Cited by 904Adipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and InteractionsUbiquitin and proteasome pathways

The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index.

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

Open access

Rui, Liangyou, Yuan, Minsheng, Frantz, Daniel, Shoelson, Steven, White, Morris F.·2002·Journal of Biological Chemistry

DOI 10.1074/jbc.c200444200

Open this paper in CoChat — free account Open PDF

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1074/jbc.c200444200

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Obesity and insulin resistance
Kahn, B. B., & Flier, J. S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10842 · Cited by 3,345
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235
Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ
Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z.-W., Karin, M., & Shoelson, S. E. (2001) · Science · doi:10.1126/science.1061620 · Cited by 1,884
Disruption of IRS-2 causes type 2 diabetes in mice
Withers, D. J., Gutierrez, J. S., Towery, H. H., Burks, D. J., Ren, J., Previs, S. F., Zhang, Y., Bernal, D., Pons, S., Shulman, G. I., et al. (1998) · Nature · doi:10.1038/36116 · Cited by 1,775
Insulin resistance and cardiovascular disease
Ginsberg, H. N. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10762 · Cited by 1,372
Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action
Aguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E., & White, M. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m101521200 · Cited by 1,010
Decreased IRS-2 and Increased SREBP-1c Lead to Mixed Insulin Resistance and Sensitivity in Livers of Lipodystrophic and ob/ob Mice
Shimomura, I., Matsuda, M., Hammer, R. E., Bashmakov, Y. K., Brown, M. S., & Goldstein, J. L. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00010-9 · Cited by 860
SOCS Proteins: Negative Regulators of Cytokine Signaling
Krebs, D. L., & Hilton, D. J. (2001) · Stem Cells · doi:10.1634/stemcells.19-5-378 · Cited by 826
New Perspectives into the Molecular Pathogenesis and Treatment of Type 2 Diabetes
Saltiel, A. R. (2001) · Cell · doi:10.1016/s0092-8674(01)00239-2 · Cited by 688
The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation
Zhang, J., Farley, A., Nicholson, S. E., Willson, T. A., Zugaro, L. M., Simpson, R. J., Moritz, R. L., Cary, D., Richardson, R. T., Hausmann, G., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.5.2071 · Cited by 626
Negative Regulation of Cytokine Signaling Pathways
Yasukawa, H., Sasaki, A. T., & Yoshimura, A. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.143 · Cited by 596
The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families
Kamura, T., Sato, S., Haque, D., Liu, L., Kaelin, W. G., Conaway, R. C., & Conaway, J. W. (1998) · Genes & Development · doi:10.1101/gad.12.24.3872 · Cited by 595
Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice.
Herz, J., & Gerard, R. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.7.2812 · Cited by 514
Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2
Kido, Y., Burks, D. J., Withers, D. J., Brüning, J. C., Kahn, C. R., White, M. F., & Accili, D. (2000) · Journal of Clinical Investigation · doi:10.1172/jci7917 · Cited by 491
SOCS: physiological suppressors of cytokine signaling
Krebs, D. L., & Hilton, D. J. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.16.2813 · Cited by 463
IRS-2 pathways integrate female reproduction and energy homeostasis
Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (2000) · Nature · doi:10.1038/35030105 · Cited by 462
SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-α in the Adipose Tissue of Obese Mice
Emanuelli, B., Peraldi, P., Filloux, C., Carine Chavey, A., Freidinger, K., Hilton, D. J., Hotamışlıgil, G. S., & OBBERGHEN, E. V. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104602200 · Cited by 449
Mechanisms of TNF-α-induced insulin resistance
Hotamışlıgil, G. S. (2009) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-0029-1212086 · Cited by 420
Regulation of Hypoxia-Inducible mRNAs by the von Hippel-Lindau Tumor Suppressor Protein Requires Binding to Complexes Containing Elongins B/C and Cul2
Lonergan, K. M., Iliopoulos, O., Ohh, M., Kamura, T., Conaway, R., Conaway, J. W., & Kaelin, W. G. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.2.732 · Cited by 383
The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2
Kamizono, S., Hanada, T., Yasukawa, H., Minoguchi, S., Kato, R., Minoguchi, M., Hattori, K., Hatakeyama, S., Yada, M., Morita, S., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010074200 · Cited by 311
Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse.
Kerouz, N., Hörsch, D., Pons, S., & Kahn, C. R. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119872 · Cited by 296
Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus
Rondinone, C. M., Wang, L.-M., Lönnroth, P., Wesslau, C., Pierce, J. H., & Smith, U. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.4171 · Cited by 295
Suppressors of Cytokine Signaling-1 and -6 Associate with and Inhibit the Insulin Receptor
Mooney, R. A., Senn, J. J., Cameron, S. J., Inamdar, N. M., Boivin, L. M., Shang, Y., & Furlanetto, R. W. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010579200 · Cited by 282
The IRS‐signalling system during insulin and cytokine action
Yenush, L., & White, M. F. (1997) · BioEssays · doi:10.1002/bies.950190608 · Cited by 273
Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway.
Sun, X., Goldberg, J. L., Qiao, L. Y., & Mitchell, J. J. (1999) · Diabetes · doi:10.2337/diabetes.48.7.1359 · Cited by 218
Regulation of Insulin/Insulin-like Growth Factor-1 Signaling by Proteasome-mediated Degradation of Insulin Receptor Substrate-2
Rui, L., Fisher, T. L., Thomas, J., & White, M. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105332200 · Cited by 210
Pdx1 restores β cell function in Irs2 knockout mice
Kushner, J. A., Ye, J., Schubert, M., Burks, D. J., Dow, M. A., Flint, C. L., Dutta, S., Wright, C. V. E., Montminy, M., & White, M. F. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14439 · Cited by 188
SOCS-1/SSI-1-Deficient NKT Cells Participate in Severe Hepatitis through Dysregulated Cross-Talk Inhibition of IFN-γ and IL-4 Signaling In Vivo
Naka, T., Tsutsui, H., Fujimoto, M., Kawazoe, Y., Kohzaki, H., Morita, Y., Nakagawa, Narazaki, M., Adachi, K., Yoshimoto, T., et al. (2001) · Immunity · doi:10.1016/s1074-7613(01)00132-7 · Cited by 184
A Janus Kinase Inhibitor, JAB, Is an Interferon-γ–Inducible Gene and Confers Resistance to Interferons
Sakamoto, H., Yasukawa, H., Masuhara, M., Tanimura, S., Sasaki, A. T., Yuge, K., Ohtsubo, M., Ohtsuka, A., Fujita, T., Ohta, T., et al. (1998) · Blood · doi:10.1182/blood.v92.5.1668.417k09_1668_1676 · Cited by 177
Socs-1 Inhibits TEL-JAK2-Mediated Transformation of Hematopoietic Cells through Inhibition of JAK2 Kinase Activity and Induction of Proteasome-Mediated Degradation
Frantsve‐Hawley, J., Schwaller, J., Sternberg, D., Kutok, J. L., & Gilliland, D. G. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3547-3557.2001 · Cited by 171
Suppressor of Cytokine Signaling-1 Inhibits VAV Function through Protein Degradation
Sepulveda, P. D., Ilangumaran, S., & Rottapel, R. K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000106200 · Cited by 168
One Ring to Rule a Superfamily of E3 Ubiquitin Ligases
Tyers, M., & Willems, A. R. (1999) · Science · doi:10.1126/science.284.5414.601 · Cited by 165
Signal Transducer and Activator of Transcription (Stat)-Induced Stat Inhibitor 1 (Ssi-1)/Suppressor of Cytokine Signaling 1 (Socs1) Inhibits Insulin Signal Transduction Pathway through Modulating Insulin Receptor Substrate 1 (Irs-1) Phosphorylation
Kawazoe, Y., Naka, T., Fujimoto, M., Kohzaki, H., Morita, Y., Narazaki, M., Okumura, K., Saitoh, H., Nakagawa, R., Uchiyama, Y., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.2.263 · Cited by 160
Expression of suppressors of cytokine signaling during liver regeneration
Campbell, J. S., Prichard, L., Schaper, F., Schmitz, J., Stephenson-Famy, A., Rosenfeld, M. E., Argast, G. M., Heinrich, P. C., & Fausto, N. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11867 · Cited by 156
SOCS-6 Binds to Insulin Receptor Substrate 4, and Mice Lacking the SOCS-6 Gene Exhibit Mild Growth Retardation
Krebs, D. L., Uren, R. T., Metcalf, D., Rakar, S., Zhang, J., Starr, R., Souza, D. P. D., Hanzinikolas, K., Eyles, J. L., Connolly, L., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.13.4567-4578.2002 · Cited by 150
SOCS Proteins, Regulators of Intracellular Signaling
Chen, X. P., Losman, J. A., & Rothman, P. B. (2000) · Immunity · doi:10.1016/s1074-7613(00)00028-5 · Cited by 145
Interferon-γ-induced Regulation of Peroxisome Proliferator-activated Receptor γ and STATs in Adipocytes
Waite, K. J., Floyd, Z. E., Arbour-Reily, P., & Stephens, J. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007894200 · Cited by 145
Perspective: The Insulin Signaling System--A Common Link in the Pathogenesis of Type 2 Diabetes
Withers, D. J., & White, M. F. (2000) · Endocrinology · doi:10.1210/endo.141.6.7584 · Cited by 141
The central roles of obesity-associated dyslipidaemia, endothelial activation and cytokines in the Metabolic Syndrome—an analysis by structural equation modelling
Chan, J., Cheung, J., Stehouwer, C. D. A., Emeis, J. J., Tong, P. C. Y., Ko, G., & Yudkin, J. S. (2002) · International Journal of Obesity · doi:10.1038/sj.ijo.0802017 · Cited by 135
IFN Regulatory Factor-1-Mediated Transcriptional Activation of Mouse STAT-Induced STAT Inhibitor-1 Gene Promoter by IFN-γ
Saito, H., Morita, Y., Fujimoto, M., Narazaki, M., Naka, T., & Kishimoto, T. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.11.5833 · Cited by 97
Potentiation of Growth Hormone-Induced Liver Suppressors of Cytokine Signaling Messenger Ribonucleic Acid by Cytokines
Colson, A., Cam, A. L., Maiter, D. M., Edery, M., & Thissen, J. (2000) · Endocrinology · doi:10.1210/endo.141.10.7724 · Cited by 64
THE EFFECT OF BURN INJURY ON SUPPRESSORS OF CYTOKINE SIGNALLING
Ogle, C. K., Kong, F., Guo, X., Wells, D. A., Aosasa, S., Noel, G. J., & Horseman, N. D. (2000) · Shock · doi:10.1097/00024382-200014030-00026 · Cited by 45
Insulin action and type 2 diabetes: lessons from knockout mice
Withers, D. J., & White, M. F. (1999) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/00060793-199904000-00010 · Cited by 10

Flagged first, then by citations

1 of the 44 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

Kushner, 2002, J. Clin. Invest., 109, 1193, 10.1172/JCI0214439 · DOI
Konstantopoulos, 2000, Diabetes, 49, A14
Sakamoto, 1998, Blood, 92, 1668, 10.1182/blood.V92.5.1668 · DOI

Sorted by citations

Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199
Inflammation, stress, and diabetes
Wellen, K. E., & Hotamisligil, G. S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25102 · Cited by 4,143
Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272
Adipocytokines: mediators linking adipose tissue, inflammation and immunity
Tilg, H., & Moschen, A. R. (2006) · Nature reviews. Immunology · doi:10.1038/nri1937 · Cited by 3,272
Critical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760

See all 904

Authors: Rui, L., Yuan, M., Frantz, D., Shoelson, S., & White, M. F.
Affiliations: Joslin Diabetes Center (US)
Corresponding author: White, Morris F.
ORCID: Rui, Liangyou
Shoelson, Steven
White, Morris F.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2002-11
Volume: 277
Issue: 44
Pages: 42394-42398
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.c200444200
OpenAlex: W2069711307
Cited by: 904
References: 44
Citations by year: 2026: 14 · 2025: 18 · 2024: 18 · 2023: 25 · 2022: 35 · 2021: 39 · 2020: 27 · 2019: 29 · 2018: 42 · 2017: 33 · 2016: 48 · 2015: 27 · 2014: 50 · 2013: 51 · 2012: 57
FWCI: 30.83
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6559 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: SOCS1, SOCS3, IRS-1, insulin receptor substrate 2, insulin signaling, ubiquitin-mediated proteolysis, SOCS box, inflammation, insulin resistance, impaired glucose tolerance, liver, diabetes mellitus
MeSH terms: Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Elongin, Animals, Carrier Proteins, Glucose, Homeostasis, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Phosphoproteins, Proteins, Repressor Proteins, Transcription Factors, Ubiquitin, Intracellular Signaling Peptides and Proteins, Suppressor of Cytokine Signaling Proteins, Mice, Insulin Receptor Substrate Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks