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Gene Review

Socs6  -  suppressor of cytokine signaling 6

Mus musculus

Synonyms: 1500012M23Rik, 5830401B18Rik, AI447482, CIS-4, CIS4, ...
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Disease relevance of Socs6


High impact information on Socs6

  • IL-12-induced increases in the production of interferon (IFN)-gamma cellular proliferation and natural killer (NK) cell cytotoxicity are abrogated in lymphocytes from STAT4-deficient mice [6].
  • Overexpression of SLIM leads to impaired STAT1 and STAT4 activity due to reduced STAT protein levels, while SLIM-deficiency results in increased STAT expression and thus enhanced IFNgamma production by Th1 cells [7].
  • T-bet was shown to bind the IFNgamma and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway [8].
  • We found that T-bet expression during T cell activation was strongly dependent on IFN-gamma signaling and STAT1 activation, but was independent of STAT4 [9].
  • An immune response also induced in the brain of the GIFN/STAT2-/- mice was associated with IFN-gamma gene expression by CD3+ T cells and the activation of the STAT1, STAT3, STAT4, and STAT5 molecules [10].

Chemical compound and disease context of Socs6

  • We conclude that the increased susceptibility of female NOD mice to the development of autoimmune diabetes could be due to the enhancement of the Th1 immune response through the increase of IL-12-induced STAT4 activation by estrogen [11].

Biological context of Socs6


Anatomical context of Socs6

  • To investigate the function of this interaction, we constitutively expressed SOCS6 in cell lines [13].
  • Positive regulatory factors induced by IL-12/STAT4 and IL-4/STAT6 signaling during T cell development contribute to polarized patterns of cytokine expression manifested by differentiated Th cells [17].
  • Furthermore, SOCS-6 expression is transiently increased by serum and insulin in normal fibroblasts [14].
  • Surprisingly, the SOCS-6 transgenics had no significant defects in the cytokine signaling and hematopoietic system but displayed significant improvements in glucose metabolism [14].
  • Although the increased expression of STAT1 RNA was widely distributed and included neurons, astrocytes, and microglia, STAT4 and STAT3 and SOCS1 and SOCS3 RNA was primarily restricted to the infiltrating mononuclear cell population [15].

Associations of Socs6 with chemical compounds

  • We investigated the binding specificity of the SOCS-6 and SOCS-7 SH2 domains and found that they preferentially bound to phosphopeptides containing a valine in the phosphotyrosine (pY) +1 position and a hydrophobic residue in the pY +2 and pY +3 positions [12].
  • Using KIT mutants and peptides, we demonstrated that SOCS6 bound directly to KIT tyrosine 567 in the juxtamembrane domain [13].
  • Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism [14].
  • Additionally, the results imply the existence of STAT4 serine phosphorylation-dependent and -independent target genes [18].
  • Altogether, these data suggest that STAT4-mediated pathways play a role locally within the airway for the exacerbation of the allergen-induced responses [19].

Physical interactions of Socs6

  • A1 prevented AP-1 binding by inhibiting STAT4 involvement and down-regulated synergistic IFN-gamma promoter activation [20].
  • However, the failure of STAT4(-/-) T cells to induce an IL-18R complex was not corrected by IFN-gamma [21].
  • Evidence suggests that STAT4 also facilitates binding of other factors to the CD25 promoter including c-Jun [22].

Regulatory relationships of Socs6


Other interactions of Socs6

  • These results indicate that SOCS6 binds to KIT juxtamembrane region, which affects upstream signaling components leading to MAPK activation [13].
  • 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 [26].
  • We found that SOCS-6 and SOCS-7 are expressed ubiquitously in murine tissues [12].
  • SOCS4 expression, in contrast, does not appear to be EPO inducible [27].
  • In addition to the polarized activation of STAT4 in T(h)1 cells and STAT6 in T(h)2 cells, we found that STAT3 and STAT5 are selectively activated in T(h)1 cells after differentiation [28].

Analytical, diagnostic and therapeutic context of Socs6

  • To examine the contribution of continued IL-12 signaling to the SOCS-1(-/-) disease, we generated mice lacking both SOCS-1 and signal transducer and activator of transcription 4 (STAT4), an essential component of the IL-12 signaling pathway [29].
  • By gene targeting, we have generated mice deficient in STAT4 to determine whether the function of this transcription factor is redundant with other signalling molecules activated by IL-12 [6].
  • We compared the ability of bone marrow transplantation (BMT) with the inclusion of spleen cells from STAT6(-/-), STAT4(-/-), and wild-type (WT) mice to produce graft-versus-host disease (GVHD) in lethally irradiated MHC-mismatched recipients [3].
  • Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance [30].
  • Either the adoptive transfer of STAT4(-/-) splenocytes or the administration of IL-4Fc fusion protein into STAT6(-/-) mice resulted in long term graft survival [31].


