WP2374 - Oncostatin M signaling - Homo sapiens

Oncostatin M (OSM) is a member of the multifunctional cytokine interleukin 6 (IL6) - type cytokine family. It is mainly produced in activated T lymphocytes, macrophages, monocytes, neutrophils, and microglial cells. OSM signaling is initiated by the interaction of the cytokine to either: the type I LIFR-gp130 receptor complex, or to the type II OSMR-gp130 receptor [O’Hara et al]. The major downstream signaling pathways that are activated in OSM signaling are JAK/STAT, Ras/Raf/MAPK and PI3K pathways [Halfter, Halfter, Stross, Brantley]. As the receptors lack intrinsic tyrosine kinase activity, associated JAKs (JAK1, JAK2, JAK3 and TYK2) phosphorylate OSM receptor complex and STATs (STAT1, STAT3, STAT5A, STAT5B, STAT6) [O’Hara, Fritz, Migita, Hintzen]. Phosphorylated STATs form homodimeric complexes (STAT1, STAT3, STAT5B) or heterodimeric complex (STAT1-STAT3) and translocate to the nucleus. Once inside nucleus STAT proteins bind to regulatory elements in the promoter of OSM-responsive genes and regulate the gene expression [O’Hara, Halfter, Halfter, Hintzen]. Alternatively, OSM induced phosphorylation of PTPN11, GRB2, SHC1, Ras/Raf molecules can bring about the activation of ERK1/2 signaling module [O’Hara]. Oncostatin M -through ERK1/2 signaling module induces the phosphorylation of CEBPB, both CEBPB and EGR1 stimulates the transcription of genes involved in lipid metabolism [Zhang]. Although OSM also causes induced phosphorylation in MAPK family members (MAPK8/9/14) the functional importance of this is at present not well understood [O’Hara, Li]. OSM mediated signaling cascade is negatively regulated by JAK1 inhibition by SOCS3 and STAT3 inhibition by PIAS3 [Stross, Brantley, Chung]. OSM also induces the activation of caspase family members (CASP3, CASP7, CASP9) through the JAK2 module and regulates apoptosis [Auernhammer, Tiffen, Chipoy]. In osteosarcoma cells, OSM mediates apoptosis through a less understood STAT5B signaling module [Chipoy].