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Gene Review

IL6ST  -  interleukin 6 signal transducer

Homo sapiens

Synonyms: CD130, CDW130, CDw130, GP130, IL-6 receptor subunit beta, ...
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Disease relevance of IL6ST

  • Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130 [1].
  • Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system [2].
  • Our studies demonstrate that upon heterodimerization with the gp130 cytoplasmic region, the cytoplasmic parts of both LIFR and OSMR were critical for activation of an acute phase protein promoter in HepG2 hepatoma cells [3].
  • METHODS: To define a role for gp130-RAPS in arthritis, a recombinant version was generated using a baculovirus expression system, and its activities were tested in vitro and in vivo [4].
  • RESULTS: Gp130-RAPS was shown to bind with high affinity to the stable IL-6/sIL-6R complex, hyper-IL-6, and to effectively modulate leukocyte migration in murine acute peritonitis [4].

Psychiatry related information on IL6ST


High impact information on IL6ST

  • Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction [6].
  • Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors [6].
  • Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130 [6].
  • Thus, cardiac myocyte apoptosis is a critical point in the transition between compensatory cardiac hypertrophy and heart failure. gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure [7].
  • Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress [7].

Chemical compound and disease context of IL6ST


Biological context of IL6ST


Anatomical context of IL6ST


Associations of IL6ST with chemical compounds

  • Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein [22].
  • Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130 [22].
  • Engineered LIFR mutants in which either or both of these two residues were mutated to alanine were transfected in Ba/F3 cells already containing gp130 [23].
  • Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment [8].
  • These observations add credence to the contention that increased production of gp130-utilizing cytokines and their receptors in pathological conditions like sex steroid deficiency is indeed responsible for not only the increased osteoclastogenesis, but also the increased osteoblastogenesis, and thereby for the increased rate of bone remodeling [24].

Physical interactions of IL6ST


Enzymatic interactions of IL6ST

  • We found that gp130 fusion proteins were phosphorylated exclusively on Ser-782 by LIF- and growth factor-stimulated 3T3-L1 cell extracts [29].

Regulatory relationships of IL6ST

  • IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase [22].
  • These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130 [30].
  • Together, our data reveal the crucial importance of overall vIL-6 structure and conformation for gp80-independent signaling and provide functional and physical evidence of the stabilization of vIL-6-induced gp130 signaling complexes by gp80 [31].
  • IL-11 acts on cells expressing gp130 and the IL-11 receptor (IL-11R) alpha-subunit (IL-11Ralpha) [32].
  • CT-1 activates gp130 and LIFR beta transducing components, as attested by analysing their tyrosine phosphorylation level [33].

Other interactions of IL6ST

  • Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130 [22].
  • Protein kinases of the Jak family were also rapidly tyrosine phosphorylated, and both APRF and Jak1 associated with gp130 [30].
  • These cytokines initiate signaling by inducing either homodimerization of gp130 or heterodimerization of gp130 with leukemia-inhibitory factor receptor beta components [34].
  • Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines [14].
  • Interestingly, binding of LIF to type 1 receptor was not affected, corroborating the notion that in this case gp130 mostly behaves as a converter protein rather than a binding receptor [35].

