Interleukin 6 signal transducer (GP130) (GP130)

Interleukin 6 signal transducer (GP130) is a ubiquitous transmembrane protein that functions as the shared signal-transducing subunit for the IL-6 family of cytokines, including IL-6, IL-11, and Oncostatin M (UniProt P40189). The D1 domain, located at the N-terminus, is an immunoglobulin-like domain essential for the formation of the active hexameric signaling complex consisting of two molecules each of IL-6, IL-6Rα, and GP130 (Boulanger et al., 2003, Science). Specifically, the D1 domain mediates 'Site 3' interactions, which are required to recruit the second GP130 molecule into the complex, thereby triggering the activation of Janus kinases (JAKs) and the STAT3 transcription factor (Garbers et al., 2018, Nature Reviews Drug Discovery). Dysregulation of GP130 signaling is a primary driver of chronic inflammatory diseases and various cancers, where it promotes pathological cell survival and systemic inflammation (Johnson et al., 2018, Nature Reviews Clinical Oncology). Therapeutic strategies targeting the GP130 D1 domain, such as the fusion protein Olamkicept or small molecules like Bazedoxifene, aim to selectively disrupt IL-6 trans-signaling—a process linked to pro-inflammatory outcomes—while potentially preserving homeostatic classic signaling (Kang et al., 2014, JBC). This site-specific targeting is a major focus for developing next-generation anti-inflammatory biologics with improved safety profiles compared to global IL-6 inhibitors.

Other names

IL6STCD130Interleukin-6 receptor subunit betaIL-6RBOncostatin M receptor subunit alphaGP130 D1 domain

Inhibition of the hexameric IL-6/IL-6R/GP130 signaling complex assembly by blocking the interaction between the IL-6/IL-6R complex and the GP130 D1 domain (Site 3), preventing JAK/STAT pathway activation.