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Chang YC , Su W , Cho EA , Zhang H , Huang Q , Philips MR , Wu J
Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation
Proc Natl Acad Sci U S A. 2019 Feb 26;116(9) :3524-3529
PMID: 30733287    PMCID: PMC6397589   
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Abstract
RAP1-interacting adapter molecule (RIAM) mediates RAP1-induced integrin activation. The RAS-association (RA) segment of the RA-PH module of RIAM interacts with GTP-bound RAP1 and phosphoinositol 4,5 bisphosphate but this interaction is inhibited by the N-terminal segment of RIAM. Here we report the structural basis for the autoinhibition of RIAM by an intramolecular interaction between the IN region (aa 27-93) and the RA-PH module. We solved the crystal structure of IN-RA-PH to a resolution of 2.4-A. The structure reveals that the IN segment associates with the RA segment and thereby suppresses RIAM:RAP1 association. This autoinhibitory configuration of RIAM can be released by phosphorylation at Tyr45 in the IN segment. Specific inhibitors of focal adhesion kinase (FAK) blocked phosphorylation of Tyr45, inhibited stimulated translocation of RIAM to the plasma membrane, and inhibited integrin-mediated cell adhesion in a Tyr45-dependent fashion. Our results reveal an unusual regulatory mechanism in small GTPase signaling by which the effector molecule is autoinhibited for GTPase interaction, and a modality of integrin activation at the level of RIAM through a FAK-mediated feedforward mechanism that involves reversal of autoinhibition by a tyrosine kinase associated with integrin signaling.
Notes
1091-6490 Chang, Yu-Chung Su, Wenjuan Cho, Eun-Ah Zhang, Hao Huang, Qingqiu Philips, Mark R ORCID: http://orcid.org/0000-0002-1179-8156 Wu, Jinhua ORCID: http://orcid.org/0000-0001-5913-0633 Journal Article United States P30 CA006927/CA/NCI NIH HHS/ R01 CA163489/CA/NCI NIH HHS/ R35 GM119560/GM/NIGMS NIH HHS/ T32 CA009035/CA/NCI NIH HHS/ Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3524-3529. doi: 10.1073/pnas.1818880116. Epub 2019 Feb 7.