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A more recent version of this article appeared on November 11, 2005
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M506134200v1
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Papers In Press, published online ahead of print August 29, 2005
J. Biol. Chem, 10.1074/jbc.M506134200
Submitted on June 6, 2005
Revised on August 10, 2005
Accepted on August 29, 2005

The phosphorylation of SER318 of insulin receptor substrate 1 is not per se inhibitory in skeletal muscle cells, but is necessary to trigger the attenuation of the insulin-stimulated signal

Cora Weigert, Anita M. Hennige, Tasja Brischmann, Alexander Beck, Klaus Moeschel, Myriam Schäuble, Katrin Brodbeck, Hans Ulrich Häring, Erwin D. Schleicher, and Rainer Lehmann

Internal medicine 4 / central laboratory, University of Tuebingen, Tuebingen 72076

Corresponding Author: Rainer.Lehmann{at}med.uni-tuebingen.de

The Ser-/Thr-phosphorylation of insulin receptor substrate (IRS)-1 is one key mechanism to stimulate and/or attenuate insulin signal transduction. Using a phospho-specific polyclonal antibody directed against phosphorylated Ser318 of IRS-1 we found a rapid and transient insulin-stimulated phosphorylation of Ser318 in human and rodent skeletal muscle cell models and in muscle tissue of insulin-treated mice. None of the investigated insulin resistance-associated factors (e.g. high glucose, TNF-a, adrenalin) stimulated the phosphorylation of Ser318. Studying the function of this phosphorylation we found that replacing Ser318 by alanine completely prevented both the attenuation of insulin-stimulated Akt/PKB Ser473 phosphorylation and the glucose uptake after 60 min of insulin stimulation. Unexpectedly, after acute insulin stimulation we observed that phosphorylation of Ser318 is not inhibitory but rather enhances insulin signal transduction since introduction of Ala318 led to a reduction of the insulin-stimulated Akt/PKB phosphorylation. Furthermore, replacing Ser318 by glutamate, i.e. mimicking phosphorylation, improved glucose uptake after acute insulin stimulation. These data suggest that phosphorylation of Ser318 is not per se inhibitory but is necessary to trigger the attenuation of the insulin-stimulated signal in skeletal muscle cells. Investigating the molecular mechanism of insulin-stimulated Ser318 phosphorylation, we found that PI 3-kinase-mediated activation of atypical PKC- and recruitment of PKC-z to IRS-1 was responsible for this phosphorylation. We conclude that Ser318 phosphorylation of IRS-1 is an early physiological event in insulin-stimulated signal transduction, which attenuates the continuing action of insulin.


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