Interleukin-6 receptor subunit beta (GP130) (GP130)

Interleukin-6 receptor subunit beta, commonly known as GP130, is a vital transmembrane protein that functions as the universal signal-transducing component for the IL-6 family of cytokines (UniProt P40189). The extracellular region of GP130 contains six domains, with the N-terminal D1 Ig-like domain being essential for the assembly of the functional hexameric signaling complex consisting of two IL-6, two IL-6Rα, and two GP130 molecules (Boulanger et al., 2003, Science). Specifically, the D1 domain interacts with the Site III epitope of IL-6, a step that is required for GP130 dimerization and the subsequent activation of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways (Skiniotis et al., 2005, Molecular Cell). This signaling mechanism is a primary driver of the inflammatory response, hematopoiesis, and the acute phase reaction in the liver (StatPearls, "Interleukin-6"). Pathologically, overactivation of the GP130 signaling complex is linked to chronic inflammatory diseases like rheumatoid arthritis and various malignancies where it supports tumor growth and survival (PubMed 25608575). Therapeutic interventions targeting the GP130 D1 domain or its interaction with IL-6, such as the monoclonal antibody Olokizumab, aim to disrupt the formation of the signaling hexamer to treat these conditions (Shaw et al., 2014). Additionally, small molecule inhibitors like SC144 are being explored to directly target GP130 and prevent its dimerization or downstream signaling (PubMed 21705458).

Other names

IL6STCD130Interleukin-6 signal transducerMembrane glycoprotein 130GP130

Inhibition of the IL-6/IL-6R/GP130 signaling complex formation by blocking the interaction between IL-6 and the GP130 extracellular domains, thereby preventing JAK/STAT pathway activation.