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Interleukin 6 signal transducer (gp130, oncostatin M receptor)

Gp130 extracellular domain crystal structure from PDB 1p9m.
Available structures
1bj8, 1bqu, 1i1r, 1p9m, 1pvh
Identifiers
Symbols IL6ST; CD130; CDw130; GP130; GP130-RAPS; IL6R-beta
External IDs OMIM600694 MGI96560 HomoloGene1645 GeneCards: IL6ST Gene
Orthologs
Species Human Mouse
Entrez 3572 16195
Ensembl ENSG00000134352 ENSMUSG00000021756
UniProt P40189 Q3TDT5
RefSeq (mRNA) NM_002184 NM_010560
RefSeq (protein) NP_002175 NP_034690
Location (UCSC) Chr 5:
55.23 - 55.29 Mb
Chr 13:
113.58 - 113.63 Mb
PubMed search [1] [2]

Glycoprotein 130 (also known as gp130, IL6ST, IL6-beta or CD130) is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of type I cytokine receptors within the IL-6 receptor family. It is often referred to as the common gp130 subunit, and is important for signal transduction following cytokine engagement. As with other type I cytokine receptors, gp130 possesses a WSXWS amino acid motif that ensures correct protein folding and ligand binding. It interacts with Janus kinases to elicit an intracellular signal following receptor interaction with its ligand. Structurally, gp130 is composed of five fibronectin type-III domains and one immunoglobulin-like C2-type (immunoglobulin-like) domain in its extracellular portion.[1][2]

Contents

Characteristics

The members of the IL-6 receptor family all complex with gp130 for signal transduction. For example, IL-6 binds to the IL-6 Receptor. The complex of these two proteins then associates with gp130. This complex of 3 proteins then homodimerizes to form a hexameric complex which can produce downstream signals.[3] There are many other proteins which associate with gp130, such as cardiotrophin 1 (CT-1), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and IL-11.[4] There are also several other proteins which have structural similarity to gp130 and contain the WSXWS motif and preserved cysteine residues. Members of this group include LIF-R, OSM-R, and G-CSF-R.

Loss of gp130

gp130 is an important part of many different types of signaling complexes. Inactivation of gp130 is lethal to mice.[5] Homozygous mice who are born show a number of defects including impaired development of the ventricular myocardium. Haematopoietic effects included reduced numbers of stem cells in the spleen and liver.

Signal Transduction

gp130 has no intrinsic tyrosine kinase activity. Instead, it is phosphorylated on tyrosine residues after complexing with other proteins. The phosphorylation leads to association with JAK/Tyk tyrosine kinases and STAT protein transcription factors.[6] In particular, STAT-3 is activated which leads to the activation of many downstream genes. Other pathways activated include RAS and MAPK signaling.

Interactions

Glycoprotein 130 has been shown to interact with TLE1,[7] SOCS3,[8] HER2/neu,[9] PTPN11,[8][10][11] Leukemia inhibitory factor receptor,[12][13] Grb2,[14] Janus kinase 1[15][11][16] and SHC1.[17]