Analytical, diagnostic and therapeutic context of IL6ST


  1. Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130. Nishimoto, N., Ogata, A., Shima, Y., Tani, Y., Ogawa, H., Nakagawa, M., Sugiyama, H., Yoshizaki, K., Kishimoto, T. J. Exp. Med. (1994) [Pubmed]
  2. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Sriuranpong, V., Park, J.I., Amornphimoltham, P., Patel, V., Nelkin, B.D., Gutkind, J.S. Cancer Res. (2003) [Pubmed]
  3. Contributions of leukemia inhibitory factor receptor and oncostatin M receptor to signal transduction in heterodimeric complexes with glycoprotein 130. Hermanns, H.M., Radtke, S., Haan, C., Schmitz-Van de Leur, H., Tavernier, J., Heinrich, P.C., Behrmann, I. J. Immunol. (1999) [Pubmed]
  4. Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Richards, P.J., Nowell, M.A., Horiuchi, S., McLoughlin, R.M., Fielding, C.A., Grau, S., Yamamoto, N., Ehrmann, M., Rose-John, S., Williams, A.S., Topley, N., Jones, S.A. Arthritis Rheum. (2006) [Pubmed]
  5. Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered in cerebrospinal fluid of Alzheimer's disease patients. März, P., Heese, K., Hock, C., Golombowski, S., Müller-Spahn, F., Rose-John, S., Otten, U. Neurosci. Lett. (1997) [Pubmed]
  6. Gp130 and the interleukin-6 family of cytokines. Taga, T., Kishimoto, T. Annu. Rev. Immunol. (1997) [Pubmed]
  7. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Hirota, H., Chen, J., Betz, U.A., Rajewsky, K., Gu, Y., Ross, J., Müller, W., Chien, K.R. Cell (1999) [Pubmed]
  8. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Hideshima, T., Chauhan, D., Hayashi, T., Akiyama, M., Mitsiades, N., Mitsiades, C., Podar, K., Munshi, N.C., Richardson, P.G., Anderson, K.C. Oncogene (2003) [Pubmed]
  9. In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway. Chatterjee, M., Hönemann, D., Lentzsch, S., Bommert, K., Sers, C., Herrmann, P., Mathas, S., Dörken, B., Bargou, R.C. Blood (2002) [Pubmed]
  10. Enhancement of gp130-mediated tyrosine phosphorylation of STAT3 and its DNA-binding activity in dexamethasone-treated AIDS-associated Kaposi's sarcoma cells: selective synergy between dexamethasone and gp130-related growth factors in Kaposi's sarcoma cell proliferation. Murakami-Mori, K., Mori, S., Taga, T., Kishimoto, T., Nakamura, S. J. Immunol. (1997) [Pubmed]
  11. Endotoxemia enhances expression of the signaling receptor (GP130) on protein and molecular level. Marsik, C., Halama, T., Cardona, F., Schlifke, I., Mittermayer, F., Jilma, B. Clin. Immunol. (2005) [Pubmed]
  12. Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway. Liu, X.H., Kirschenbaum, A., Lu, M., Yao, S., Klausner, A., Preston, C., Holland, J.F., Levine, A.C. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  13. Human gp130 transducer chain gene (IL6ST) is localized to chromosome band 5q11 and possesses a pseudogene on chromosome band 17p11. Rodriguez, C., Grosgeorge, J., Nguyen, V.C., Gaudray, P., Theillet, C. Cytogenet. Cell Genet. (1995) [Pubmed]
  14. Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. Gu, Z.J., Costes, V., Lu, Z.Y., Zhang, X.G., Pitard, V., Moreau, J.F., Bataille, R., Wijdenes, J., Rossi, J.F., Klein, B. Blood (1996) [Pubmed]
  15. The immunoglobulin-like module of gp130 is required for signaling by interleukin-6, but not by leukemia inhibitory factor. Hammacher, A., Richardson, R.T., Layton, J.E., Smith, D.K., Angus, L.J., Hilton, D.J., Nicola, N.A., Wijdenes, J., Simpson, R.J. J. Biol. Chem. (1998) [Pubmed]
  16. Functional expression of soluble human interleukin-11 (IL-11) receptor alpha and stoichiometry of in vitro IL-11 receptor complexes with gp130. Neddermann, P., Graziani, R., Ciliberto, G., Paonessa, G. J. Biol. Chem. (1996) [Pubmed]
  17. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Gearing, D.P., Comeau, M.R., Friend, D.J., Gimpel, S.D., Thut, C.J., McGourty, J., Brasher, K.K., King, J.A., Gillis, S., Mosley, B. Science (1992) [Pubmed]
  18. Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130. Zhang, X.G., Gu, J.J., Lu, Z.Y., Yasukawa, K., Yancopoulos, G.D., Turner, K., Shoyab, M., Taga, T., Kishimoto, T., Bataille, R. J. Exp. Med. (1994) [Pubmed]
  19. Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Senaldi, G., Varnum, B.C., Sarmiento, U., Starnes, C., Lile, J., Scully, S., Guo, J., Elliott, G., McNinch, J., Shaklee, C.L., Freeman, D., Manu, F., Simonet, W.S., Boone, T., Chang, M.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. Functional inhibition of hematopoietic and neurotrophic cytokines by blocking the interleukin 6 signal transducer gp130. Taga, T., Narazaki, M., Yasukawa, K., Saito, T., Miki, D., Hamaguchi, M., Davis, S., Shoyab, M., Yancopoulos, G.D., Kishimoto, T. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  21. High glucose enhances interleukin-6-induced vascular endothelial growth factor 165 expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in gingival fibroblasts. Omori, K., Naruishi, K., Nishimura, F., Yamada-Naruishi, H., Takashiba, S. J. Biol. Chem. (2004) [Pubmed]
