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Phosphorylation of RIAM by Src Promotes Integrin Activation by Unmasking the PH Domain of RIAM
Structure. 2021 Apr 1;29(4) :320-329 e4
PMID: 33275877 PMCID: PMC8026550 URL: https://www.ncbi.nlm.nih.gov/pubmed/33275877
AbstractIntegrin activation controls cell adhesion, migration, invasion, and extracellular matrix remodeling. RIAM (RAP1-GTP-interacting adaptor molecule) is recruited by activated RAP1 to the plasma membrane (PM) to mediate integrin activation via an inside-out signaling pathway. This process requires the association of the pleckstrin homology (PH) domain of RIAM with the membrane PIP2. We identify a conserved intermolecular interface that masks the PIP2-binding site in the PH domains of RIAM. Our data indicate that phosphorylation of RIAM by Src family kinases disrupts this PH-mediated interface, unmasks the membrane PIP2-binding site, and promotes integrin activation. We further demonstrate that this process requires phosphorylation of Tyr267 and Tyr427 in the RIAM PH domain by Src. Our data reveal an unorthodox regulatory mechanism of small GTPase effector proteins by phosphorylation-dependent PM association of the PH domain and provide new insights into the link between Src kinases and integrin signaling.
Notes1878-4186 Cho, Eun-Ah Zhang, Pingfeng Kumar, Vikas Kavalchuk, Mikhail Zhang, Hao Huang, Qingqiu Duncan, James S Wu, Jinhua Journal Article United States Structure. 2020 Nov 27:S0969-2126(20)30423-8. doi: 10.1016/j.str.2020.11.011.