Oncostatin M signaling pathway (WP3277)

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 [1]. The major downstream signaling pathways that are activated in OSM signaling are JAK/STAT, Ras/Raf/MAPK and PI3K pathways [2-5]. 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) [1, 6-8]. 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 [1-3, 8]. Alternatively, OSM induced phosphorylation of PTPN11, GRB2, SHC1, Ras/Raf molecules can bring about the activation of ERK1/2 signaling module [1]. 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 [9]. Although OSM also causes induced phosphorylation in MAPK family members (MAPK8/9/14) the functional importance of this is at present not well understood [1, 11]. OSM mediated signaling cascade is negatively regulated by JAK1 inhibition by SOCS3 and STAT3 inhibition by PIAS3 [4-5, 10].OSM also induced the activation of caspase family members (CASP3, CASP7, CASP9) through the JAK2 module and regulates apoptosis [12-14]. In osteosarcoma cells OSM is found to mediate apoptosis through a less understood STAT5B signaling module [14]. 1. O'Hara, K.A., et al., Oncostatin M: an interleukin-6-like cytokine relevant to airway remodelling and the pathogenesis of asthma. Clin Exp Allergy, 2003. 33(8): p. 1026-32. 2. Halfter, H., et al., Activation of Jak-Stat and MAPK2 pathways by oncostatin M leads to growth inhibition of human glioma cells. Mol Cell Biol Res Commun, 1999. 1(2): p. 109-16. 3. Halfter, H., et al., Activation 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 Res, 2000. 80(2): p. 198-206. 4. Stross, C., et al., Oncostatin M receptor-mediated signal transduction is negatively regulated by SOCS3 through a receptor tyrosine-independent mechanism. J Biol Chem, 2006. 281(13): p. 8458-68. 5. Brantley, E.C. and E.N. Benveniste, Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res, 2008. 6(5): p. 675-84. 6. Fritz, D.K., et al., Oncostatin-M up-regulates VCAM-1 and synergizes with IL-4 in eotaxin expression: involvement of STAT6. J Immunol, 2006. 176(7): p. 4352-60. 7. Migita, K., et al., CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. Arthritis Res Ther, 2011. 13(3): p. R72. 8. Hintzen, C., et al., Box 2 region of the oncostatin M receptor determines specificity for recruitment of Janus kinases and STAT5 activation. J Biol Chem, 2008. 283(28): p. 19465-77. 9. Zhang, F., et al., Specific interaction of Egr1 and c/EBPbeta leads to the transcriptional activation of the human low density lipoprotein receptor gene. J Biol Chem, 2003. 278(45): p. 44246-54. 10. Chung, C.D., et al., Specific inhibition of Stat3 signal transduction by PIAS3. Science, 1997. 278(5344): p. 1803-5. 11. Li, W.Q., F. Dehnade, and M. Zafarullah, Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. J Immunol, 2001. 166(5): p. 3491-8. 12. Auernhammer, C.J., et al., The oncostatin M receptor/gp130 ligand murine oncostatin M induces apoptosis in adrenocortical Y-1 tumor cells. J Endocrinol, 2004. 180(3): p. 479-86. 13. Tiffen, P.G., et al., A dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo. Mol Endocrinol, 2008. 22(12): p. 2677-88. 14. Chipoy, C., et al., Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53. Oncogene, 2007. 26(46): p. 6653-64.

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