Interleukin 6 signaling cascade

IL-6 demonstrates its biologic activities only by binding to its specific receptor, IL-6R. This cytokine-receptor complex then associates with the IL-6R beta-subunit, gp130, leading to its dimerization and intracellular signaling. Classical IL-6 receptor signaling occurs in cells that express IL-6R and gp130. IL-6R can be proteolytically cleaved from the cell membrane by ADAM17, generating sIL-6R. This mechanism of trans-signaling allows IL-6 to act on cells that lack IL-6R. Both modes of IL-6 receptor signaling lead to gp130 activation of Janus kinases 1 and 2 and Tyrosine kinase 2, and a series of proximal tyrosine residues that activate STAT1, STAT3, MAPK and PI3K cascade. Besides the JAK/STAT pathway, IL-6 signaling also stimulates SFK-dependent signaling, which probably leads to the activation of different transcriptional regulators including YAP. Phosphorylation of the tyrosine residue 759 in the cytoplasmic tail of gp130 is important for negative regulation of IL-6 signal transduction. SHP2 and SOCS3 bind to this phosphotyrosine and attenuate the IL-6 downstream JAK/STAT signaling.