Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin
摘要：
Protein kinase C-ζ (PKC-ζ) is a serine/threonine kinase downstream from phosphatidylinositol 3-kinase in insulin signaling pathways. However, specific substrates for PKC-ζ that participate in the biological actions of insulin have not been reported. In the present study, we identified insulin receptor substrate-1 (IRS-1) as a novel substrate for PKC-ζ. Under conditions, wild-type PKC-ζ (but not kinase-deficient mutant PKC-ζ) significantly phosphorylated IRS-1. This phosphorylation was reversed by treatment with the serine-specific phosphatase, protein phosphatase 2A. In addition, the overexpression of PKC-ζ in NIH-3T3cells caused significant phosphorylation of cotransfected IRS-1 as demonstrated by [P]orthophosphate labeling experiments. In rat adipose cells, endogenous IRS-1 coimmunoprecipitated with endogenous PKC-ζ, and this association was increased 2-fold upon insulin stimulation. Furthermore, the overexpression of PKC-ζ in NIH-3T3cells significantly impaired insulin-stimulated tyrosine phosphorylation of cotransfected IRS-1. Importantly, this was accompanied by impaired IRS-1-associated phosphatidylinositol 3-kinase activity. Taken together, our results raise the possibility that IRS-1 is a novel physiological substrate for PKC-ζ. Because PKC-ζ is located downstream from IRS-1 and phosphatidylinositol 3-kinase in established insulin signaling pathways, PKC-ζ may participate in negative feedback pathways to IRS-1 similar to those described previously for Akt and GSK-3.
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关键词：
Animals Humans Mice 3T3 Cells Tyrosine Insulin Protein Kinase C Phosphoproteins Signal Transduction Substrate Specificity
DOI：
10.1074/jbc.M007231200
被引量：
年份：
2001
Elsevier
doi.org
万方医学
NCBI
Europe PMC
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