FAK Signaling

Engagement of integrin receptors with extracellular ligands activates formation of complex multi-protein structures that link the ECM to the cytoplasmic actin cytoskeleton and signaling proteins including talin, α-actinin, vinculin, zyxin, paxillin and FAK (PTK2). Signaling through these complexes and focal adhesions regulates a number of key cellular processes including growth factor-induced mitogenic signals, cell survival, cell proliferation and migration, cell locomotion and regulation of cell cycle. FAK is a non-receptor cytosolic protein tyrosine kinase (PTK) with a central catalytic domain flanked by large N- and C-terminal domains that indirectly localize to sites of integrin receptor clustering through interation with integrin-associated proteins. FAK contains three domains: an amino terminal domain that binds to the cytoplasmic tail of β-integrin subunits and the intracellular domain of EGFR, a central tyrosine kinase domain, and a carboxy terminal domain that consists of two proline rich motifs and a FAT sequence that associate with other focal adhesion proteins including paxillin and talin.Clustering of integrins leads to the rapid recruitment of FAK to the focal adhesion complex and its concurrent phosphorylation at Tyr397. This is important for tyrosine phosphorylation of paxillin and CAS. This phosphorylation also creates a high affinity binding site recognized by the SH2 domain of Src family kinases and leads to the recruitment and activation of Src through the formation of a bipartite kinase complex. Activation of the FAK-Src complex regulates downstream signaling pathways that control cell spreading, cell movement and cell survival. Phosphorylated FAK also recruits PI3K and PLC-γ. Once activated by FAK, Ras activates PI3K and Raf to the cytoplasmic membrane. In addition, FAK serves as a scaffold for p130CAS, ASAP1 or GRAF, which bind to either of two C-terminal proline-rich regions. Phosphorylated CAS binds to Crk and DOCK180 leading to an increase in the affinity of the membranes for Rac. Activated Rac regulates numerous biochemical pathways including activation of MAPK/ERK, PIX, PAK, PKL and p38/JNK; key regulators of gene expression and cell cycle. In addition, Rac activation is closely coupled to activation of WASP, allowing for the coincident and coordinated cytoskeleton organization. Hyaluronan binding to RHAMM results in FAK phosphorylation; this is a necessary step for disassembly of focal contacts and subsequent motility. Dephosphorylation of FAK also involves PTEN, but PTEN's predominant enzymatic activity dephosphorylates phosphoinositides, PI(3,4,5)P3 and PI(3,4)P2 thus antagonizing downstream effectors such as AKT and PDK1.FAK plays a pivotal role in signal transduction at integrin linked cellular adhesions which mediate cell contact with the ECM. It plays a central role in the survival of anchorage-dependent cells and is essential for integrin-linked cell migration, the processes that play important roles in the development of malignancies. FAK is upregulated in a wide variety of human epithelial cancers with expression being closely correlated to invasive potential. FAK expression has been implicated in the progression of tumor cells to malignancy and the pathogenesis of cancer, suggesting opportunities for the development of anti-cancer therapeutics. (Upgraded 09/2021)