  22. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Murakami, M., Hibi, M., Nakagawa, N., Nakagawa, T., Yasukawa, K., Yamanishi, K., Taga, T., Kishimoto, T. Science (1993) [Pubmed]
  23. Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor. Plun-Favreau, H., Perret, D., Diveu, C., Froger, J., Chevalier, S., Lelièvre, E., Gascan, H., Chabbert, M. J. Biol. Chem. (2003) [Pubmed]
  24. Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. Taguchi, Y., Yamamoto, M., Yamate, T., Lin, S.C., Mocharla, H., DeTogni, P., Nakayama, N., Boyce, B.F., Abe, E., Manolagas, S.C. Proc. Assoc. Am. Physicians (1998) [Pubmed]
  25. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. Kallen, K.J., Grötzinger, J., Lelièvre, E., Vollmer, P., Aasland, D., Renné, C., Müllberg, J., Myer zum Büschenfelde, K.H., Gascan, H., Rose-John, S. J. Biol. Chem. (1999) [Pubmed]
  26. Interleukin-6 signal transducer gp130 mediates oncostatin M signaling. Liu, J., Modrell, B., Aruffo, A., Marken, J.S., Taga, T., Yasukawa, K., Murakami, M., Kishimoto, T., Shoyab, M. J. Biol. Chem. (1992) [Pubmed]
  27. Solution structure of the C-terminal domain of the ciliary neurotrophic factor (CNTF) receptor and ligand free associations among components of the CNTF receptor complex. Man, D., He, W., Sze, K.H., Gong, K., Smith, D.K., Zhu, G., Ip, N.Y. J. Biol. Chem. (2003) [Pubmed]
  28. Cdk9, a member of the cdc2-like family of kinases, binds to gp130, the receptor of the IL-6 family of cytokines. Falco, G.D., Neri, L.M., Falco, M.D., Bellan, C., Yu, Z., Luca, A.D., Leoncini, L., Giordano, A. Oncogene (2002) [Pubmed]
  29. Phosphorylation of human gp130 at Ser-782 adjacent to the Di-leucine internalization motif. Effects on expression and signaling. Gibson, R.M., Schiemann, W.P., Prichard, L.B., Reno, J.M., Ericsson, L.H., Nathanson, N.M. J. Biol. Chem. (2000) [Pubmed]
  30. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Lütticken, C., Wegenka, U.M., Yuan, J., Buschmann, J., Schindler, C., Ziemiecki, A., Harpur, A.G., Wilks, A.F., Yasukawa, K., Taga, T. Science (1994) [Pubmed]
  31. Structural Requirements for gp80 Independence of Human Herpesvirus 8 Interleukin-6 (vIL-6) and Evidence for gp80 Stabilization of gp130 Signaling Complexes Induced by vIL-6. Chen, D., Nicholas, J. J. Virol. (2006) [Pubmed]
  32. Definition of receptor binding sites on human interleukin-11 by molecular modeling-guided mutagenesis. Tacken, I., Dahmen, H., Boisteau, O., Minvielle, S., Jacques, Y., Grötzinger, J., Küster, A., Horsten, U., Blanc, C., Montero-Julian, F.A., Heinrich, P.C., Müller-Newen, G. Eur. J. Biochem. (1999) [Pubmed]
  33. Regulation of interleukin 6 expression by cardiotrophin 1. Robledo, O., Chevalier, S., Froger, J., Barthelaix-Pouplard, A., Pennica, D., Gascan, H. Cytokine (1997) [Pubmed]
  34. Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. Chauhan, D., Kharbanda, S.M., Ogata, A., Urashima, M., Frank, D., Malik, N., Kufe, D.W., Anderson, K.C. J. Exp. Med. (1995) [Pubmed]
  35. Identification of a gp130 cytokine receptor critical site involved in oncostatin M response. Olivier, C., Auguste, P., Chabbert, M., Lelièvre, E., Chevalier, S., Gascan, H. J. Biol. Chem. (2000) [Pubmed]
  36. Signaling of type II oncostatin M receptor. Auguste, P., Guillet, C., Fourcin, M., Olivier, C., Veziers, J., Pouplard-Barthelaix, A., Gascan, H. J. Biol. Chem. (1997) [Pubmed]
  37. Expression and function of members of the cytokine receptor superfamily on breast cancer cells. Douglas, A.M., Goss, G.A., Sutherland, R.L., Hilton, D.J., Berndt, M.C., Nicola, N.A., Begley, C.G. Oncogene (1997) [Pubmed]
  38. Characterization of soluble gp130 released by melanoma cell lines: A polyvalent antagonist of cytokines from the interleukin 6 family. Montero-Julian, F.A., Brailly, H., Sautès, C., Joyeux, I., Dorval, T., Mosseri, V., Yasukawa, K., Wijdenes, J., Adler, A., Gorin, I., Fridman, W.H., Tartour, E. Clin. Cancer Res. (1997) [Pubmed]
  39. Identification of a novel IL-6 isoform binding to the endogenous IL-6 receptor. Bihl, M.P., Heinimann, K., Rüdiger, J.J., Eickelberg, O., Perruchoud, A.P., Tamm, M., Roth, M. Am. J. Respir. Cell Mol. Biol. (2002) [Pubmed]
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