Protein Kinase C-ζ Phosphorylates Insulin Receptor Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol 3-Kinase in Response to Insulin
Open Access
- 1 February 2001
- journal article
- Published by Elsevier BV in Journal of Biological Chemistry
- Vol. 276 (5), 3543-3549
- https://doi.org/10.1074/jbc.m007231200
Abstract
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 in vitro 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-3T3IR cells caused significant phosphorylation of cotransfected IRS-1 as demonstrated by [32P]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-3T3IRcells 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.Keywords
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