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Phosphorylation of RIAM by src promotes integrin activation by unmasking the PH domain of RIAM
Structure ( IF 5.7 ) Pub Date : 2020-12-03 , DOI: 10.1016/j.str.2020.11.011
Eun-Ah Cho 1 , Pingfeng Zhang 1 , Vikas Kumar 2 , Mikhail Kavalchuk 1 , Hao Zhang 1 , Qingqiu Huang 3 , James S Duncan 2 , Jinhua Wu 1
Affiliation  

Integrin 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.



中文翻译:

src 对 RIAM 的磷酸化通过揭示 RIAM 的 PH 结构域促进整合素活化

整合素激活控制细胞粘附、迁移、侵袭和细胞外基质重塑。RIAM(RAP1-GTP 相互作用的衔接分子)被激活的 RAP1 募集到质膜 (PM) 以通过由内向外的信号通路介导整合素的激活。该过程需要将 RIAM 的 pleckstrin 同源性 (PH) 结构域与膜 PIP2 关联。我们确定了一个保守的分子间界面,它掩盖了 RIAM PH 域中的 PIP2 结合位点。我们的数据表明,Src 家族激酶对 RIAM 的磷酸化破坏了这种 PH 介导的界面,揭示了膜 PIP2 结合位点,并促进了整合素的激活。我们进一步证明该过程需要 Src 磷酸化 RIAM PH 域中的 Tyr267 和 Tyr427。

更新日期:2020-12-03
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