HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 6, 4422-4428, February 11, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/6/4422    most recent M410610200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liberman, Z. Articles by Eldar-Finkelman, H. Search for Related Content PubMed PubMed Citation Articles by Liberman, Z. Articles by Eldar-Finkelman, H. Social Bookmarking                      What's this?

Serine 332 Phosphorylation of Insulin Receptor Substrate-1 by Glycogen Synthase Kinase-3 Attenuates Insulin Signaling^*

Ziva Liberman and Hagit Eldar-Finkelman

From the Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

The ability of glycogen synthase kinase-3 (GSK-3) to phosphorylate insulin receptor substrate-1 (IRS-1) is a potential inhibitory mechanism for insulin resistance in type 2 diabetes. However, the serine site(s) phosphorylated by GSK-3 within IRS-1 had not been yet identified. Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1^1–320 and PTB-2^1–350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320–350. Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. This suggested that Ser³³² is a GSK-3 phosphorylation site and that Ser³³⁶ serves as the "priming" site typically required for GSK-3 action. Indeed, dephosphorylation of IRS-1 prevented GSK-3 phosphorylation. Furthermore, the phosphorylated peptide derived from the IRS-1 sequence was readily phosphorylated by GSK-3, in contrast to the nonphosphorylated peptide, which was not phosphorylated by the enzyme. When IRS-1 mutants S332A^IRS-1, S336A^IRS-1, or S332A/336A^IRS-1 were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. This effect was stronger in the double mutant S332A/336A^IRS-1 and led to enhanced insulin-mediated activation of protein kinase B. Finally, immunoblot analysis with polyclonal antibody directed against IRS-1 phosphorylated at Ser³³² confirmed IRS-1 phosphorylation in cultured cells. Moreover, treatment with the GSK-3 inhibitor lithium reduced Ser³³² phosphorylation, whereas overexpression of GSK-3 enhanced this phosphorylation. In summary, our studies identify Ser³³² as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling.

Received for publication, September 15, 2004 , and in revised form, November 29, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel. Tel.: 972-3-640-5307; Fax: 972-3-640-8749; E-mail: heldar{at}post.tau.ac.il.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. J. Henriksen, M. K. Teachey, K. A. Lindborg, C. J. Diehl, and A. N. Beneze The high-fat-fed lean Zucker rat: a spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1813 - R1821. [Abstract] [Full Text] [PDF]

				Z. Liberman, B. Plotkin, T. Tennenbaum, and H. Eldar-Finkelman Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C{beta}II in the diabetic fat tissue Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1169 - E1177. [Abstract] [Full Text] [PDF]

				A. Moh, W. Zhang, S. Yu, J. Wang, X. Xu, J. Li, and X.-Y. Fu STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3{beta} Diabetes, May 1, 2008; 57(5): 1227 - 1235. [Abstract] [Full Text] [PDF]

				D. Leclerc and R. Rozen Endoplasmic Reticulum Stress Increases the Expression of Methylenetetrahydrofolate Reductase through the IRE1 Transducer J. Biol. Chem., February 8, 2008; 283(6): 3151 - 3160. [Abstract] [Full Text] [PDF]

				H. Sharfi and H. Eldar-Finkelman Sequential phosphorylation of insulin receptor substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E307 - E315. [Abstract] [Full Text] [PDF]

				T. P. Ciaraldi, S. E. Nikoulina, R. A. Bandukwala, L. Carter, and R. R. Henry Role of Glycogen Synthase Kinase-3{alpha} in Insulin Action in Cultured Human Skeletal Muscle Cells Endocrinology, September 1, 2007; 148(9): 4393 - 4399. [Abstract] [Full Text] [PDF]

				G. Shahid and T. Hussain GRK2 Negatively Regulates Glycogen Synthesis in Mouse Liver FL83B Cells J. Biol. Chem., July 13, 2007; 282(28): 20612 - 20620. [Abstract] [Full Text] [PDF]

				Z. Ma, S. L. Gibson, M. A. Byrne, J. Zhang, M. F. White, and L. M. Shaw Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis Mol. Cell. Biol., December 15, 2006; 26(24): 9338 - 9351. [Abstract] [Full Text] [PDF]

				R. Ilouz, N. Kowalsman, M. Eisenstein, and H. Eldar-Finkelman Identification of Novel Glycogen Synthase Kinase-3beta Substrate-interacting Residues Suggests a Common Mechanism for Substrate Recognition J. Biol. Chem., October 13, 2006; 281(41): 30621 - 30630. [Abstract] [Full Text] [PDF]

				C.-L. Lin, J.-Y. Wang, Y.-T. Huang, Y.-H. Kuo, K. Surendran, and F.-S. Wang Wnt/beta-Catenin Signaling Modulates Survival of High Glucose-Stressed Mesangial Cells J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2812 - 2820. [Abstract] [Full Text] [PDF]

				O. Kaidanovich-Beilin and H. Eldar-Finkelman Long-Term Treatment with Novel Glycogen Synthase Kinase-3 Inhibitor Improves Glucose Homeostasis in ob/ob Mice: Molecular Characterization in Liver and Muscle J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 17 - 24. [Abstract] [Full Text] [PDF]

				A. Danielsson, A. Ost, F. H. Nystrom, and P. Stralfors Attenuation of Insulin-stimulated Insulin Receptor Substrate-1 Serine 307 Phosphorylation in Insulin Resistance of Type 2 Diabetes J. Biol. Chem., October 14, 2005; 280(41): 34389 - 34392. [Abstract] [Full Text] [PDF]

				F. S. L. Thong, C. B. Dugani, and A. Klip Turning Signals On and Off: GLUT4 Traffic in the Insulin-Signaling Highway Physiology, August 1, 2005; 20(4): 271 - 284. [Abstract] [Full Text] [PDF]