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Gene Review

SOCS3  -  suppressor of cytokine signaling 3

Homo sapiens

Synonyms: ATOD4, CIS-3, CIS3, Cish3, Cytokine-inducible SH2 protein 3, ...
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Disease relevance of SOCS3


Psychiatry related information on SOCS3

  • Food deprivation (48 h) reduced SOCS3 gene expression in hamsters acclimated to either long (LD) or short (SD) photoperiods, suggesting that leptin signals acute starvation regardless of photoperiod [6].
  • Although the original Escobar criteria were built upon the symptom list of DSM-III-R somatization disorder, SSI-3/5 is an empirically derived equivalent according to DSM-IV in our study (a minimum of 3 symptoms for men or 5 symptoms for women out of the list of 33 somatization symptoms according to DSM-IV) [7].
  • In contrast, the ability of a maximally stimulating dose of GH to modulate selected biological responses in vivo was not impaired by chronic alcohol consumption and was associated with a lack of a GH-induced increase in SOCS-3 mRNA [8].

High impact information on SOCS3


Chemical compound and disease context of SOCS3


Biological context of SOCS3


Anatomical context of SOCS3


Associations of SOCS3 with chemical compounds


Physical interactions of SOCS3

  • Further, we show that SOCS-3 coimmunoprecipitates with the PRLR [25].
  • RESULTS: We showed that endogenous CIS3 bound to JAK2 in intact cells [26].
  • We conclude that SOCS-3 binds to the IGFIR and may be a direct substrate for the receptor tyrosine kinase [27].
  • Here we show that human SOCS-3 binds to pY401 with a Kd of 9.5 microm while another EpoR tyrosine motif, pY429pY431, can also interact with SOCS-3 but with a ninefold higher affinity than we found for the previously reported motif pY401 [28].
  • This was underscored by the tight conservation in the location and sequence of the tandem STAT binding sites between the murine and human Socs3 promoters [29].

Regulatory relationships of SOCS3

  • Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth [22].
  • Therefore, CIS3 and JAB inhibit JAK2 tyrosine kinase activity by an essentially similar mechanism [26].
  • Consequently, IL-22 upregulated mRNA for Suppressor of Cytokine Signaling 3 (SOCS3), a STAT3-responsive gene [30].
  • In myeloid 32D cells, SOCS1 and SOCS3 are induced by G-CSF [31].
  • In conclusion, suppression of IFN signaling by HSV-1-induced SOCS3 is required for efficient replication and lytic infection of HSV-1 [19].
  • These data indicate that TNF-alpha regulates SOCS3 expression on the level of mRNA stability via activation of the MKK6/p38(MAPK) cascade and that the activation of MK2, a downstream target of p38(MAPK), is important for the regulation of SOCS3 expression [32].

Other interactions of SOCS3


Analytical, diagnostic and therapeutic context of SOCS3


  1. Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. Federici, M., Giustizieri, M.L., Scarponi, C., Girolomoni, G., Albanesi, C. J. Immunol. (2002) [Pubmed]
  2. Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals. Evans, M.K., Yu, C.R., Lohani, A., Mahdi, R.M., Liu, X., Trzeciak, A.R., Egwuagu, C.E. Oncogene (2007) [Pubmed]
  3. Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 contributes to inhibition of the interferon signaling pathway. Yokota, S., Yokosawa, N., Okabayashi, T., Suzutani, T., Miura, S., Jimbow, K., Fujii, N. J. Virol. (2004) [Pubmed]
  4. Methylation status of the SOCS3 gene in human malignant melanomas. Tokita, T., Maesawa, C., Kimura, T., Kotani, K., Takahashi, K., Akasaka, T., Masuda, T. Int. J. Oncol. (2007) [Pubmed]
  5. A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency. Wang, X., Athayde, N., Trudinger, B. Am. J. Obstet. Gynecol. (2003) [Pubmed]
  6. Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression. Tups, A., Ellis, C., Moar, K.M., Logie, T.J., Adam, C.L., Mercer, J.G., Klingenspor, M. Endocrinology (2004) [Pubmed]
  7. The classification of multiple somatoform symptoms. Rief, W., Heuser, J., Mayrhuber, E., Stelzer, I., Hiller, W., Fichter, M.M. J. Nerv. Ment. Dis. (1996) [Pubmed]
  8. Acute effects of growth hormone in alcohol-fed rats. Lang, C.H., Liu, X., Nystrom, G., Wu, D., Cooney, R.N., Frost, R.A. Alcohol Alcohol. (2000) [Pubmed]
  9. Suppressors of cytokine signaling and immunity. Kubo, M., Hanada, T., Yoshimura, A. Nat. Immunol. (2003) [Pubmed]
  10. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Babon, J.J., McManus, E.J., Yao, S., DeSouza, D.P., Mielke, L.A., Sprigg, N.S., Willson, T.A., Hilton, D.J., Nicola, N.A., Baca, M., Nicholson, S.E., Norton, R.S. Mol. Cell (2006) [Pubmed]
  11. Molecular and anatomical determinants of central leptin resistance. Münzberg, H., Myers, M.G. Nat. Neurosci. (2005) [Pubmed]
  12. Functional inactivation of CXC chemokine receptor 4-mediated responses through SOCS3 up-regulation. Soriano, S.F., Hernanz-Falcón, P., Rodríguez-Frade, J.M., De Ana, A.M., Garzón, R., Carvalho-Pinto, C., Vila-Coro, A.J., Zaballos, A., Balomenos, D., Martínez-A, C., Mellado, M. J. Exp. Med. (2002) [Pubmed]
  13. Estrogen receptor-alpha regulates SOCS-3 expression in human breast cancer cells. Matthews, J., Almlöf, T., Kietz, S., Leers, J., Gustafsson, J.A. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  14. Polycythemia vera and its molecular basis: an update. Chen, G., Prchal, J.T. Best practice & research. Clinical haematology. (2006) [Pubmed]
  15. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Calvisi, D.F., Ladu, S., Gorden, A., Farina, M., Conner, E.A., Lee, J.S., Factor, V.M., Thorgeirsson, S.S. Gastroenterology (2006) [Pubmed]
  16. Interleukin-10 (IL-10) selectively enhances CIS3/SOCS3 mRNA expression in human neutrophils: evidence for an IL-10-induced pathway that is independent of STAT protein activation. Cassatella, M.A., Gasperini, S., Bovolenta, C., Calzetti, F., Vollebregt, M., Scapini, P., Marchi, M., Suzuki, R., Suzuki, A., Yoshimura, A. Blood (1999) [Pubmed]
  17. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. Haan, S., Ferguson, P., Sommer, U., Hiremath, M., McVicar, D.W., Heinrich, P.C., Johnston, J.A., Cacalano, N.A. J. Biol. Chem. (2003) [Pubmed]
  18. The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. Bode, J.G., Ludwig, S., Freitas, C.A., Schaper, F., Ruhl, M., Melmed, S., Heinrich, P.C., Häussinger, D. Biol. Chem. (2001) [Pubmed]
  19. Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 confers efficient viral replication. Yokota, S., Yokosawa, N., Okabayashi, T., Suzutani, T., Fujii, N. Virology (2005) [Pubmed]
