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J. Biol. Chem. 277 (44): 42394-42398

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2*

Liangyou RuiDagger §, Minsheng YuanDagger , Daniel FrantzDagger , Steven ShoelsonDagger , and Morris F. WhiteDagger ||

From the  Howard Hughes Medical Institute, Dagger  Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Inflammation associates with peripheral insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. Inflammation induces the expression of SOCS proteins. We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy.

* This work was supported by National Research Service Award (to L. R.) and National Institutes of Health grants (to S. S. and M. W.).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.

§ Current address: Dept. of Physiology, University of Michigan Medical School, Ann Arbor, MI 48109.

|| To whom correspondence should be addressed: Howard Hughes Medical Inst., Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215. Tel.: 617-732-2578; Fax: 617-732-2593; E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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JAK/STAT3 Pathway Is Involved in Survival of Neurons in Response to Insulin-like Growth Factor and Negatively Regulated by Suppressor of Cytokine Signaling-3.
A. Yadav, A. Kalita, S. Dhillon, and K. Banerjee (2005)
J. Biol. Chem. 280, 31830-31840
   Abstract »    Full Text »    PDF »
Mechanisms of SOCS3 Phosphorylation upon Interleukin-6 Stimulation: CONTRIBUTIONS OF Src- AND RECEPTOR-TYROSINE KINASES.
U. Sommer, C. Schmid, R. M. Sobota, U. Lehmann, N. J. Stevenson, J. A. Johnston, F. Schaper, P. C. Heinrich, and S. Haan (2005)
J. Biol. Chem. 280, 31478-31488
   Abstract »    Full Text »    PDF »
Socs1 Deficiency Enhances Hepatic Insulin Signaling.
E. Jamieson, M. M. W. Chong, G. R. Steinberg, V. Jovanovska, B. C. Fam, D. V. R. Bullen, Y. Chen, B. E. Kemp, J. Proietto, T. W. H. Kay, et al. (2005)
J. Biol. Chem. 280, 31516-31521
   Abstract »    Full Text »    PDF »
Adipocyte-Specific Overexpression of FOXC2 Prevents Diet-Induced Increases in Intramuscular Fatty Acyl CoA and Insulin Resistance.
J. K. Kim, H.-J. Kim, S.-Y. Park, A. Cederberg, R. Westergren, D. Nilsson, T. Higashimori, Y.-R. Cho, Z.-X. Liu, J. Dong, et al. (2005)
Diabetes 54, 1657-1663
   Abstract »    Full Text »    PDF »
Human biliverdin reductase: A member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity.
N. Lerner-Marmarosh, J. Shen, M. D. Torno, A. Kravets, Z. Hu, and M. D. Maines (2005)
PNAS 102, 7109-7114
   Abstract »    Full Text »    PDF »
Suppressor of Cytokine Signaling 7 Inhibits Prolactin, Growth Hormone, and Leptin Signaling by Interacting with STAT5 or STAT3 and Attenuating Their Nuclear Translocation.
N. Martens, G. Uzan, M. Wery, R. Hooghe, E. L. Hooghe-Peters, and A. Gertler (2005)
J. Biol. Chem. 280, 13817-13823
   Abstract »    Full Text »    PDF »
Metabolic Syndrome: A Comprehensive Perspective Based on Interactions Between Obesity, Diabetes, and Inflammation.
P. Dandona, A. Aljada, A. Chaudhuri, P. Mohanty, and R. Garg (2005)
Circulation 111, 1448-1454
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Suppressors of Cytokine Signaling 4 and 5 Regulate Epidermal Growth Factor Receptor Signaling.
E. Kario, M. D. Marmor, K. Adamsky, A. Citri, I. Amit, N. Amariglio, G. Rechavi, and Y. Yarden (2005)
J. Biol. Chem. 280, 7038-7048
   Abstract »    Full Text »    PDF »
Activation of SOCS-3 by Resistin.
C. M. Steppan, J. Wang, E. L. Whiteman, M. J. Birnbaum, and M. A. Lazar (2005)
Mol. Cell. Biol. 25, 1569-1575
   Abstract »    Full Text »    PDF »
Type 2 Diabetes-a Matter of {beta}-Cell Life and Death?.
C. J. Rhodes (2005)
Science 307, 380-384
   Abstract »    Full Text »    PDF »
Role of Tyrosine 441 of Interferon-{gamma} Receptor Subunit 1 in SOCS-1-mediated Attenuation of STAT1 Activation.
Y. Qing, A. P. Costa-Pereira, D. Watling, and G. R. Stark (2005)
J. Biol. Chem. 280, 1849-1853
   Abstract »    Full Text »    PDF »
Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in {beta}-Cells.
I. Briaud, L. M. Dickson, M. K. Lingohr, J. F. McCuaig, J. C. Lawrence, and C. J. Rhodes (2005)
J. Biol. Chem. 280, 2282-2293
   Abstract »    Full Text »    PDF »
VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.
T. Kamura, K. Maenaka, S. Kotoshiba, M. Matsumoto, D. Kohda, R. C. Conaway, J. W. Conaway, and K. I. Nakayama (2004)
Genes & Dev. 18, 3055-3065
   Abstract »    Full Text »    PDF »
Metabolic Syndrome and Robustness Tradeoffs.
H. Kitano, K. Oda, T. Kimura, Y. Matsuoka, M. Csete, J. Doyle, and M. Muramatsu (2004)
Diabetes 53, S6-S15
   Abstract »    Full Text »    PDF »
{beta}-Arrestin-1 Competitively Inhibits Insulin-Induced Ubiquitination and Degradation of Insulin Receptor Substrate 1.
I. Usui, T. Imamura, J. Huang, H. Satoh, S. K. Shenoy, R. J. Lefkowitz, C. J. Hupfeld, and J. M. Olefsky (2004)
Mol. Cell. Biol. 24, 8929-8937
   Abstract »    Full Text »    PDF »
SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome.
B. Q. Vuong, T. L. Arenzana, B. M. Showalter, J. Losman, X. P. Chen, J. Mostecki, A. S. Banks, A. Limnander, N. Fernandez, and P. B. Rothman (2004)
Mol. Cell. Biol. 24, 9092-9101
   Abstract »    Full Text »    PDF »
SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin.
C. Duan, M. Li, and L. Rui (2004)
J. Biol. Chem. 279, 43684-43691
   Abstract »    Full Text »    PDF »
Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis.
A. Ahmad and F. Alvarez (2004)
J. Leukoc. Biol. 76, 743-759
   Abstract »    Full Text »    PDF »

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