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J Biol Chem, Vol. 273, Issue 12, 7162-7168, March 20, 1998

p125^Fak Focal Adhesion Kinase Is a Substrate for the Insulin and Insulin-like Growth Factor-I Tyrosine Kinase Receptors

From INSERM, U145, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cédex 2, France

The focal adhesion kinase p125^Fak 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 p125^Fak phosphorylation, insulin has been shown to promote its dephosphorylation. In this study, we compared p125^Fak phosphorylation in insulin-stimulated cells maintained in suspension or in an adhesion state. We found that, in nonattached cells, insulin promotes p125^Fak phosphorylation, whereas dephosphorylation occurred in attached cells. This was observed in Rat-1 fibroblasts overexpressing the insulin receptor, as well as in Hep G2 hepatocytes and in 3T3-L1 adipocytes expressing more natural levels of insulin receptors. Insulin-induced p125^Fak phosphorylation correlated with an increase in paxillin phosphorylation, indicating that p125^Fak kinase activity may be stimulated by insulin. Mixing of purified insulin or insulin-like growth factor-I (IGF-I) receptors with p125^Fak resulted in an increase in p125^Fak phosphorylation. Using a kinase-deficient p125^Fak mutant, we found that this protein is a direct substrate of the insulin and IGF-I receptor tyrosine kinases. This view is supported by two additional findings. (i) A peptide corresponding to p125^Fak sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor; and (ii) p125^Fak phosphorylation by the insulin receptor is prevented by addition of this peptide. Finally, we observed that p125^Fak phosphorylation by the receptor results in its activation. Our results show that the nature of the cross-talk between the insulin/IGF-I receptors and p125^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.

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