Oncostatin M (OSM) is a member of the multifunctional cytokine interleukin 6 (IL6) - type cytokine family. It is mainly produced in cell types such as activated T lymphocytes, macrophages, monocytes, neutrophils and in 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 lacks 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 induced the activation of caspase family members (CASP3, CASP7, CASP9) through the JAK2 module and regulates apoptosis [Auernhammer, Tiffen, Chipoy]. In osteosarcoma cells OSM is found to mediate apoptosis through a less understood STAT5B signaling module [Chipoy]. f58a3dc86cf4cbeb55dcda74e1dd70d40ebcf72ada15012602PubMedThe oncostatin M receptor/gp130 ligand murine oncostatin M induces apoptosis in adrenocortical Y-1 tumor cells.J Endocrinol2004Auernhammer CJDorn FVlotides GHengge SKopp FBSpoettl GCengic NEngelhardt DWeber MM12947119PubMedSpecific interaction of Egr1 and c/EBPbeta leads to the transcriptional activation of the human low density lipoprotein receptor gene.J Biol Chem2003Zhang FLin MAbidi PThiel GLiu J21548952PubMedCP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes.Arthritis Res Ther2011Migita KKomori ATorigoshi TMaeda YIzumi YJiuchi YMiyashita TNakamura MMotokawa SIshibashi H17471233PubMedSensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53.Oncogene2007Chipoy CBrounais BTrichet VBattaglia SBerreur MOliver LJuin PRédini FHeymann DBlanchard F18505913PubMedSignal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas.Mol Cancer Res2008Brantley ECBenveniste EN16459330PubMedOncostatin M receptor-mediated signal transduction is negatively regulated by SOCS3 through a receptor tyrosine-independent mechanism.J Biol Chem2006Stross CRadtke SClahsen TGerlach CVolkmer-Engert RSchaper FHeinrich PCHermanns HM18927239PubMedA dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo.Mol Endocrinol2008Tiffen PGOmidvar NMarquez-Almuina NCroston DWatson CJClarkson RW9388184PubMedSpecific inhibition of Stat3 signal transduction by PIAS3.Science1997Chung CDLiao JLiu BRao XJay PBerta PShuai Koncostatin M signaling pathwayPW:0000905Pathway Ontology16547273PubMedOncostatin-M up-regulates VCAM-1 and synergizes with IL-4 in eotaxin expression: involvement of STAT6.J Immunol2006Fritz DKKerr CTong LSmyth DRichards CD12911774PubMedOncostatin M: an interleukin-6-like cytokine relevant to airway remodelling and the pathogenesis of asthma.Clin Exp Allergy2003O'Hara KAKedda MAThompson PJKnight DA11038252PubMedActivation of the Jak-Stat- and MAPK-pathways by oncostatin M is not sufficient to cause growth inhibition of human glioma cells.Brain Res Mol Brain Res2000Halfter HPostert CFriedrich MRingelstein EBStögbauer F11207308PubMedOncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway.J Immunol2001Li WQDehnade FZafarullah M10356359PubMedActivation of Jak-Stat and MAPK2 pathways by oncostatin M leads to growth inhibition of human glioma cells.Mol Cell Biol Res Commun1999Halfter HFriedrich MPostert CRingelstein EBStögbauer F18430728PubMedBox 2 region of the oncostatin M receptor determines specificity for recruitment of Janus kinases and STAT5 activation.J Biol Chem2008Hintzen CEvers CLippok BEVolkmer RHeinrich PCRadtke SHermanns HM