  1. STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia. Lentsch, A.B., Kato, A., Davis, B., Wang, W., Chao, C., Edwards, M.J. J. Clin. Invest. (2001) [Pubmed]
  2. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. Chitnis, T., Najafian, N., Benou, C., Salama, A.D., Grusby, M.J., Sayegh, M.H., Khoury, S.J. J. Clin. Invest. (2001) [Pubmed]
  3. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. Nikolic, B., Lee, S., Bronson, R.T., Grusby, M.J., Sykes, M. J. Clin. Invest. (2000) [Pubmed]
  4. Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence. Holz, A., Bot, A., Coon, B., Wolfe, T., Grusby, M.J., von Herrath, M.G. J. Immunol. (1999) [Pubmed]
  5. IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. Fairweather, D., Frisancho-Kiss, S., Yusung, S.A., Barrett, M.A., Davis, S.E., Steele, R.A., Gatewood, S.J., Rose, N.R. J. Immunol. (2005) [Pubmed]
  6. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Kaplan, M.H., Sun, Y.L., Hoey, T., Grusby, M.J. Nature (1996) [Pubmed]
  7. SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Tanaka, T., Soriano, M.A., Grusby, M.J. Immunity (2005) [Pubmed]
  8. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Lovett-Racke, A.E., Rocchini, A.E., Choy, J., Northrop, S.C., Hussain, R.Z., Ratts, R.B., Sikder, D., Racke, M.K. Immunity (2004) [Pubmed]
  9. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., Murphy, T.L., Murphy, K.M. Nat. Immunol. (2002) [Pubmed]
  10. Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain. Wang, J., Pham-Mitchell, N., Schindler, C., Campbell, I.L. J. Clin. Invest. (2003) [Pubmed]
  11. Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in nonobese diabetic mice. Bao, M., Yang, Y., Jun, H.S., Yoon, J.W. J. Immunol. (2002) [Pubmed]
  12. 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.G., Starr, R., De Souza, D.P., Hanzinikolas, K., Eyles, J., Connolly, L.M., Simpson, R.J., Nicola, N.A., Nicholson, S.E., Baca, M., Hilton, D.J., Alexander, W.S. Mol. Cell. Biol. (2002) [Pubmed]
  13. Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling. Bayle, J., Letard, S., Frank, R., Dubreuil, P., De Sepulveda, P. J. Biol. Chem. (2004) [Pubmed]
  14. Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism. Li, L., Grønning, L.M., Anderson, P.O., Li, S., Edvardsen, K., Johnston, J., Kioussis, D., Shepherd, P.R., Wang, P. J. Biol. Chem. (2004) [Pubmed]
  15. Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis. Maier, J., Kincaid, C., Pagenstecher, A., Campbell, I.L. Am. J. Pathol. (2002) [Pubmed]
  16. 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]
  17. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. Egwuagu, C.E., Yu, C.R., Zhang, M., Mahdi, R.M., Kim, S.J., Gery, I. J. Immunol. (2002) [Pubmed]
  18. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Morinobu, A., Gadina, M., Strober, W., Visconti, R., Fornace, A., Montagna, C., Feldman, G.M., Nishikomori, R., O'Shea, J.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  19. STAT4 signal pathways regulate inflammation and airway physiology changes in allergic airway inflammation locally via alteration of chemokines. Raman, K., Kaplan, M.H., Hogaboam, C.M., Berlin, A., Lukacs, N.W. J. Immunol. (2003) [Pubmed]
  20. Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN-gamma production induced by IL-12 alone or together with IL-18. Sugimoto, N., Nakahira, M., Ahn, H.J., Micallef, M., Hamaoka, T., Kurimoto, M., Fujiwara, H. Eur. J. Immunol. (2003) [Pubmed]
  21. An absolute requirement for STAT4 and a role for IFN-gamma as an amplifying factor in IL-12 induction of the functional IL-18 receptor complex. Nakahira, M., Tomura, M., Iwasaki, M., Ahn, H.J., Bian, Y., Hamaoka, T., Ohta, T., Kurimoto, M., Fujiwara, H. J. Immunol. (2001) [Pubmed]
  22. STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus. O'Sullivan, A., Chang, H.C., Yu, Q., Kaplan, M.H. J. Biol. Chem. (2004) [Pubmed]
  23. The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins. Bayle, J., Lopez, S., Iwaï, K., Dubreuil, P., De Sepulveda, P. FEBS Lett. (2006) [Pubmed]
  24. Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation. Ahn, H.J., Tomura, M., Yu, W.G., Iwasaki, M., Park, W.R., Hamaoka, T., Fujiwara, H. J. Immunol. (1998) [Pubmed]
  25. The production of IFN-gamma by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4. Schindler, H., Lutz, M.B., Röllinghoff, M., Bogdan, C. J. Immunol. (2001) [Pubmed]
  26. 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]
  27. Differential roles of SOCS family members in EpoR signal transduction. Jegalian, A.G., Wu, H. J. Interferon Cytokine Res. (2002) [Pubmed]
  28. Differential activation of signal transducer and activator of transcription (STAT)3 and STAT5 and induction of suppressors of cytokine signalling in T(h)1 and T(h)2 cells. Anderson, P., Sundstedt, A., Li, L., O'Neill, E.J., Li, S., Wraith, D.C., Wang, P. Int. Immunol. (2003) [Pubmed]
  29. Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1. Eyles, J.L., Metcalf, D., Grusby, M.J., Hilton, D.J., Starr, R. J. Biol. Chem. (2002) [Pubmed]
  30. Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance. Zhou, P., Szot, G.L., Guo, Z., Kim, O., He, G., Wang, J., Grusby, M.J., Newell, K.A., Thistlethwaite, J.R., Bluestone, J.A., Alegre, M.L. J. Immunol. (2000) [Pubmed]
  31. Physiological mechanisms of regulating alloimmunity: cytokines, CTLA-4, CD25+ cells, and the alloreactive T cell clone size. Sho, M., Yamada, A., Najafian, N., Salama, A.D., Harada, H., Sandner, S.E., Sanchez-Fueyo, A., Zheng, X.X., Strom, T.B., Sayegh, M.H. J. Immunol. (2002) [Pubmed]
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