Interleukin 6 signaling cascade

Interleukin (IL)-6 signaling cascade. Interleukin-6 demonstrates its biological activities only by binding to its specific receptor, IL-6R. This cytokine-receptor complex then associates with the IL-6R β-subunit, gp130, leading to intracellular signaling. Classical IL-6 receptor signaling occurs in cells that express IL-6R and gp130. IL-6 receptor 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 the STAT1, STAT3, MAPK, and PI3K cascade. In addition to 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 motif 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. In trans-presentation, mIL-6Rα in complex with IL-6 is presented by dendritic cells and sensed by gp130 molecules expressed on T cells.