Signaling through focal adhesion kinase

Integrin receptor binding to extracellular matrix proteins generates intrac ellular signals via enhanced tyrosine phosphorylation events that are impor tant for cell growth, survival, and migration. This review will focus on th e functions of the focal adhesion kinase (FAK) protein-tyrosine kinase (PTK ) and its role in linking integrin receptors to intracellular signaling pat hways. FAK associates with several different signaling proteins such as Src -family PTKs, p130(Cas), Shc, Grb2, PI 3-kinase, and paxillin. This enables FAK to function within a network of integrin-stimulated signaling pathways leading to the activation of targets such as the ERK and JNK/mitogen-activ ated protein kinase pathways. Focus will be placed on the structural domain s and sites of FAK tyrosine phosphorylation important for FAK-mediated sign aling events and how these sites are conserved in the FAK-related PTK, Pyk2 . We will review what is known about FAK activation by integrin receptor-me diated events and also non-integrin stimuli. In addition, we discuss the em ergence of a consensus FAK substrate phosphorylation sequence. Emphasis wil l also be placed on the role of FAK in generating cell survival signals and the cleavage of FAK during caspase-mediated apoptosis. An in-depth discuss ion will be presented of integrin-stimulated signaling events occurring in the FAK knockout fibroblasts (FAK(-)) and how these cells exhibit deficits in cell migration. FAK re-expression in the FAK- cells confirms the role of this PTK in the regulation of cell morphology and in promoting cell migrat ion events. In addition, these results reinforce the potential role for FAK in promoting an invasive phenotype in human tumors. (C) 1998 Elsevier Scie nce Ltd. All rights reserved.