Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis

Abstract

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.

Fig. 1. FAK structural features and interaction proteins

FAK is composed of a central kinase domain flanked by a N-terminal FERM domain and a C-terminal region containing two proline-rich (PR1 and PR2) motifs and a FAT domain. Several known phosphorylation sites as well as residues or regions of FAK mediating association with some of its interacting-proteins are indicated in the diagram.

Fig. 2. Regulation of cell migration and invasion by FAK through multiple signaling pathways

Several mechanisms by which FAK regulates cell migration and invasion are depicted here. These include serving as a scaffold for Src phosphorylation of p130cas, direct phosphorylation of Grb7 in a PI3K dependent manner and phosphorylation of N-WASP to regulate its cytoplasmic retention to control cell migration in a variety of cells, and mediating phosphorylation of endophilin A2 by Src to regulate surface expression of MT1-MMP in cancer cells.

Fig. 3. A working model of kinase-dependent and -independent functions of FAK in vascular development

In control embryos, normal FAK functions in ECs allow completion of embryonic development. In FAK conditional knockout (CFKO) embryos, absence of FAK leads to EC apoptosis and embryonic lethality at E13.5. In EC-specific FAK kinase-defective mutant knockin (CFKI) embryos, the kinase-independent functions of FAK support EC survival to allow development beyond E13.5. However, lack of FAK kinase activity results in other defects in EC junctions and angiogenesis, leading to embryonic lethality at E15.5.