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Originally published In Press as doi:10.1074/jbc.M104405200 on July 31, 2001

J. Biol. Chem., Vol. 276, Issue 40, 37109-37119, October 5, 2001
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Insulin Receptor Substrate-2 Phosphorylation Is Necessary for Protein Kinase Czeta Activation by Insulin in L6hIR Cells*

Francesco OrienteDagger §, Pietro FormisanoDagger §, Claudia MieleDagger , Francesca FioryDagger , Maria Alessandra MaitanDagger , Giovanni VigliottaDagger , Alessandra TrenciaDagger , Stefania SantopietroDagger , Matilde CarusoDagger , Emmanuel Van Obberghen||, and Francesco BeguinotDagger **

From the Dagger  Dipartimento di Biologia e Patologia Cellulare e Molecolare and Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Federico II University of Naples, 80131 Italy and || INSERM Unit 145, IFR 50 Nice, 06107 France

We have investigated glycogen synthase (GS) activation in L6hIR cells expressing a peptide corresponding to the kinase regulatory loop binding domain of insulin receptor substrate-2 (IRS-2) (KRLB). In several clones of these cells (B2, F4), insulin-dependent binding of the KRLB to insulin receptors was accompanied by a block of IRS-2, but not IRS-1, phosphorylation, and insulin receptor binding. GS activation by insulin was also inhibited by >70% in these cells (p < 0.001). The impairment of GS activation was paralleled by a similarly sized inhibition of glycogen synthase kinase 3alpha (GSK3alpha ) and GSK3beta inactivation by insulin with no change in protein phosphatase 1 activity. PDK1 (a phosphatidylinositol trisphosphate-dependent kinase) and Akt/protein kinase B (PKB) activation by insulin showed no difference in B2, F4, and in control L6hIR cells. At variance, insulin did not activate PKCzeta in B2 and F4 cells. In L6hIR, inhibition of PKCzeta activity by either a PKCzeta antisense or a dominant negative mutant also reduced by 75% insulin inactivation of GSK3alpha and -beta (p < 0.001) and insulin stimulation of GS (p < 0.002), similar to Akt/PKB inhibition. In L6hIR, insulin induced protein kinase Czeta (PKCzeta ) co-precipitation with GSK3alpha and beta . PKCzeta also phosphorylated GSK3alpha and -beta . Alone, these events did not significantly affect GSK3alpha and -beta activities. Inhibition of PKCzeta activity, however, reduced Akt/PKB phosphorylation of the key serine sites on GSK3alpha and -beta by >80% (p < 0.001) and prevented full GSK3 inactivation by insulin. Thus, IRS-2, not IRS-1, signals insulin activation of GS in the L6hIR skeletal muscle cells. In these cells, insulin inhibition of GSK3alpha and -beta requires dual phosphorylation by both Akt/PKB and PKCzeta .

* This work was supported in part by European Community Grant QLG1-CT-1999-00674 and grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (to F. B. and P. F.), the Ministero dell' Università e della Ricerca Scientifica (to F. B.), and the Consiglio Nazionale delle Ricerche Target Project on Biotechnology (to F. B.). The financial support of Telethon-Italy Grant 0896 (to F. B.) is gratefully acknowledged. INSERM Unit 145 was supported in part by INSERM, Région PACA, University of Nice-Sophia-Antipolis, a grant from Aventis (Frankfurt am Main, Germany), and Grant QLG1-CT-1999-00674 from the European Community.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.

§ Contributed equally to this manuscript.

Recipients of fellowships of the Federazione Italiana per la Ricerca sul Cancro (FIRC).

** To whom correspondence should be addressed: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via S. Pansini, 5, 80131 Naples, Italy. Tel.: 39 081 7463248; Fax: 39 081 7463235; E-mail: beguino@unina.it.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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