Glycoprotein 130

Characteristics

The members of the IL-6 receptor family are 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. 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. 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.

Inhibition of gp130

gp130 is an important part of many different types of signaling complexes. Inactivation of gp130 during development is lethal to mice. 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. Loss of gp130 in the adult mouse, either globally or in a tissue-specific manner, is however increasingly linked with beneficial effects in a number of mouse models of disease. Of note, soluble gp130 (sgp130), which was thought a specific inhibitor of IL6 trans signalling, was instead found to inhibit not only IL6 signalling but also multiple other IL6-family cytokines (e.g. OSM, IL11 and CNTF). Thus the widespread benefits of sgp130 in mouse models, and in human trials, may represent the benefits of global (or near global) inhibition of gp130. This suggests gp130 itself as a therapeutic target for human diseases including sepsis, systemic sclerosis, inflammatory bowel disease, among others.

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. 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,
• HER2/neu,
• Janus kinase 1
• Leukemia inhibitory factor receptor,
• PTPN11,
• SHC1,
• SOCS3, and
• TLE1.

References

References

1. (Dec 1990). "Molecular cloning and expression of an IL-6 signal transducer, gp130". Cell.
2. (Mar 1998). "Crystal structure of a cytokine-binding region of gp130". The EMBO Journal.
3. (Jun 1993). "IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase". Science.
4. (Aug 1995). "Interleukin-6 family of cytokines and gp130". Blood.
5. (Jan 1996). "Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders". Proceedings of the National Academy of Sciences of the United States of America.
6. (2024-01-23). "Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130". International Journal of Molecular Sciences.
7. (October 2023). "Targeting IL-6 trans-signalling: past, present and future prospects". Nature Reviews. Immunology.
8. (2023-03-07). "Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial". JAMA.
9. (Jan 1994). "Cytokine signal transduction". Cell.
10. (January 1997). "Vav is associated with signal transducing molecules gp130, Grb2 and Erk2, and is tyrosine phosphorylated in response to interleukin-6". FEBS Letters.
11. (January 2002). "An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells". Oncogene.
12. (October 2001). "Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction". Journal of Biological Chemistry.
13. (January 2002). "Structural requirements of the interleukin-6 signal transducer gp130 for its interaction with Janus kinase 1: the receptor is crucial for kinase activation". The Biochemical Journal.
14. (June 2002). "A functional role of the membrane-proximal extracellular domains of the signal transducer gp130 in heterodimerization with the leukemia inhibitory factor receptor". European Journal of Biochemistry.
15. (December 1996). "Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation". Journal of Biological Chemistry.
16. (December 1997). "Transmembrane domain of gp130 contributes to intracellular signal transduction in hepatic cells". Journal of Biological Chemistry.
17. (September 2000). "Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation". Journal of Immunology.
18. (May 1997). "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase". Journal of Immunology.
19. (January 2003). "SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130". Journal of Biological Chemistry.
20. (March 2002). "The transcription co-repressor TLE1 interacted with the intracellular region of gpl30 through its Q domain". Molecular and Cellular Biochemistry.