Glycoprotein 130 Explained

Glycoprotein 130 (also known as gp130, IL6ST, IL6R-beta or CD130) is a transmembrane protein which is the founding member of the class of tall cytokine receptors. It forms one subunit of the type I cytokine receptor 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]}

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:

• Grb2,^[7]
• HER2/neu,^[8]
• Janus kinase 1^{[9] [10]}
• Leukemia inhibitory factor receptor,^{[11] [12]}
• PTPN11,^{[13] [14]}
• SHC1,^[15]
• SOCS3,^[16] and
• TLE1.^[17]

Further reading

• Ip NY, Nye SH, Boulton TG, Davis S, Taga T, Li Y, Birren SJ, Yasukawa K, Kishimoto T, Anderson DJ . 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 . 1992 . 1617725 . 10.1016/0092-8674(92)90634-O . 45816061 .
• Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T . Molecular cloning and expression of an IL-6 signal transducer, gp130 . Cell . 63 . 6 . 1149–57 . 1991 . 2261637 . 10.1016/0092-8674(90)90411-7 . 30852638 .
• Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T . Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130 . Cell . 58 . 3 . 573–81 . 1989 . 2788034 . 10.1016/0092-8674(89)90438-8 . 41245022 .
• Rodriguez C, Grosgeorge J, Nguyen VC, Gaudray P, Theillet C . 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 . 1995 . 7736792 . 10.1159/000133993 .
• Narazaki M, Yasukawa K, Saito T, Ohsugi Y, Fukui H, Koishihara Y, Yancopoulos GD, Taga T, Kishimoto T . 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 . 1993 . 8353278 . 10.1182/blood.V82.4.1120.1120. free .
• Davis S, Aldrich TH, Stahl N, Pan L, Taga T, Kishimoto T, Ip NY, Yancopoulos GD . LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor . Science . 260 . 5115 . 1805–8 . 1993 . 8390097 . 10.1126/science.8390097 . 1993Sci...260.1805D .
• Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K, Yamanishi K, Taga T, Kishimoto T . IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase . Science . 260 . 5115 . 1808–10 . 1993 . 8511589 . 10.1126/science.8511589 . 1993Sci...260.1808M .
• Sharkey AM, Dellow K, Blayney M, Macnamee M, Charnock-Jones S, Smith SK . Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos . Biol. Reprod. . 53 . 4 . 974–81 . 1996 . 8547494 . 10.1095/biolreprod53.4.974 . free .
• Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS, Cosman D . 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 . 1997 . 8999038 . 10.1074/jbc.271.51.32635 . free .
• Lee IS, Liu Y, Narazaki M, Hibi M, Kishimoto T, Taga T . 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 . 1997 . 9013873 . 10.1016/S0014-5793(96)01456-1 . 32632406 . free .
• Auguste P, Guillet C, Fourcin M, Olivier C, Veziers J, Pouplard-Barthelaix A, Gascan H . Signaling of type II oncostatin M receptor . J. Biol. Chem. . 272 . 25 . 15760–4 . 1997 . 9188471 . 10.1074/jbc.272.25.15760 . free .
• Schiemann WP, Bartoe JL, Nathanson NM . 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 . 1997 . 9195977 . 10.1074/jbc.272.26.16631 . free .
• Diamant M, Rieneck K, Mechti N, Zhang XG, Svenson M, Bendtzen K, Klein B . 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 . 1997 . 9256256 . 10.1016/S0014-5793(97)00750-3 . 12420499 . free .
• Koshelnick Y, Ehart M, Hufnagl P, Heinrich PC, Binder BR . 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 . 1997 . 9353320 . 10.1074/jbc.272.45.28563 . free .
• Kim H, Baumann H . Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells . J. Biol. Chem. . 272 . 49 . 30741–7 . 1998 . 9388212 . 10.1074/jbc.272.49.30741 . free .
• Bravo J, Staunton D, Heath JK, Jones EY . Crystal structure of a cytokine-binding region of gp130 . EMBO J. . 17 . 6 . 1665–74 . 1998 . 9501088 . 1170514 . 10.1093/emboj/17.6.1665 .
• Barton VA, Hudson KR, Heath JK . Identification of three distinct receptor binding sites of murine interleukin-11 . J. Biol. Chem. . 274 . 9 . 5755–61 . 1999 . 10026196 . 10.1074/jbc.274.9.5755 . free .
• Hirota H, Chen J, Betz UA, Rajewsky K, Gu Y, Ross J, Müller W, Chien KR . 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 . 1999 . 10219240 . 10.1016/S0092-8674(00)80729-1 . 17955799 . free .
• Tacken I, Dahmen H, Boisteau O, Minvielle S, Jacques Y, Grötzinger J, Küster A, Horsten U, Blanc C, Montero-Julian FA, Heinrich PC, Müller-Newen G . Definition of receptor binding sites on human interleukin-11 by molecular modeling-guided mutagenesis . Eur. J. Biochem. . 265 . 2 . 645–55 . 1999 . 10504396 . 10.1046/j.1432-1327.1999.00755.x . free .
• Chung TD, Yu JJ, Kong TA, Spiotto MT, Lin JM . Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines . Prostate . 42 . 1 . 1–7 . 2000 . 10579793 . 10.1002/(SICI)1097-0045(20000101)42:1<1::AID-PROS1>3.0.CO;2-Y . 86404104 .

