Focal adhesion kinase: in command and control of cell motility

Abstract

In 1992, focal adhesion kinase (FAK) was identified as a substrate for viral Src and as a highly tyrosine-phosphorylated protein that localized to cell adhesion sites known as focal contacts. Since then, FAK has been shown to have a key role in both normal and tumour cell migration downstream of growth factor- and integrin- receptors. It is the formation of a FAK–Src signalling complex that is an initial and important event required for maximal FAK activation and cell migration. FAK can be activated through intermolecular and intramolecular mechanisms, and tyrosine-phosphorylated FAK promotes interactions with various Src-homology (SH)2- and SH3-containing proteins. These proteins allow FAK activation to be connected to several signalling pathways such as the extracellular signal-regulated kinase 2 (ERK2)/mitogen-activated protein kinase (MAPK) cascade and small GTPases such as Rac and Rho. Phosphorylation of the C-terminal domain of FAK might control its localization to focal contacts by altering the binding of paxillin. FAK functions as a signalling-protein scaffold for the assembly and subsequent maturation of focal contacts. FAK–Src kinase activity contributes to these events by promoting signalling that leads to the phosphorylation of phosphatidylinositol lipids. FAK–Src also functions to promote the disassembly of focal contacts, in part by activating intracellular proteases such as calpain and extracellular matrix metalloproteinases. New findings also link FAK–Src signalling to the regulation of cadherin-mediated cell–cell contacts. In cell protrusions of migrating cells, coordinated changes in actin and microtubule structures are regulated by FAK signalling to Rho-family GTPases. FAK binds to and can phosphorylate GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs) for Rho, and neuronal Wiskott–Aldrich syndrome protein (N-WASP), and can exert control over actin crosslinking by phosphorylating α-actinin. The receptor-proximal position of FAK facilitates its role as an integrator of biochemical signals and mechanical forces that are experienced by moving cells. It is in this unique signalling position that FAK can regulate cytoskeletal or cell adhesion site dynamics and thereby control cell motility.