Signal transduction by focal adhesion kinase in cancer

Abstract

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.

The role of focal adhesion kinase in tumor initiation and progression

“…In particular, the FA component focal adhesion kinase (FAK), a nonreceptor tyrosine kinase, acts as a primary regulator of FA signaling by performing a scaffolding function for protein-protein interactions, phosphorylating multiple substrates, and regulating cross-talk between integrin and growth factor signaling to regulate cell proliferation, survival and migration. 6,7 For instance, phosphorylation of FAK at Y397 creates a highaffinity site that is recognized by several Src homology 2 (SH2) domain-containing proteins such as Src, Shc, PI3K and GRB7, and FAK phosphorylation at Y925 by Src links FAK via Grb2 to the Ras pathway (reviewed in refs. 6 and 7).…”

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

“…Subsequent studies portray a more complex picture (11) and indicate that FAK is also involved in increasing adhesion strength, particularly in response to tension forces (12,13). FAK is frequently overexpressed in various human cancers (14). Its overexpression highly correlates with tumor invasiveness; hence, FAK is widely pursued as a drug target for cancer therapy (15,16).…”

Identification of lymphatic metastasis-associated genes in a metastatic ovarian cancer cell line

“…FAK was selected as a target for experimental confirmation. FAK is a non-receptor protein-tyrosine kinase that mediates integrin interaction with the extracellular matrix (27)(28)(29). In the context of cancer, FAK is involved in tumor cell growth, migration and invasion, in addition to epithelial-to-mesenchymal transition and angiogenesis (28,30,31).…”