Notes and References

1. Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T . Molecular cloning and expression of an IL-6 signal transducer, gp130 . Cell . 63 . 6 . 1149–1157 . 1990 . 2261637 . 10.1016/0092-8674(90)90411-7 . 30852638 .
2. Bravo J, Staunton D, Heath JK, Jones EY . Crystal structure of a cytokine-binding region of gp130 . EMBO J . 17 . 6 . 1665–1674 . 1998 . 9501088 . 1170514 . 10.1093/emboj/17.6.1665 .
3. Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K, Yamanishi K, Taga T, Kishimoto T . IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase . Science . 260 . 5115 . 1808–1810 . 1993 . 8511589 . 10.1126/science.8511589 . 1993Sci...260.1808M .
4. Kishimoto T, Akira S, Narazaki M, Taga T . Interleukin-6 family of cytokines and gp130 . Blood . 86 . 4 . 1243–1254 . 1995 . 7632928 . 10.1182/blood.V86.4.1243.bloodjournal8641243 . free .
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 WZ, Mori C, Shiota K, Yoshida N, Kishimoto T . Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders . Proc. Natl. Acad. Sci. USA . 93 . 1 . 407–411 . 1996 . 8552649 . 40247 . 10.1073/pnas.93.1.407 . 1996PNAS...93..407Y . free .
6. Kishimoto T, Taga T, Akira S . Cytokine signal transduction . Cell . 76 . 2 . 253–262 . 1994 . 8293462 . 10.1016/0092-8674(94)90333-6 . 31924790 .
7. Lee IS, Liu Y, Narazaki M, Hibi M, Kishimoto T, Taga T . 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 . January 1997 . 9013873 . 10.1016/s0014-5793(96)01456-1. 32632406 . free .
8. Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, Begley CG . An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells . Oncogene . 21 . 3 . 460–74 . January 2002 . 11821958 . 10.1038/sj.onc.1205100 . 19754641 .
9. Haan C, Is'harc H, Hermanns HM, Schmitz-Van De Leur H, Kerr IM, Heinrich PC, Grötzinger J, Behrmann I . Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction . J. Biol. Chem. . 276 . 40 . 37451–8 . October 2001 . 11468294 . 10.1074/jbc.M106135200 . free .
10. Haan C, Heinrich PC, Behrmann I . 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. . 361 . Pt 1 . 105–11 . January 2002 . 11742534 . 1222284 . 10.1042/0264-6021:3610105.
11. Timmermann A, Küster A, Kurth I, Heinrich PC, Müller-Newen G . 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. . 269 . 11 . 2716–26 . June 2002 . 12047380 . 10.1046/j.1432-1033.2002.02941.x.
12. Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS, Cosman D . 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 . December 1996 . 8999038 . 10.1074/jbc.271.51.32635. free .
13. Kim H, Baumann H . Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells . J. Biol. Chem. . 272 . 49 . 30741–7 . December 1997 . 9388212 . 10.1074/jbc.272.49.30741. free .
14. Anhuf D, Weissenbach M, Schmitz J, Sobota R, Hermanns HM, Radtke S, Linnemann S, Behrmann I, Heinrich PC, Schaper F . Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation . J. Immunol. . 165 . 5 . 2535–43 . September 2000 . 10946280 . 10.4049/jimmunol.165.5.2535. free .
15. Giordano V, De Falco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L, Delmastro P, Gadina M, Scala G . Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase . J. Immunol. . 158 . 9 . 4097–103 . May 1997 . 10.4049/jimmunol.158.9.4097 . 9126968 . 44339682 . free .
16. Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J, Yoshimura A, Neel BG, Heinrich PC, Schaper F . SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130 . J. Biol. Chem. . 278 . 1 . 661–71 . January 2003 . 12403768 . 10.1074/jbc.M210552200 . free .
17. Liu F, Liu Y, Li D, Zhu Y, Ouyang W, Xie X, Jin B . The transcription co-repressor TLE1 interacted with the intracellular region of gpl30 through its Q domain . Mol. Cell. Biochem. . 232 . 1–2 . 163–7 . March 2002 . 12030375 . 10.1023/A:1014880813692. 8270300 .