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Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation.
Proc Natl Acad Sci U S A. 2019 02 26; 116(9):3524-3529.PN

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-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.

Authors+Show Affiliations

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111.Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016.Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111.Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111.MacCHESS, Cornell University, Ithaca, NY 14853.Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; philim01@nyulangone.org Jinhua.wu@fccc.edu.Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111; philim01@nyulangone.org Jinhua.wu@fccc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30733287

Citation

Chang, Yu-Chung, et al. "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, vol. 116, no. 9, 2019, pp. 3524-3529.
Chang YC, Su W, Cho EA, et al. Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation. Proc Natl Acad Sci USA. 2019;116(9):3524-3529.
Chang, Y. C., Su, W., Cho, E. A., Zhang, H., Huang, Q., Philips, M. R., & Wu, J. (2019). 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, 116(9), 3524-3529. https://doi.org/10.1073/pnas.1818880116
Chang YC, et al. Molecular Basis for Autoinhibition of RIAM Regulated By FAK in Integrin Activation. Proc Natl Acad Sci USA. 2019 02 26;116(9):3524-3529. PubMed PMID: 30733287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation. AU - Chang,Yu-Chung, AU - Su,Wenjuan, AU - Cho,Eun-Ah, AU - Zhang,Hao, AU - Huang,Qingqiu, AU - Philips,Mark R, AU - Wu,Jinhua, Y1 - 2019/02/07/ PY - 2019/2/9/pubmed PY - 2019/5/3/medline PY - 2019/2/9/entrez KW - RIAM KW - autoinhibition KW - focal adhesion kinase KW - integrin signaling KW - small GTPase SP - 3524 EP - 3529 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 116 IS - 9 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/30733287/Molecular_basis_for_autoinhibition_of_RIAM_regulated_by_FAK_in_integrin_activation L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=30733287 DB - PRIME DP - Unbound Medicine ER -