  20. Vanadate enhances leptin-induced activation of JAK/STAT pathway in CHO cells. Kita, A., Uotani, S., Kuwahara, H., Takahashi, R., Oshima, K., Yamasaki, H., Mizuguchi, H., Hayakawa, T., Nagayama, Y., Yamaguchi, Y., Eguchi, K. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  21. Sp3 is involved in the regulation of SOCS3 gene expression. Ehlting, C., Häussinger, D., Bode, J.G. Biochem. J. (2005) [Pubmed]
  22. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Niwa, Y., Kanda, H., Shikauchi, Y., Saiura, A., Matsubara, K., Kitagawa, T., Yamamoto, J., Kubo, T., Yoshikawa, H. Oncogene (2005) [Pubmed]
  23. Probiotics and commensals reverse TNF-alpha- and IFN-gamma-induced dysfunction in human intestinal epithelial cells. Resta-Lenert, S., Barrett, K.E. Gastroenterology (2006) [Pubmed]
  24. Interleukin 11 signaling components signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) regulate human endometrial stromal cell differentiation. Dimitriadis, E., Stoikos, C., Tan, Y.L., Salamonsen, L.A. Endocrinology (2006) [Pubmed]
  25. Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor. Dif, F., Saunier, E., Demeneix, B., Kelly, P.A., Edery, M. Endocrinology (2001) [Pubmed]
  26. Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain. Sasaki, A., Yasukawa, H., Suzuki, A., Kamizono, S., Syoda, T., Kinjyo, I., Sasaki, M., Johnston, J.A., Yoshimura, A. Genes Cells (1999) [Pubmed]
  27. Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor. Dey, B.R., Furlanetto, R.W., Nissley, P. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  28. A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. Hörtner, M., Nielsch, U., Mayr, L.M., Heinrich, P.C., Haan, S. Eur. J. Biochem. (2002) [Pubmed]
  29. IL-6 signaling via the STAT3/SOCS3 pathway: Functional Analysis of the Conserved STAT3 N-domain. Zhang, L., Badgwell, D.B., Bevers, J.J., Schlessinger, K., Murray, P.J., Levy, D.E., Watowich, S.S. Mol. Cell. Biochem. (2006) [Pubmed]
  30. Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Nagalakshmi, M.L., Rascle, A., Zurawski, S., Menon, S., de Waal Malefyt, R. Int. Immunopharmacol. (2004) [Pubmed]
  31. Distinct activities of suppressor of cytokine signaling (SOCS) proteins and involvement of the SOCS box in controlling G-CSF signaling. van de Geijn, G.J., Gits, J., Touw, I.P. J. Leukoc. Biol. (2004) [Pubmed]
  32. Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-alpha involves activation of the MKK6/p38MAPK/MK2 cascade. Ehlting, C., Lai, W.S., Schaper, F., Brenndörfer, E.D., Matthes, R.J., Heinrich, P.C., Ludwig, S., Blackshear, P.J., Gaestel, M., Häussinger, D., Bode, J.G. J. Immunol. (2007) [Pubmed]
  33. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. He, B., You, L., Uematsu, K., Zang, K., Xu, Z., Lee, A.Y., Costello, J.F., McCormick, F., Jablons, D.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  34. Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Leung, K.C., Doyle, N., Ballesteros, M., Sjogren, K., Watts, C.K., Low, T.H., Leong, G.M., Ross, R.J., Ho, K.K. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  35. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. Song, M.M., Shuai, K. J. Biol. Chem. (1998) [Pubmed]
  36. Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Ogata, H., Kobayashi, T., Chinen, T., Takaki, H., Sanada, T., Minoda, Y., Koga, K., Takaesu, G., Maehara, Y., Iida, M., Yoshimura, A. Gastroenterology (2006) [Pubmed]
  37. STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Mitsuyama, K., Matsumoto, S., Rose-John, S., Suzuki, A., Hara, T., Tomiyasu, N., Handa, K., Tsuruta, O., Funabashi, H., Scheller, J., Toyonaga, A., Sata, M. Gut (2006) [Pubmed]
  38. SOCS1 and SOCS3 are targeted by hepatitis C virus core/gC1qR ligation to inhibit T-cell function. Yao, Z.Q., Waggoner, S.N., Cruise, M.W., Hall, C., Xie, X., Oldach, D.W., Hahn, Y.S. J. Virol. (2005) [Pubmed]
  39. Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma. Cho-Vega, J.H., Rassidakis, G.Z., Amin, H.M., Tsioli, P., Spurgers, K., Remache, Y.K., Vega, F., Goy, A.H., Gilles, F., Medeiros, L.J. Leukemia (2004) [Pubmed]
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