References

  1. ^ Hibi et al. (1990). "Molecular cloning and expression of an IL-6 signal transducer, gp130". Cell 63: 1149–1157. doi:10.1016/0092-8674(90)90411-7.  
  2. ^ Bravo et al. (1998). "Crystal structure of a cytokine-binding region of gp130". EMBO J 17: 1665–1674. doi:10.1093/emboj/17.6.1665.  
  3. ^ Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K, Yamanishi K, Taga T, Kishimoto T (1993). "IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase". Science 260: 1808–1810. doi:10.1126/science.8511589.  
  4. ^ Kishimoto T, Akira S, Narazaki M, Taga T (1995). "Interleukin-6 family of cytokines and gp130". Blood 86: 1243–1254.  
  5. ^ Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang W-Z, Mori C, Shiota K, Yoshida N, Kishimoto T (1996). "Targeted disruption of gp130, a common signal transducer for IL-6-family of cytokines, leads to myocardial and hematological disorders". Proc Natl Acad Sci 93: 407–411. doi:10.1073/pnas.93.1.407.  
  6. ^ Kishimoto T, Taga T, Akira S (1994). "Cytokine signal transduction". Cell 76: 253–262. doi:10.1016/0092-8674(94)90333-6.  
  7. ^ Liu, Fei; Liu Yin, Li Demin, Zhu Yong, Ouyang Weiming, Xie Xin, Jin Boquan (Mar. 2002). "The transcription co-repressor TLE1 interacted with the intracellular region of gpl30 through its Q domain". Mol. Cell. Biochem. (Netherlands) 232 (1-2): 163–7. ISSN 0300-8177. PMID 12030375.  
  8. ^ a b Lehmann, Ute; Schmitz Jochen, Weissenbach Manuela, Sobota Radoslaw M, Hortner Michael, Friederichs Kerstin, Behrmann Iris, Tsiaris William, Sasaki Atsuo, Schneider-Mergener Jens, Yoshimura Akihiko, Neel Benjamin G, Heinrich Peter C, Schaper Fred (Jan. 2003). "SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130". J. Biol. Chem. (United States) 278 (1): 661–71. doi:10.1074/jbc.M210552200. ISSN 0021-9258. PMID 12403768.  
  9. ^ Grant, Susan L; Hammacher Annet, Douglas Andrea M, Goss Geraldine A, Mansfield Rachel K, Heath John K, Begley C Glenn (Jan. 2002). "An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells". Oncogene (England) 21 (3): 460–74. doi:10.1038/sj.onc.1205100. ISSN 0950-9232. PMID 11821958.  
  10. ^ Anhuf, D; Weissenbach M, Schmitz J, Sobota R, Hermanns H M, Radtke S, Linnemann S, Behrmann I, Heinrich P C, Schaper F (Sep. 2000). "Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation". J. Immunol. (UNITED STATES) 165 (5): 2535–43. ISSN 0022-1767. PMID 10946280.  
  11. ^ a b Kim, H; Baumann H (Dec. 1997). "Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells". J. Biol. Chem. (UNITED STATES) 272 (49): 30741–7. ISSN 0021-9258. PMID 9388212.  
  12. ^ Timmermann, Andreas; Küster Andrea, Kurth Ingo, Heinrich Peter C, Müller-Newen Gerhard (Jun. 2002). "A functional role of the membrane-proximal extracellular domains of the signal transducer gp130 in heterodimerization with the leukemia inhibitory factor receptor". Eur. J. Biochem. (Germany) 269 (11): 2716–26. ISSN 0014-2956. PMID 12047380.  
  13. ^ Mosley, B; De Imus C, Friend D, Boiani N, Thoma B, Park L S, Cosman D (Dec. 1996). "Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation". J. Biol. Chem. (UNITED STATES) 271 (51): 32635–43. ISSN 0021-9258. PMID 8999038.  
  14. ^ Lee, I S; Liu Y, Narazaki M, Hibi M, Kishimoto T, Taga T (Jan. 1997). "Vav is associated with signal transducing molecules gp130, Grb2 and Erk2, and is tyrosine phosphorylated in response to interleukin-6". FEBS Lett. (NETHERLANDS) 401 (2-3): 133–7. ISSN 0014-5793. PMID 9013873.  
  15. ^ Haan, C; Is'harc H, Hermanns H M, Schmitz-Van De Leur H, Kerr I M, Heinrich P C, Grötzinger J, Behrmann I (Oct. 2001). "Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction". J. Biol. Chem. (United States) 276 (40): 37451–8. doi:10.1074/jbc.M106135200. ISSN 0021-9258. PMID 11468294.  
  16. ^ Haan, Claude; Heinrich Peter C, Behrmann Iris (Jan. 2002). "Structural requirements of the interleukin-6 signal transducer gp130 for its interaction with Janus kinase 1: the receptor is crucial for kinase activation". Biochem. J. (England) 361 (Pt 1): 105–11. ISSN 0264-6021. PMID 11742534.  
  17. ^ Giordano, V; De Falco G, Chiari R, Quinto I, Pelicci P G, Bartholomew L, Delmastro P, Gadina M, Scala G (May. 1997). "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase". J. Immunol. (UNITED STATES) 158 (9): 4097–103. ISSN 0022-1767. PMID 9126968.  

