Activation of protein kinase C alpha inhibits insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1.
Chinese hamster ovary (CHO) cells were transfected with a cDNA encoding protein kinase C alpha (PKC) and a cell line (CHO-PKC alpha) expressing approximately 7-fold greater amounts of PKC as the parental cells were isolated. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate in the CHO-PKC alpha cells inhibited by approximately 75% the: 1) insulin-stimulated increase in antiphosphotyrosine precipitable phosphatidylinositol 3-kinase activity in these cells; 2) insulin-stimulated increase in PI 3-kinase activity associated with insulin receptor substrate-1; and 3) tyrosine phosphorylation of the endogenous substrate, insulin receptor substrate-1. In contrast, 12-O-tetradecanoylphorbol-13-acetate treatment did not inhibit any of these responses in the parental CHO cells. These results indicate that excessive PKC activity can interfere in a very early step in insulin receptor signaling and are consistent with the hypothesis that excessive PKC activity may contribute to some states of insulin resistance.
Chin
J E
JE
Department of Molecular Pharmacology, Stanford University School of Medicine, California 94305.
Liu
F
F
Roth
R A
RA
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D007163:Immunosorbent Techniques; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D019000:Phosphotyrosine; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018076:DNA, Complementary; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D019000:Phosphotyrosine; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate