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Gene Review

Socs1  -  suppressor of cytokine signaling 1

Mus musculus

Synonyms: Cish1, Cish7, JAB, JAK-binding protein, JAK2-binding protein, ...
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Disease relevance of Socs1


High impact information on Socs1

  • Analyses of genetically modified mice in which SOCS proteins are overexpressed or deleted have established that this family of negative regulators has indispensable roles in regulating cytokine responses in cells of the immune system as well as other tissues [5].
  • SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine [6].
  • SOCS1 is an SH2-containing protein that is primarily expressed in thymocytes in a cytokine- and T cell receptor-independent manner [7].
  • The results demonstrate that lymphocytes are critical to SOCS1-associated perinatal lethality and implicate SOCS1 in lymphocyte differentiation or regulation [7].
  • When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2 [8].

Chemical compound and disease context of Socs1


Biological context of Socs1

  • Suppressor of cytokine signaling 1 (Socs1) is critical for the regulation of interferon-gamma responses and T cell homeostasis [10].
  • Moreover, negative selection was also impaired, suggesting that autoimmunity contributes to the disease observed in Socs1(-/-) mice [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 [11].
  • In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein [12].
  • In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity [12].

Anatomical context of Socs1

  • Socs1-deficient T cell receptor-transgenic mice showed severely impaired positive selection and a substantial alteration in CD4-CD8 T cell fate specification [10].
  • We conclude that the constitutive expression of Socs1 in the thymus protects the process of thymic development and selection from the effects of systemic inflammation [10].
  • To rigorously test this, we isolated macrophages from Socs1-/- mice on multiple genetic backgrounds [13].
  • We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF) [8].
  • In this paper, we show that murine embryonic fibroblasts lacking the SSI-1 gene are more sensitive than their littermate controls to tumor necrosis factor-alpha (TNF-alpha)-induced cell death [14].

Associations of Socs1 with chemical compounds

  • In hyperinsulinemic clamp studies, however, Socs1-/- Ifng-/- mice had enhanced hepatic insulin sensitivity demonstrated by greater suppression of endogenous glucose production compared with controls with no difference in glucose disposal [1].
  • Using the yeast two-hybrid system, we have now isolated a new SH2-domain-containing protein, JAB, which is a JAK-binding protein that interacts with the Jak2 tyrosine-kinase JH1 domain [15].
  • Here we show that Socs-1 interacts with members of the Pim family of serine/threonine kinases in thymocytes [16].
  • In thymocytes expressing SSI-1 transgene, tyrosine phosphorylation of STATs in response to cytokines such as IFN-gamma, IL-6, and IL-7 was inhibited, suggesting that SSI-1 suppresses cytokine signaling in primary lymphocytes [17].
  • 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 [18].
  • In agreement, expression of IFN-gamma responsive genes, but not IL-1beta, IL-6, or TNF-alpha were relatively increased in C. pneumoniae-infected SOCS1(-/-) BMM [19].

Physical interactions of Socs1

  • Mutation of Tyr(441) also blocked the ability of SOCS-1 to bind to IFNGR1 and JAK2 in response to IFNgamma and the normal down-regulation of STAT1 activation and antiviral activity [20].

Regulatory relationships of Socs1


Other interactions of Socs1

  • 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].
  • Furthermore L929/SSI-1 cells treated with TNF-alpha sustain the activation of p38 mitogen-activated protein (MAP) kinase [14].
  • In situ hybridisation analysis showed that SOCS-1 and SOCS-3 had a low and widespread pattern of expression, whereas SOCS-2 expression was higher and tightly regulated [24].
  • One of them, SOCS1, is also known to be involved in auto-regulation of IRS-1-mediated signaling [2].
  • SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable [25].

