title: RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences.
abstract: Rap1 small GTPases interact with Rap1-GTP-interacting adaptor molecule (RIAM), a member of the MRL (Mig-10/RIAM/Lamellipodin) protein family, to promote talin-dependent integrin activation. Here, we show that MRL proteins function as scaffolds that connect the membrane targeting sequences in Ras GTPases to talin, thereby recruiting talin to the plasma membrane and activating integrins. The MRL proteins bound directly to talin via short, N-terminal sequences predicted to form amphipathic helices. RIAM-induced integrin activation required both its capacity to bind to Rap1 and to talin. Moreover, we constructed a minimized 50-residue Rap-RIAM module containing the talin binding site of RIAM joined to the membrane-targeting sequence of Rap1A. This minimized Rap-RIAM module was sufficient to target talin to the plasma membrane and to mediate integrin activation, even in the absence of Rap1 activity. We identified a short talin binding sequence in Lamellipodin (Lpd), another MRL protein; talin binding Lpd sequence joined to a Rap1 membrane-targeting sequence is sufficient to recruit talin and activate integrins. These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093-0726, USA.
authors.forename: Ho-Sup
authors.initials: HS
authors.lastname: Lee
authors.forename: Chinten James
authors.initials: CJ
authors.lastname: Lim
authors.forename: Wilma
authors.initials: W
authors.lastname: Puzon-McLaughlin
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016608:Talin / Q000235:genetics / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C493340:APBB1IP protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016023:Integrins; D008565:Membrane Proteins; D021382:Protein Sorting Signals; C430803:RAP1A protein, human; C493339:RAPH1 protein, human; D016608:Talin; D016283:Proto-Oncogene Proteins p21(ras); D020827:rap1 GTP-Binding Proteins