Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis.
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays critical roles in integrin-mediated signal transductions and also participates in signaling by other cell surface receptors. In integrin-mediated cell adhesion, FAK is activated via disruption of an auto-inhibitory intra-molecular interaction between its amino terminal FERM domain and the central kinase domain. The activated FAK forms a complex with Src family kinases, which initiates multiple downstream signaling pathways through phosphorylation of other proteins to regulate different cellular functions. Multiple downstream signaling pathways are identified to mediate FAK regulation of migration of various normal and cancer cells. Extensive studies in cultured cells as well as conditional FAK knockout mouse models indicated a critical role of FAK in angiogenesis during embryonic development and cancer progression. More recent studies also revealed kinase-independent functions for FAK in endothelial cells and fibroblasts. Consistent with its roles in cell migration and angiogenesis, increased expression and/or activation of FAK are found in a variety of human cancers. Therefore, small molecular inhibitors for FAK kinase activity as well as future development of novel therapies targeting the potentially kinase-independent functions of FAK are promising treatments for metastatic cancer as well as other diseases.
Division of Molecular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Xiaofeng
X
Zhao
Jun-Lin
JL
Guan
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
D016023:Integrins; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases