Negative regulation of FAK signaling by SOCS proteins.

Focal adhesion kinase (FAK) becomes activated upon integrin-mediated cell adhesion and controls cellular responses to the engagement of integrins, including cell migration and survival. We show here that a coordinated signaling by integrins and growth factor receptors induces expression of suppressor of cytokine signaling-3 (SOCS-3) and subsequent interaction between endogenous ...
FAK and SOCS-3 proteins in 3T3 fibroblasts. Cotransfection studies demonstrated that SOCS-3, and also SOCS-1, interact with FAK in a FAK-Y397-dependent manner, and that both the Src homology 2 (SH2) and the kinase inhibitory region (KIR) domains of the SOCS proteins contribute to FAK binding. SOCS-1 and SOCS-3 were found to inhibit FAK-associated kinase activity in vitro and tyrosine phosphorylation of FAK in cells. The SOCS proteins also promoted polyubiquitination and degradation of FAK in a SOCS box-dependent manner and inhibited FAK-dependent signaling events, such as cell motility on fibronectin. These studies suggest a negative role of SOCS proteins in FAK signaling, and for a previously unidentified regulatory mechanism for FAK function.
Mesh Terms:
3T3 Cells, Animals, COS Cells, Carrier Proteins, Cell Movement, Down-Regulation, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Mice, Mitogen-Activated Protein Kinases, Nuclear Proteins, Protein-Tyrosine Kinases, Signal Transduction, Tyrosine
EMBO J.
Date: Oct. 01, 2003
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