Activation of protein kinase C alpha inhibits signaling by members of the insulin receptor family.
Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase C alpha resulted in a subsequent inhibition of the ligand-stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase C alpha inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase C alpha, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase C alpha in the cells that served as a source of the substrates. Finally, the insulin-like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase C alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Danielsen
A G
AG
Department of Molecular Pharmacology, Stanford University School of Medicine, California 94305, USA.
Liu
F
F
Hosomi
Y
Y
Shii
K
K
Roth
R A
RA
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D002455:Cell Division; D006224:Cricetinae; D004330:Drosophila; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000096:biosynthesis / Q000502:physiology*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019000:Phosphotyrosine; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000502:physiology*; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D020690:GTPase-Activating Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D010750:Phosphoproteins; D011506:Proteins; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate