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Gene Review

Socs3  -  suppressor of cytokine signaling 3

Mus musculus

Synonyms: CIS-3, CIS3, Cis3, Cish3, Cytokine-inducible SH2 protein 3, ...
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Disease relevance of Socs3

  • Furthermore, Socs3(+/-) mice are significantly protected against the development of diet-induced obesity and associated metabolic complications [1].
  • Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained [2].
  • Forced expression of SOCS3 was just as effective as IL-1beta in reducing the GH induction of ALS promoter activity in H4-II-E rat hepatoma cells [3].
  • This study suggests that SOCS-3 plays an important role in the suppression of cytokine signaling by GH in down-regulating the acute phase response after injury [4].
  • Mycobacterium bovis bacillus Calmette-Guérin infection induces the production of SOCS-1 and SOCS-3 in murine J774 macrophages [5].

High impact information on Socs3


Chemical compound and disease context of Socs3


Biological context of Socs3

  • These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance [2].
  • IL-6 induces a wider transcriptional response in Socs3-deficient macrophages than in wild-type cells; this response is dominated by interferon (IFN)-regulated genes owing to an excess of STAT1 phosphorylation [9].
  • Here, we identify functional binding sites for GFI-1B, a proto-oncogenic transcriptional repressor, in the promoters of murine Socs1 and Socs3 [10].
  • Furthermore, cotransfection of Gfi-1B expression plasmid repressed reporter activity of wild-type (but not mutagenized) Socs1 and Socs3 promoters, strongly suggestive of direct GFI-1B binding to these promoters [10].
  • Thus, SOCS3 functions to control the quality of the response to IL-6 and prevents the activation of an IFN-induced program of gene expression [9].

Anatomical context of Socs3


Associations of Socs3 with chemical compounds

  • In macrophages lacking Socs3, however, continuous IL-6 signaling induced uniformly high levels of STAT3 tyrosine phosphorylation, and early IL-6-inducible genes were inappropriately expressed at intermediate time points [14].
  • Thus, the Thr-Phe motif in the Pre-SH2 domain plays a critical role in SOCS-3-mediated inhibition of the IL-4-dependent Jak-Stat signaling, likely by regulating the mode of SOCS-Jak interaction [15].
  • Neither endogenous IL-10 nor the translation inhibitor cycloheximide blocked SOCS1/SOCS3 induction by B. burgdorferi and its lipoproteins, indicating that the expression of other genes is not required [16].
  • First, using a yeast two-hybrid system, we show that SOCS-3 binds to the insulin receptor at phosphotyrosine 960, which is precisely where Stat5B binds [17].
  • Indeed, in cells expressing an insulin receptor mutant in which tyrosine 960 has been mutated to phenylalanine, insulin does not modify the cellular localization of SOCS-3 [17].

Physical interactions of Socs3

  • Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4(+) T cells [18].
  • Taken together, these results demonstrate that the induction of SOCS-3 by IFNgamma depends upon the presence of a STAT-binding element in the SOCS-3 promoter that is specifically activated by STAT1 [19].
  • The recruitment of BCL10 to TLR4 signaling complexes was attenuated by induced expression of SOCS3 in a feedback loop [20].

Enzymatic interactions of Socs3

  • When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin [21].

Regulatory relationships of Socs3


Other interactions of Socs3

  • Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different [23].
  • The Pre-SH2 domains of SOCS-2 and SOCS-3 confer the specificity of their regulatory function [15].
  • Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3 [24].
  • Using immunohistochemical staining with IL-4/IL-12p40 and phosphorylated STAT6/p-STAT4 and RT-PCR for IL-4/IL-12p40, STAT6/STAT4 and mRNA expression and in situ hybridization of SOCS3 and 5, evaluation was made of the immunoregulatory effects of this okLTA in the treatment of spontaneous AD-like lesions in NC/Nga mice [25].
  • Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity [2].

