Role of focal adhesion kinase in integrin signaling.
Integrins are the major cell surface receptors for extracellular matrix molecules, which play critical roles in a variety of biological processes. Focal adhesion kinase has recently been established as a key component of the signal transduction pathways triggered by integrins. Aggregation of FAK with integrins and cytoskeletal proteins in focal contacts has been proposed to be responsible for FAK activation and autophosphorylation by integrins in cell adhesion. This may be achieved by FAK interaction with talin or other cytoskeletal proteins that in turn associate with the cytoplasmic domain of integrin beta subunits. Autophosphorylation of FAK at Y397 leads to its association with Src, resulting in activation of both kinases. The activated FAK/Src complex acts on potential substrates tensin, paxillin and p130cas. Besides cytoskeletal regulation, FAK phosphorylation and/or binding to paxillin and p130cas may trigger downstream activation of MAP kinase by the adoptor protein Crk. Src association with FAK may also lead to its phosphorylation of other sites on FAK, including a binding site for Grb2. Cell adhesion-dependent association of FAK and Grb2 may provide a mechanism by which MAP kinase is activated in cell adhesion. PI 3-kinase has also been shown to bind FAK in a cell adhesion-dependent manner at the major autophosphorylation site Y397. This association could lead to activation of PI 3-kinase and its downstream effectors. Recent results from a number of different approaches have shown that integrin signaling through FAK leads to increased cell migration on fibronectin as well as potentially regulating cell proliferation and survival.
Guan
J L
JL
Department of Pathology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016023:Integrins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D016023:Integrins; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases