Role of glycoprotein 130 (gp130) downstream signalling in the heart. Scheme of gp130 receptor activation showing interleukin-6 (IL-6) type cytokines binding to their transmembrane receptor α-subunits, which induces homodimerization of the gp130 receptor β-subunits or heterodimerization of gp130 with either one of the structurally and functionally similar leukaemia inhibitory factor (LIF) receptor and oncostatin M (OSM) receptor β-subunits. Following dimerization of the gp130 receptor complex, Janus kinase-1/2 (JAK1/2) constitutively connected to the intracytoplasmatic membrane proximal regions of the receptor subunits are catalytically activated and themselves transphosphorylate tyrosine residues in the gp130 receptor intracellular domain. Subsequently, two major intracellular signalling cascades are triggered, the signal transducer and activator of transcription (STAT)-1/3 pathway and the SH2 domain-containing cytoplasmic protein tyrosine phosphatase (SHP2)/MEK/extracellular signal-regulated kinase (ERK) pathway. Via the formation of complexes with growth factor receptor binding protein-2 (Grb2)-associated binding protein-1/2 (Gab1/2) and phosphatidylinositol-3-kinase (PI3K), SHP2 activation furthermore initiates the Akt pathway and additionally enhances MEK/ERK signalling. Activation of gp130-mediated signalling plays essential roles in stem cells and cardiomyogenesis. In the adult heart, it is involved in numerous physiological and pathophysiological processes. MEK, mitogen-activated protein kinase (MAPK)/ERK kinase.