title: Negative regulation of FAK signaling by SOCS proteins.
abstract: 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: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D020928:Mitogen-Activated Protein Kinases