Further reading

  • Ip NY, Nye SH, Boulton TG, et al. (1992). "CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130.". Cell 69 (7): 1121–32. doi:10.1016/0092-8674(92)90634-O. PMID 1617725.  
  • Hibi M, Murakami M, Saito M, et al. (1991). "Molecular cloning and expression of an IL-6 signal transducer, gp130.". Cell 63 (6): 1149–57. doi:10.1016/0092-8674(90)90411-7. PMID 2261637.  
  • Taga T, Hibi M, Hirata Y, et al. (1989). "Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.". Cell 58 (3): 573–81. doi:10.1016/0092-8674(89)90438-8. PMID 2788034.  
  • Rodriguez C, Grosgeorge J, Nguyen VC, et al. (1995). "Human gp130 transducer chain gene (IL6ST) is localized to chromosome band 5q11 and possesses a pseudogene on chromosome band 17p11.". Cytogenet. Cell Genet. 70 (1-2): 64–7. doi:10.1159/000133993. PMID 7736792.  
  • Narazaki M, Yasukawa K, Saito T, et al. (1993). "Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130.". Blood 82 (4): 1120–6. PMID 8353278.  
  • Davis S, Aldrich TH, Stahl N, et al. (1993). "LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor.". Science 260 (5115): 1805–8. doi:10.1126/science.8390097. PMID 8390097.  
  • Murakami M, Hibi M, Nakagawa N, et al. (1993). "IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase.". Science 260 (5115): 1808–10. doi:10.1126/science.8511589. PMID 8511589.  
  • Sharkey AM, Dellow K, Blayney M, et al. (1996). "Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos.". Biol. Reprod. 53 (4): 974–81. doi:10.1095/biolreprod53.4.974. PMID 8547494.  
  • Mosley B, De Imus C, Friend D, et al. (1997). "Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation.". J. Biol. Chem. 271 (51): 32635–43. doi:10.1074/jbc.271.51.32635. PMID 8999038.  
  • Lee IS, Liu Y, Narazaki M, et al. (1997). "Vav is associated with signal transducing molecules gp130, Grb2 and Erk2, and is tyrosine phosphorylated in response to interleukin-6.". FEBS Lett. 401 (2-3): 133–7. doi:10.1016/S0014-5793(96)01456-1. PMID 9013873.  
  • Auguste P, Guillet C, Fourcin M, et al. (1997). "Signaling of type II oncostatin M receptor.". J. Biol. Chem. 272 (25): 15760–4. doi:10.1074/jbc.272.25.15760. PMID 9188471.  
  • Schiemann WP, Bartoe JL, Nathanson NM (1997). "Box 3-independent signaling mechanisms are involved in leukemia inhibitory factor receptor alpha- and gp130-mediated stimulation of mitogen-activated protein kinase. Evidence for participation of multiple signaling pathways which converge at Ras.". J. Biol. Chem. 272 (26): 16631–6. doi:10.1074/jbc.272.26.16631. PMID 9195977.  
  • Diamant M, Rieneck K, Mechti N, et al. (1997). "Cloning and expression of an alternatively spliced mRNA encoding a soluble form of the human interleukin-6 signal transducer gp130.". FEBS Lett. 412 (2): 379–84. doi:10.1016/S0014-5793(97)00750-3. PMID 9256256.  
  • Koshelnick Y, Ehart M, Hufnagl P, et al. (1997). "Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598.". J. Biol. Chem. 272 (45): 28563–7. doi:10.1074/jbc.272.45.28563. PMID 9353320.  
  • Kim H, Baumann H (1998). "Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells.". J. Biol. Chem. 272 (49): 30741–7. doi:10.1074/jbc.272.49.30741. PMID 9388212.  
  • Bravo J, Staunton D, Heath JK, Jones EY (1998). "Crystal structure of a cytokine-binding region of gp130.". EMBO J. 17 (6): 1665–74. doi:10.1093/emboj/17.6.1665. PMID 9501088.  
  • Barton VA, Hudson KR, Heath JK (1999). "Identification of three distinct receptor binding sites of murine interleukin-11.". J. Biol. Chem. 274 (9): 5755–61. doi:10.1074/jbc.274.9.5755. PMID 10026196.  
  • Hirota H, Chen J, Betz UA, et al. (1999). "Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress.". Cell 97 (2): 189–98. doi:10.1016/S0092-8674(00)80729-1. PMID 10219240.  
  • Tacken I, Dahmen H, Boisteau O, et al. (1999). "Definition of receptor binding sites on human interleukin-11 by molecular modeling-guided mutagenesis.". Eur. J. Biochem. 265 (2): 645–55. doi:10.1046/j.1432-1327.1999.00755.x. PMID 10504396.  
  • Chung TD, Yu JJ, Kong TA, et al. (2000). "Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines.". Prostate 42 (1): 1–7. doi:10.1002/(SICI)1097-0045(20000101)42:1<1::AID-PROS1>3.0.CO;2-Y. PMID 10579793.  

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