title: Two modes of integrin activation form a binary molecular switch in adhesion maturation.
abstract: Talin-mediated integrin activation drives integrin-based adhesions. Here we examine the roles of two proteins that induce talin-integrin interactions--vinculin and Rap1-GTP-interacting adaptor molecule (RIAM)--in the formation and maturation of integrin-based adhesions. RIAM-containing adhesions are primarily in the lamellipodium; RIAM is subsequently reduced in mature focal adhesions due to direct competition with vinculin for talin-binding sites. We show that vinculin binding to talin induces Rap1-independent association of talin with integrins and resulting integrin activation, in sharp contrast to Rap1-dependent RIAM-induced activation. Vinculin stabilizes adhesions, increasing their ability to transmit force, whereas RIAM played a critical role in lamellipodial protrusion. Thus displacement of RIAM by vinculin acts as a molecular switch that mediates the transition of integrin-based adhesions from drivers of lamellipodial protrusion to stable, force-bearing adhesions. Consequently changes in the abundance of two multiprotein modules within maturing adhesions, one regulated by Rap1 and one by tension, result in the temporal evolution of adhesion functions.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ho-Sup
authors.initials: HS
authors.lastname: Lee
authors.forename: Praju
authors.initials: P
authors.lastname: Anekal
authors.forename: Chinten James
authors.initials: CJ
authors.lastname: Lim
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Liu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002448:Cell Adhesion; D002645:Chickens; D003412:Cricetulus; D022001:Focal Adhesions / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D000089804:Shelterin Complex; D016608:Talin / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism
chemical_list: C493340:APBB1IP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; D008565:Membrane Proteins; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D016608:Talin; D034501:Telomere-Binding Proteins; C488955:VCL protein, human; D016596:Vinculin