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Free keywords:
TYROSINE KINASES; PTB DOMAIN; SH2 DOMAIN; MYOSIN-II; BINDING; PROTEIN;
ADHESION; ADHESOME; GROWTH; TALINCell Biology;
Abstract:
Integrins mediate cell adhesion by connecting the extracellular matrix to the intracellular cytoskeleton and orchestrate signal transduction in response to chemical and mechanical stimuli by interacting with many cytoplasmic proteins. We used BioID to interrogate the interactomes of beta 1 and beta 3 integrins in epithelial cells and identified PEAK1 as an interactor of the RGD-binding integrins alpha 5 beta 1, alpha V beta 3, and alpha V beta 5 in focal adhesions. We demonstrate that the interaction between integrins and PEAK1 occurs indirectly through Tensin3, requiring both the membrane-proximal NPxY motif on the integrin beta tail and binding of the SH2 domain of Tensin3 to phosphorylated Tyr-635 on PEAK1. Phosphorylation of Tyr-635 is mediated by Src and regulates cell migration. Additionally, we found that Shc1 localizes in focal adhesions in a PEAK1 phosphorylated Tyr-1188-dependent fashion. Besides binding Shc1, PEAK1 also associates with a protein cluster that mediates late EGFR/Shc1 signaling. We propose a model in which PEAK1 binds Tensin3 and Shc1 to converge integrin and growth factor receptor signal transduction.
