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J. Biol. Chem., Vol. 276, Issue 5, 3543-3549, February 2, 2001
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From the Cardiology Branch, NHLBI, National Institutes of Health,
Bethesda, Maryland 20892 and the Protein kinase C-
Protein Kinase C-
Phosphorylates Insulin Receptor
Substrate-1 and Impairs Its Ability to Activate Phosphatidylinositol
3-Kinase in Response to Insulin*
, Department of Oncology
and Neurosciences, University "G. D'Annunzio,"
Chieti 66013, Italy
(PKC-) is a
serine/threonine kinase downstream from phosphatidylinositol
3-kinase in insulin signaling pathways. However, specific
substrates for PKC- 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-.
Under in vitro conditions, wild-type PKC- (but not
kinase-deficient mutant PKC-) significantly phosphorylated IRS-1.
This phosphorylation was reversed by treatment with the serine-specific
phosphatase, protein phosphatase 2A. In addition, the
overexpression of PKC- 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-,
and this association was increased 2-fold upon insulin stimulation.
Furthermore, the overexpression of PKC- in NIH-3T3IR
cells 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-. Because PKC- is
located downstream from IRS-1 and phosphatidylinositol 3-kinase in
established insulin signaling pathways, PKC- may participate in
negative feedback pathways to IRS-1 similar to those described
previously for Akt and GSK-3.
*
This work was supported in part by Telethon-Italy Grant
E.606 (to D. L. E.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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