Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes

Signaling molecules downstream from the insulin receptor, such as the insul in receptor substrate protein 1 (IRS-1), are also activated by other recept or tyrosine kinases. Here we demonstrate that the non-receptor tyrosine kin ases, focal adhesion kinase pp125(FAK) and Src-class kinase pp59(Lyn), afte r insulin-independent activation by phosphoinositolglycans (PIG), can cross talk to metabolic insulin signaling in rat and 3T3-L1 adipocytes. Introduc tion by electroporation of neutralizing antibodies against pp59(Lyn) and pp 125(FAK) into isolated rat adipocytes blocked IRS-1 tyrosine phosphorylatio n in response to PIG but not insulin. Introduction of peptides encompassing either the major autophosphorylation site of pp125(FAK), tyrosine 397, or its regulatory loop with the twin tyrosines 576 and 577 inhibited PIG-induc ed IRS-1 tyrosine phosphorylation and glucose transport. PIG-induced pp59(L yn) kinase activation and pp125(FAK) tyrosine phosphorylation were impaired by the former and latter peptide, respectively. Up-regulation of pp125(FAK ) by integrin clustering diminished PIG-induced IRS-1 tyrosine phosphorylat ion and glucose transport in nonadherent but not adherent adipocytes. In co nclusion, PIG induced IRS-1 tyrosine phosphorylation by causing (integrin a ntagonized) recruitment of IRS-1 and pp59(Lyn) to the common signaling plat form molecule pp125(FAK), where cross talk of PIG-like structures and extra cellular matrix proteins to metabolic insulin signaling may converge, possi bly for the integration of the demands of glucose metabolism and cell archi tecture.