Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation

Proceedings of the National Academy of Sciences of the United States of America - Tập 116 Số 9 - Trang 3524-3529 - 2019
Yu-Chung Chang1, Wenjuan Su2, Eun-Ah Cho1, Hao Zhang1, Qingqiu Huang3, Mark R. Philips2, Jinhua Wu1
1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111;
2Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; and
3MacCHESS, Cornell University, Ithaca, NY 14853

Tóm tắt

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-Å. 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.

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Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 116 Số 9

3524-3529

Thông tin tác giả