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Gene Review

SOCS6  -  suppressor of cytokine signaling 6

Homo sapiens

Synonyms: CIS-4, CIS4, Cish4, Cytokine-inducible SH2 protein 4, HSPC060, ...
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Disease relevance of SOCS6


Psychiatry related information on SOCS6

  • Somatoform autonomic dysfunction, a diagnostic category proposed by ICD-10, included fewer patients diagnosed with somatization disorder than the criteria of Escobar and colleagues for abridged somatization disorder (SSI-4/6: this Journal 177:140-146, 1989) [4].
  • In-depth explorations, including problem solving and projection to the future, occurred 2.59 times in interviews alone (CI 3.62-1.56) and 0.794 times in CIRs (CI 1.12-0.46) (p <.001) [5].

High impact information on SOCS6

  • The crystal structure of an NH2-terminal conserved domain (N-domain) comprising the first 123 residues of STAT-4 was determined at 1.45 angstroms [6].
  • Three exons overlap with ING2 (a putative tumor suppressor) and with a homologue of CIS4 (cytokine-inducible SH2 protein 4), both of which are encoded by the opposite strand [7].
  • IL12 phosphorylation of STAT4 can be observed in HUVEC that have been transduced to express the IL12R [8].
  • STAT4 signaling, activated by either interleukin 12 (IL12) or interferon alpha (IFNalpha), promotes T(H)1 responses in CD4(+) T cells [8].
  • Interferon alpha but not interleukin 12 activates STAT4 signaling in human vascular endothelial cells [8].

Biological context of SOCS6


Anatomical context of SOCS6

  • The increased SOCS6 stability and Erk activation by PMA were both conserved in another cell line, MCF7 [9].
  • Cultured human umbilical vein EC (HUVEC) express low levels of STAT4, which may be tyrosine-phosphorylated by treatment with IFNalpha but not IL12 [8].
  • Th2 cells remained responsive to IL-12, which repressed STAT6 DNA binding and activated STAT4, and switched the cells to Th1 [12].
  • In Th1 cells, IL-12 activated both STAT6 and STAT4, and IL-4 activated STAT6, but in both cases the Th1 phenotype remained [12].
  • The number of CD4+, CD8+ cells and macrophages expressing nuclear factor-kappa B (NF-kappaB), STAT-4 and IFN-gamma proteins as well as endothelial adhesion molecule-1 in endothelium is increased in mild/moderate disease [13].

Associations of SOCS6 with chemical compounds

  • We confirmed that IL-2-mediated signaling involves activation by phosphorylation of Jak2 tyrosine kinase and subsequently STAT4 [11].
  • They also reveal the existence of sperm specific mRNAs coding for the transcription factor Stat 4, the cyclin B1 and for the testicular isozyme of the angiotensin converting enzyme ACE [14].

Other interactions of SOCS6

  • However, Th2 cells remained responsive to IL-12, which repressed STAT6 DNA binding but activated STAT4, and this coincided with a suppression of IL-4/IL-5 and an induction of IFN-gamma [12].
  • Atopic T cells expressed regular levels of CD3, CD28 and Stat4, the main signal transducer and activator of transcription for IL-12 [15].
  • The transcription factor STAT4 binds the TTCCAATAA motif within this responsive element and, therefore, is probably involved in enhancing c-myc transcription upon IL-2 stimulation [11].

Analytical, diagnostic and therapeutic context of SOCS6

  • STAT4 (signal transducer and activator of transcription-4) mediates biological effects in response to interleukin-12 (IL-12) [10].
  • The aim of the present study was to evaluate the genetic status of three novel putative tumor suppressors, Cadh-7, DNAX accessory molecule-1 (Dnam-1) and suppressor of cytokine signaling (Socs6) on chromosome 18q and to correlate molecular results with patient survival and benefit from adjuvant chemotherapy [1].


  1. Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer. Storojeva, I., Boulay, J.L., Ballabeni, P., Buess, M., Terracciano, L., Laffer, U., Mild, G., Herrmann, R., Rochlitz, C. Oncology (2005) [Pubmed]
  2. The role of signal transducers and activators of transcription in T inflammatory bowel diseases. Mudter, J., Neurath, M.F. Inflamm. Bowel Dis. (2003) [Pubmed]
  3. STAT4 activation in smokers and patients with chronic obstructive pulmonary disease. Di Stefano, A., Caramori, G., Capelli, A., Gnemmi, I., Ricciardolo, F.L., Oates, T., Donner, C.F., Chung, K.F., Barnes, P.J., Adcock, I.M. Eur. Respir. J. (2004) [Pubmed]
  4. 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]
  5. Promoting reflection on professionalism: a comparison trial of educational interventions for medical students. Baernstein, A., Fryer-Edwards, K. Academic medicine : journal of the Association of American Medical Colleges. (2003) [Pubmed]
  6. Structure of the amino-terminal protein interaction domain of STAT-4. Vinkemeier, U., Moarefi, I., Darnell, J.E., Kuriyan, J. Science (1998) [Pubmed]
  7. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. Nolte, D., Niemann, S., Müller, U. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  8. Interferon alpha but not interleukin 12 activates STAT4 signaling in human vascular endothelial cells. Torpey, N., Maher, S.E., Bothwell, A.L., Pober, J.S. J. Biol. Chem. (2004) [Pubmed]
  9. Increased SOCS6 stability with PMA requires its N-terminal region and the Erk pathway via Pkcdelta activation. Hwang, M.N., Ha, T.H., Park, J., Shim, J., Lee, H., Kim, Y.N., Lee, E.S., Yoon, S. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  10. STAT4 requires the N-terminal domain for efficient phosphorylation. Chang, H.C., Zhang, S., Oldham, I., Naeger, L., Hoey, T., Kaplan, M.H. J. Biol. Chem. (2003) [Pubmed]
  11. Regulation of c-myc transcription by interleukin-2 (IL-2). Identification of a novel IL-2 response element interacting with STAT-4. Grigorieva, I., Grigoriev, V.G., Rowney, M.K., Hoover, R.G. J. Biol. Chem. (2000) [Pubmed]
  12. Activation of STAT proteins and cytokine genes in human Th1 and Th2 cells generated in the absence of IL-12 and IL-4. Moriggl, R., Kristofic, C., Kinzel, B., Volarevic, S., Groner, B., Brinkmann, V. J. Immunol. (1998) [Pubmed]
  13. Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Di Stefano, A., Caramori, G., Ricciardolo, F.L., Capelli, A., Adcock, I.M., Donner, C.F. Clin. Exp. Allergy (2004) [Pubmed]
  14. Accumulation of transcripts in the mature human sperm nucleus: implication of the haploid genome in a functional role. Siffroi, J.P., Dadoune, J.P. Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia. (2001) [Pubmed]
  15. IFN-gamma is only partially restored by co-stimulation with IL-12, IL-2, IL-15, IL-18 or engagement of CD28. Jung, T., Witzak, K., Dieckhoff, K., Zachmann, K., Heidrich, S., Aversa, G., Neumann, C. Clin. Exp. Allergy (1999) [Pubmed]
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