Structure
Volume 29, Issue 4, 1 April 2021, Pages 320-329.e4
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Article
Phosphorylation of RIAM by src promotes integrin activation by unmasking the PH domain of RIAM

https://doi.org/10.1016/j.str.2020.11.011Get rights and content
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Highlights

  • All crystal structures of RIAM RA-PH possess a common interface

  • The PIP2-binding site of the PH domain is masked by the interface

  • Phosphorylation of RIAM by Src family kinases promotes RIAM translocation to the PM

  • Phosphorylation of Y267 and Y427 is essential for RIAM-mediated integrin activation

Summary

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.

Keywords

RIAM
RAP1
lamellipodin
integrin signaling
PIP2 binding
Src kinase
LCK
FYN
phosphorylation
PH domain

Cited by (0)

4

Present address: Cancer Center at Renmin Hospital of Wuhan University, Wuhan 430062, China

5

Present address: Department of Biology, ETH Zürich, Zürich, Switzerland

6

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