identifier": [], + "Initials": "R", + "LastName": "Cai" + }, + { + "AffiliationInfo": [ + { + "Affiliation": "Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 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"PubMedPubDate": { + "Day": "16", + "Month": "7", + "Year": "2019" + }, + "PubStatus": "pubmed" + }, + { + "PubMedPubDate": { + "Day": "29", + "Month": "1", + "Year": "2020" + }, + "PubStatus": "medline" + }, + { + "PubMedPubDate": { + "Day": "15", + "Month": "7", + "Year": "2019" + }, + "PubStatus": "entrez" + } + ], + "ReferenceList": [] + } + } +} \ No newline at end of file diff --git a/test/document.js b/test/document.js index be7003aae..f4f582871 100644 --- a/test/document.js +++ b/test/document.js @@ -1,5 +1,7 @@ import * as conf from './util/conf'; +import fs from 'fs'; +import path from 'path'; import { expect } from 'chai'; import Syncher from '../src/model/syncher'; import ElementFactory from '../src/model/element/factory'; @@ -19,6 +21,8 @@ const TAXON_ID_2 = 10090; const NS = 'document_tests'; const NS_ELE = 'document_tests_elements'; +const docJson = JSON.parse( fs.readFileSync( path.resolve( __dirname, './data/document.json' ), 'utf8' ) ); + describe('Document', function(){ let doc; let intn; @@ -91,6 +95,13 @@ describe('Document', function(){ expect( intn.has( ent ), 'intn has ent' ).to.be.true; }); + + it('generates a citation given an article"', async function(){ + await doc.fromJson(docJson); + const { title } = doc.citation(); + expect( title ).to.not.be.null; + expect( title ).to.be.a('string'); + }); } describe('(client)', function(){ @@ -697,4 +708,5 @@ describe('Document', function(){ }); }); }); + });