Analytical, diagnostic and therapeutic context of Socs1


  1. Socs1 deficiency enhances hepatic insulin signaling. Jamieson, E., Chong, M.M., Steinberg, G.R., Jovanovska, V., Fam, B.C., Bullen, D.V., Chen, Y., Kemp, B.E., Proietto, J., Kay, T.W., Andrikopoulos, S. J. Biol. Chem. (2005) [Pubmed]
  2. Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-I receptor signal transduction. Inaba, M., Saito, H., Fujimoto, M., Sumitani, S., Ohkawara, T., Tanaka, T., Kouhara, H., Kasayama, S., Kawase, I., Kishimoto, T., Naka, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  3. 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]
  4. Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNgamma and IL-4 are involved. Chinen, T., Kobayashi, T., Ogata, H., Takaesu, G., Takaki, H., Hashimoto, M., Yagita, H., Nawata, H., Yoshimura, A. Gastroenterology (2006) [Pubmed]
  5. The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Alexander, W.S., Hilton, D.J. Annu. Rev. Immunol. (2004) [Pubmed]
  6. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Alexander, W.S., Starr, R., Fenner, J.E., Scott, C.L., Handman, E., Sprigg, N.S., Corbin, J.E., Cornish, A.L., Darwiche, R., Owczarek, C.M., Kay, T.W., Nicola, N.A., Hertzog, P.J., Metcalf, D., Hilton, D.J. Cell (1999) [Pubmed]
  7. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Marine, J.C., Topham, D.J., McKay, C., Wang, D., Parganas, E., Stravopodis, D., Yoshimura, A., Ihle, J.N. Cell (1999) [Pubmed]
  8. Structure and function of a new STAT-induced STAT inhibitor. Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., Akira, S., Kishimoto, T. Nature (1997) [Pubmed]
  9. SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. Yoshida, T., Ogata, H., Kamio, M., Joo, A., Shiraishi, H., Tokunaga, Y., Sata, M., Nagai, H., Yoshimura, A. J. Exp. Med. (2004) [Pubmed]
  10. Suppressor of cytokine signaling 1 is required for the differentiation of CD4+ T cells. Catlett, I.M., Hedrick, S.M. Nat. Immunol. (2005) [Pubmed]
  11. 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]
  12. The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. Monni, R., Santos, S.C., Mauchauffe, M., Berger, R., Ghysdael, J., Gouilleux, F., Gisselbrecht, S., Bernard, O., Penard-Lacronique, V. Oncogene (2001) [Pubmed]
  13. Re-examination of the role of suppressor of cytokine signaling 1 (SOCS1) in the regulation of toll-like receptor signaling. Gingras, S., Parganas, E., de Pauw, A., Ihle, J.N., Murray, P.J. J. Biol. Chem. (2004) [Pubmed]
  14. Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts. Morita, Y., Naka, T., Kawazoe, Y., Fujimoto, M., Narazaki, M., Nakagawa, R., Fukuyama, H., Nagata, S., Kishimoto, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  15. A new protein containing an SH2 domain that inhibits JAK kinases. Endo, T.A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., Yoshimura, A. Nature (1997) [Pubmed]
  16. Pim serine/threonine kinases regulate the stability of Socs-1 protein. Chen, X.P., Losman, J.A., Cowan, S., Donahue, E., Fay, S., Vuong, B.Q., Nawijn, M.C., Capece, D., Cohan, V.L., Rothman, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  17. Defective thymocyte development and perturbed homeostasis of T cells in STAT-induced STAT inhibitor-1/suppressors of cytokine signaling-1 transgenic mice. Fujimoto, M., Naka, T., Nakagawa, R., Kawazoe, Y., Morita, Y., Tateishi, A., Okumura, K., Narazaki, M., Kishimoto, T. J. Immunol. (2000) [Pubmed]
  18. 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]
  19. SOCS-1 protects against Chlamydia pneumoniae-induced lethal inflammation but hampers effective bacterial clearance. Yang, T., Stark, P., Janik, K., Wigzell, H., Rottenberg, M.E. J. Immunol. (2008) [Pubmed]
  20. Role of tyrosine 441 of interferon-gamma receptor subunit 1 in SOCS-1-mediated attenuation of STAT1 activation. Qing, Y., Costa-Pereira, A.P., Watling, D., Stark, G.R. J. Biol. Chem. (2005) [Pubmed]
  21. 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]
  22. Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. Wang, Q., Miyakawa, Y., Fox, N., Kaushansky, K. Blood (2000) [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. Expression of "suppressor of cytokine signalling" (SOCS) genes in the developing and adult mouse nervous system. Polizzotto, M.N., Bartlett, P.F., Turnley, A.M. J. Comp. Neurol. (2000) [Pubmed]
  25. 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. J. Clin. Invest. (2001) [Pubmed]
  26. Differences in suppressor of cytokine signaling-1 (SOCS-1) expressing islet allograft destruction in normal BALB/c and spontaneously-diabetic NOD recipient mice. Solomon, M., Flodström-Tullberg, M., Sarvetnick, N. Transplantation (2005) [Pubmed]
  27. The lethal effects of transplantation of Socs1-/- bone marrow cells into irradiated adult syngeneic recipients. Metcalf, D., Mifsud, S., Di Rago, L., Alexander, W.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  28. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Starr, R., Metcalf, D., Elefanty, A.G., Brysha, M., Willson, T.A., Nicola, N.A., Hilton, D.J., Alexander, W.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  29. Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Metcalf, D., Mifsud, S., Di Rago, L., Nicola, N.A., Hilton, D.J., Alexander, W.S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  30. Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene. Hanada, T., Tanaka, K., Matsumura, Y., Yamauchi, M., Nishinakamura, H., Aburatani, H., Mashima, R., Kubo, M., Kobayashi, T., Yoshimura, A. J. Immunol. (2005) [Pubmed]
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