Signal transduction by focal adhesion kinase in cancer.
Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.
Zhao
Jihe
J
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, 12208, USA. zhaojh@mail.amc.edu
Guan
Jun-Lin
JL
D000818:Animals; D002465:Cell Movement; D018450:Disease Progression; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases