期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 9, 页码 3524-3529出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1818880116
关键词
RIAM; integrin signaling; focal adhesion kinase; autoinhibition; small GTPase
资金
- NIH [GM119560, CA163489]
- Pennsylvania Department of Health [4100068716]
- American Cancer Society [RSG-15-167-01-DMC]
- Cancer Center Support Grant [5P30CA006927-51]
- Elizabeth Knight Patterson Postdoctoral Fellowship
- [T32 CA09035-41]
RAP1-interacting adapter molecule (RIAM) mediates RAP1-induced integrin activation. The RAS-association (RA) segment of the RAPH 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 bywhich 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.
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