INSULIN STIMULATES THE PHOSPHORYLATION OF TYR(538) AND THE CATALYTIC ACTIVITY OF PTP1C, A PROTEIN-TYROSINE-PHOSPHATASE WITH SRC HOMOLOGY-2 DOMAINS

PTP1C is a non-transmembrane protein-tyrosine phosphatase and contains two Src homology-2 (SH2) domains. Insulin stimulated the tyrosine pho sphorylation of PTP1C in human 1M-9 lymphoblast cells, in rat H35 hepa toma cells and in Chinese hamster ovary cells over-expressing both ins ulin receptors and PTP1C. Insulin also stimulated the tyrosine phospho rylation of a mutant PTP1C lacking SH2 domains in Chinese hamster ovar y cells, suggesting that the SH2 domains are not required for insulin- stimulated tyrosine phosphorylation of PTP1C. The insulin receptor tyr osine kinase catalyzed the tyrosine phosphorylation of PTP1C in a cell -free system. Peptide mapping of phosphorylated PTP1C showed that Tyr( 538) in the C-terminal region was phosphorylated in response to insuli n. The tyrosine phosphorylation of PTP1C by the insulin receptor kinas e increased phosphatase activity. Furthermore, PTP1C was shown to bind to autophosphorylated insulin receptors through its C-terminal region , but PTP1C did not bind to unphosphorylated receptors. These results suggest that PTP1C is a target protein for the insulin receptor tyrosi ne kinase and that the C-terminal region of PTP1C may function both in the regulation of phosphatase activity and in the association of PTP1 C with autophosphorylated insulin receptors.