Analytical, diagnostic and therapeutic context of Socs3


  1. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Howard, J.K., Cave, B.J., Oksanen, L.J., Tzameli, I., Bjørbaek, C., Flier, J.S. Nat. Med. (2004) [Pubmed]
  2. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., Torisu, T., Chien, K.R., Yasukawa, H., Yoshimura, A. Nat. Med. (2004) [Pubmed]
  3. Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1beta on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells. Boisclair, Y.R., Wang, J., Shi, J., Hurst, K.R., Ooi, G.T. J. Biol. Chem. (2000) [Pubmed]
  4. Growth hormone down-regulation of Interleukin-1beta and Interleukin-6 induced acute phase protein gene expression is associated with increased gene expression of suppressor of cytokine signal-3. Wu, X., Herndon, D.N., Wolf, S.E. Shock (2003) [Pubmed]
  5. Mycobacterium bovis bacillus Calmette-Guérin infection promotes SOCS induction and inhibits IFN-gamma-stimulated JAK/STAT signaling in J774 macrophages. Imai, K., Kurita-Ochiai, T., Ochiai, K. FEMS Immunol. Med. Microbiol. (2003) [Pubmed]
  6. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Marine, J.C., McKay, C., Wang, D., Topham, D.J., Parganas, E., Nakajima, H., Pendeville, H., Yasukawa, H., Sasaki, A., Yoshimura, A., Ihle, J.N. Cell (1999) [Pubmed]
  7. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Ueki, K., Kondo, T., Kahn, C.R. Mol. Cell. Biol. (2004) [Pubmed]
  8. Gene delivery of SOCS3 protects mice from lethal endotoxic shock. Fang, M., Dai, H., Yu, G., Gong, F. Cell. Mol. Immunol. (2005) [Pubmed]
  9. SOCS3 regulates the plasticity of gp130 signaling. Lang, R., Pauleau, A.L., Parganas, E., Takahashi, Y., Mages, J., Ihle, J.N., Rutschman, R., Murray, P.J. Nat. Immunol. (2003) [Pubmed]
  10. Regulation of Socs gene expression by the proto-oncoprotein GFI-1B: two routes for STAT5 target gene induction by erythropoietin. Jegalian, A.G., Wu, H. J. Biol. Chem. (2002) [Pubmed]
  11. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Chen, Z., Laurence, A., Kanno, Y., Pacher-Zavisin, M., Zhu, B.M., Tato, C., Yoshimura, A., Hennighausen, L., O'Shea, J.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  12. Activation of SOCS-3 messenger ribonucleic acid in the hypothalamus by ciliary neurotrophic factor. Bjørbaek, C., Elmquist, J.K., El-Haschimi, K., Kelly, J., Ahima, R.S., Hileman, S., Flier, J.S. Endocrinology (1999) [Pubmed]
  13. Interferon-gamma produced by encephalitogenic cells induces suppressors of cytokine signaling in primary murine astrocytes. Stark, J.L., Lyons, J.A., Cross, A.H. J. Neuroimmunol. (2004) [Pubmed]
  14. The comparative roles of suppressor of cytokine signaling-1 and -3 in the inhibition and desensitization of cytokine signaling. Wormald, S., Zhang, J.G., Krebs, D.L., Mielke, L.A., Silver, J., Alexander, W.S., Speed, T.P., Nicola, N.A., Hilton, D.J. J. Biol. Chem. (2006) [Pubmed]
  15. Identification of critical residues required for suppressor of cytokine signaling-specific regulation of interleukin-4 signaling. Haque, S.J., Harbor, P.C., Williams, B.R. J. Biol. Chem. (2000) [Pubmed]
  16. Interleukin-10 Anti-Inflammatory Response to Borrelia burgdorferi, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3. Dennis, V.A., Jefferson, A., Singh, S.R., Ganapamo, F., Philipp, M.T. Infect. Immun. (2006) [Pubmed]
  17. SOCS-3 is an insulin-induced negative regulator of insulin signaling. Emanuelli, B., Peraldi, P., Filloux, C., Sawka-Verhelle, D., Hilton, D., Van Obberghen, E. J. Biol. Chem. (2000) [Pubmed]
  18. Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression. Takatori, H., Nakajima, H., Kagami, S., Hirose, K., Suto, A., Suzuki, K., Kubo, M., Yoshimura, A., Saito, Y., Iwamoto, I. J. Immunol. (2005) [Pubmed]
  19. Analysis of SOCS-3 promoter responses to interferon gamma. Gatto, L., Berlato, C., Poli, V., Tininini, S., Kinjyo, I., Yoshimura, A., Cassatella, M.A., Bazzoni, F. J. Biol. Chem. (2004) [Pubmed]
  20. BCL10 mediates lipopolysaccharide/toll-like receptor-4 signaling through interaction with Pellino2. Liu, Y., Dong, W., Chen, L., Xiang, R., Xiao, H., De, G., Wang, Z., Qi, Y. J. Biol. Chem. (2004) [Pubmed]
  21. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. Emanuelli, B., Peraldi, P., Filloux, C., Chavey, C., Freidinger, K., Hilton, D.J., Hotamisligil, G.S., Van Obberghen, E. J. Biol. Chem. (2001) [Pubmed]
  22. SOCS3 negatively regulates IL-6 signaling in vivo. Croker, B.A., Krebs, D.L., Zhang, J.G., Wormald, S., Willson, T.A., Stanley, E.G., Robb, L., Greenhalgh, C.J., Förster, I., Clausen, B.E., Nicola, N.A., Metcalf, D., Hilton, D.J., Roberts, A.W., Alexander, W.S. Nat. Immunol. (2003) [Pubmed]
  23. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. Nicholson, S.E., Willson, T.A., Farley, A., Starr, R., Zhang, J.G., Baca, M., Alexander, W.S., Metcalf, D., Hilton, D.J., Nicola, N.A. EMBO J. (1999) [Pubmed]
  24. Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. Denson, L.A., Held, M.A., Menon, R.K., Frank, S.J., Parlow, A.F., Arnold, D.L. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  25. Lipoteichoic acid-related molecule derived from the streptococcal preparation, OK-432, which suppresses atopic dermatitis-like lesions in NC/Nga mice. Horiuchi, Y., Bae, S., Katayama, I., Oshikawa, T., Okamoto, M., Sato, M. Arch. Dermatol. Res. (2006) [Pubmed]
  26. A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor. Smeets, R.L., Veenbergen, S., Arntz, O.J., Bennink, M.B., Joosten, L.A., van den Berg, W.B., van de Loo, F.A. Arthritis Rheum. (2006) [Pubmed]
  27. Pituitary corticotroph SOCS-3: novel intracellular regulation of leukemia-inhibitory factor-mediated proopiomelanocortin gene expression and adrenocorticotropin secretion. Auernhammer, C.J., Chesnokova, V., Bousquet, C., Melmed, S. Mol. Endocrinol. (1998) [Pubmed]
  28. Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4. Li, Y., McClintick, J., Zhong, L., Edenberg, H.J., Yoder, M.C., Chan, R.J. Blood (2005) [Pubmed]
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