Insulin stimulates the phosphorylation of Tyr538 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 phosphorylation of PTP1C in human 1M-9 lymphoblast cells, in rat H35 hepatoma cells and in Chinese hamster ovary cells over-expressing both insulin receptors and PTP1C. Insulin also stimulated the tyrosine phosphorylation of a mutant PTP1C lacking SH2 domains in Chinese hamster ovary cells, suggesting that the SH2 domains are not required for insulin-stimulated tyrosine phosphorylation of PTP1C. The insulin receptor tyrosine kinase catalyzed the tyrosine phosphorylation of PTP1C in a cell-free system. Peptide mapping of phosphorylated PTP1C showed that Tyr538 in the C-terminal region was phosphorylated in response to insulin. The tyrosine phosphorylation of PTP1C by the insulin receptor kinase 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 tyrosine kinase and that the C-terminal region of PTP1C may function both in the regulation of phosphatase activity and in the association of PTP1C with autophosphorylated insulin receptors.
Uchida
T
T
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
Matozaki
T
T
Noguchi
T
T
Yamao
T
T
Horita
K
K
Suzuki
T
T
Fujioka
Y
Y
Sakamoto
C
C
Kasuga
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D017931:DNA Primers; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019000:Phosphotyrosine; D016133:Polymerase Chain Reaction; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D017931:DNA Primers; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D011972:Receptor, Insulin; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat