Signaling network of Oncostatin M pathway.

Abstract

Oncostatin M (OSM), belonging to the IL-6 family of cytokines (Heinrich et al. 2003), was first reported and purified from U937 monocytic cells (Zarling et al. 1986; Ensoli et al. 1999; Hasegawa et al. 1999). In normal physiological condition, OSM is associated with multiple biological processes and cellular responses including growth, differentiation, and inflammation However, anti-proliferative activity of OSM against breast cancer cell line generated the interest of biomedical community on this molecule (Douglas et al. 1997, 1998). OSM was also found associated with pathological conditions such as proliferation of ovarian cancer cells (Taga and Kishimoto 1997), prostate cancer 22Rv1 cells (Hoffman et al. 1996), up-regulation of the ER chaperone Grp78/BiP in the liver cells, atherosclerotic lesions, ischemic heart disease and rheumatoid arthritis (Linsley et al. 1990; Dunham et al. 1999). The dual role of OSM in either inducing or inhibiting the proliferation of various types of cells called upon the scientific community to investigate role of OSM in various physiological and experimental contexts in detail. However, diverse molecular level information pertaining to OSM signaling is not available in a centralized resource. Therefore, we have systematically gathered and curated molecular information from literature and created a public resource for OSM induced signaling events. We integrated OSM signaling pathway into NetPath (Kandasamy et al. 2010), which is a public resource of human signaling pathways. OSM is known to mediate its biological effects by binding to two distinct heterodimers of gp130 with either leukemia inhibiting factor receptor (LIFR) or OSM receptor-beta (OSMR-beta) (Thoma et al. 1994). Former heterodimer between gp130 and LIFR is called type I receptor complex and the latter between gp130 and OSMR-beta is called type II receptor complex. Type I receptor can bind to either OSM or leukemia inhibiting factor, whereas type II receptor has more affinity towards OSM (O’Hara et al. 2003). The binding of OSM to either gp130/OSMR-beta or gp130/LIFR induces the activation of Janus Kinase family members through tyrosine phosphorylation (Tanaka and Miyajima 2003). The activated JAK family members in turn induce the activation of Signal Transduction and Activator of Transcription (STAT) proteins (Schaefer et al. 2000). Alternatively, the activated receptors can also activate mitogen-activated protein kinase (MAPK) pathway (Van Wagoner et al. 2000) and PI3K/AKT pathways (Arita et al. 2008). It was also reported that OSM bring about ligand-induced receptor degradation of gp130, OSMR-beta, and LIFR before enhancing the synthesis of the receptor subunits (Blanchard et al. 2001).