Mol Cell Biol. 2013 Nov 18. [Epub ahead of print]
Grb2 Promotes Integrin-induced Focal Adhesion Kinase (FAK) Autophosphorylation and Directs the Phosphorylation of PTPα by the Src-FAK Kinase Complex.
From the Depts. of Pathology and Laboratory Medicine, Medicine, and Pediatrics, Child and
Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z
4H4, Canada, and Dept. of Reproductive Medicine, Moores UCSD Cancer Center, University of
California San Diego, 3855 Health Sciences Dr., MC 0803, La Jolla, CA 92093, USA
The integrin-activated Src-FAK kinase complex phosphorylates PTPα at Tyr789, initiating PTPα-mediated signaling that promotes cell migration. Recruitment of the BCAR3-Cas complex by PTPα-phosphoTyr789 at focal adhesions is one mechanism of PTPα signaling. The adaptor protein Grb2 is also recruited by PTPα-phosphoTyr789, although the role of the PTPα-Grb2 complex in integrin signaling is unknown. We show that silencing Grb2 expression in fibroblasts abolishes PTPα-Tyr789 phosphorylation, and that this is due to two unexpected actions of Grb2. Firstly, Grb2 promotes integrin-induced autophosphorylation of FAK-Tyr397. This is impaired in Grb2-depleted cells and prohibits FAK activation and formation of the Src-FAK complex. Grb2-depleted cells contain less paxillin, and paxillin overexpression rescues FAK-Tyr397 phosphorylation, suggesting the FAK-activating action of Grb2 involves paxillin. A second distinct role for Grb2 in PTPα-Tyr789 phosphorylation involves Grb2-mediated coupling of Src-FAK and PTPα. This requires two phosphosites, FAK-Tyr925 and PTPα-Tyr789, for Grb2-SH2 binding. We propose that a Grb2 dimer links FAK and PTPα, and this positions active Src-FAK in proximity with other, perhaps integrin clustered, molecules of PTPα to enable maximal PTPα-Tyr789 phosphorylation. These findings identify Grb2 as a new FAK activator and reveal its essential role in co-ordinating PTPα tyrosine phosphorylation to enable downstream integrin signaling and migration.
PMID:24248601[PubMed - as supplied by publisher]
Keywords: Wound Healing, Cell Biology, Cell Signaling