p125Fak Focal Adhesion Kinase Is a Substrate for the Insulin and Insulin-like Growth Factor-I Tyrosine Kinase Receptors

Abstract

The focal adhesion kinase p125Fak is a widely expressed cytosolic tyrosine kinase, which is involved in integrin signaling and in signal transduction of a number of growth factors. In contrast to tyrosine kinase receptors such as the platelet-derived growth factor and the hepatocyte growth factor receptors, which induce p125Fak phosphorylation, insulin has been shown to promote its dephosphorylation. Fak is dependent on the cell architecture, and hence the interaction of the insulin/IGF-I signaling system with the integrin system will vary accordingly. The focal adhesion kinase p125Fak is a cytosolic tyrosine kinase initially isolated from Src-transformed cells (1, 2). It is localized at focal adhesion plaques of cultured cells and binds to a number of proteins involved in the organization of the cytoskeleton and to signaling molecules, resulting in the formation of multicomponents complexes (reviewed in Refs. 3-6). Tyrosine phosphorylation of p125Fak occurs rapidly in response to integrin clustering or binding to the extracellular matrix, and this correlates with increased kinase activity (2, 7-9). For most cell types, cooperation of adhesion-mediated and growth factor-mediated signaling pathways is required for appropriate growth control, and it is now widely accepted that p125Fak may be a point of convergence in the actions of integrins and growth factors (10, 11). Indeed, p125Fak is not only activated by integrins, but also by mitogenic neuropeptides (12), thrombin (13), sphingosine (14), the bioactive lipid lysophosphatidic acid (15-17), and by ligands for tyrosine kinase receptors such as platelet-derived growth factor and hepatocyte growth factor (18 -20).In contrast to other tyrosine kinase receptors, which induce tyrosine phosphorylation of p125Fak , it has been reported that in fibroblasts insulin promotes a decrease in p125Fak phosphorylation (21-23).The insulin receptor is a heterotetrameric oligomer consisting of two extracellular 135-kDa ␣-subunits and two 95-kDa transmembrane ␤-subunits containing a tyrosine kinase (24,25). Insulin binding to the ␣-subunit stimulates autophosphorylation of the ␤-subunit cytoplasmic domain on multiple tyrosine residues. This activates the receptor kinase, leading to phosphorylation of several substrates including IRS-1, 1 IRS-2, Shc, and Gab-1 (26 -31). IRS-1/2 and Gab-1 carry multiple potential tyrosine phosphorylation sites, which upon phosphorylation become docking sites for SH2 domain-containing proteins. These include the p85 regulatory subunit of phosphatidylinositol 3-kinase, Grb2, and the phosphotyrosine phosphatase SHP-2 (32-34).IRS-1 is also found to be associated with Csk, the C-terminal Src kinase that is an inhibitor of the Src kinase family. It has been shown recently that the insulin-induced complex of IRS-1 and Csk could be involved in dephosphorylation of p125 Fak observed after insulin treatment of fibroblasts (35).The fact that insulin induces p125 Fak dephosphorylation suggests the existence of an antagonistic action of insulin on the integrin s...

Regulation of Neutrophil Adhesion by Pituitary Growth Hormone Accompanies Tyrosine Phosphorylation of Jak2, p125FAK, and Paxillin

“…These factors show many similarities in their effects on the enhancement of motility and the tyrosine phosphorylation of p125 FAK and paxillin (29,30,41,45). Recombinant GH, IGF-I, and PDGF have shown the activation of PI-3 kinase, which modulates direct membrane ruffling (24,30,43,46). Similar to IGF-I and PDGF, our results strongly suggest that p125 FAK and paxillin are involved in mediating the biological effects of pituitary GH, which stimulates neutrophil adhesion at least in terms of inducing membrane ruffling and uropod formation.…”

“…Growth factors such as GH, PDGF, IGF-I, and prolactin act through receptors that are catalyzed by intracellular tyrosine kinase (JAKs). These factors show many similarities in their effects on the enhancement of motility and the tyrosine phosphorylation of p125 FAK and paxillin (29,30,41,45). Recombinant GH, IGF-I, and PDGF have shown the activation of PI-3 kinase, which modulates direct membrane ruffling (24,30,43,46).…”

Differential Regulation of Focal Adhesion Kinase and Mitogen‐Activated Protein Kinase Tyrosine Phosphorylation During Insulin‐Like Growth Factor‐I‐Mediated Cytoskeletal Reorganization

“…FAK is a cytoplasmic tyrosine kinase (Ilic et al, 1997;Zachary, 1997) instrumental in growth factor-mediated changes in cytoskeletal organization (reviewed by Carpenter and Cantley, 1996). IGF-I and insulin can either phosphorylate or dephosphorylate FAK, depending on the cell type and the adhesion status (Pillay et al, 1995;Leventhal et al, 1997;Baron et al, 1998). We have found that IGF-I stimulates the tyrosine phosphorylation of FAK in neurons as growth cones advance over the substrate ).…”

Accelerated Glucose Intolerance, Nephropathy, and Atherosclerosis in Prostaglandin D2 Synthase Knock-out Mice

“…FAK phosphorylation, which is involved in growth and migration, has been shown to be affected by insulin (27). We FIG.…”