Oncostatin M Signaling Pathway (Homo sapiens)

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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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CompareRevisionActionTimeUserComment
73668view20:34, 13 February 2014MaintBotFixing labels with red fill color
72050view17:00, 24 October 2013Mkutmonupdated annotations for HIF1A and VEGFA
71378view18:39, 17 October 2013MaintBotAutomated update of data sources
67549view11:24, 26 June 2013DdiglesOntology Term : 'oncostatin M signaling pathway' added !
61293view22:00, 6 April 2013MaintBotremoved old publication references
61234view17:35, 5 April 2013MaintBotupdated pathway elements from provided gpml
57683view20:52, 31 January 2013KhanspersModified categories
54418view11:10, 29 November 2012MaintBotOntology Term : 'osteosarcoma' added !
54417view11:09, 29 November 2012MaintBotOntology Term : 'lymphocyte' added !
54416view11:08, 29 November 2012MaintBotOntology Term : 'cytokine mediated signaling pathway' added !
54197view13:32, 23 November 2012NetPathModified description
54196view13:30, 23 November 2012NetPathModified description
54195view13:29, 23 November 2012NetPathNew pathway

External references

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NameTypeDatabase referenceComment
SERPINE1Rna5054 (Entrez Gene)
RPS6Protein6194 (Entrez Gene)
KRASProtein3845 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
CYR61Rna3491 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
IRS1Protein3667 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
PTK2BProtein2185 (Entrez Gene)
LIFRProtein3977 (Entrez Gene)
MMP13Rna4322 (Entrez Gene)
JAK2Protein3717 (Entrez Gene)
MMP1Rna4312 (Entrez Gene)
PRKCHProtein5583 (Entrez Gene)
JUNDProtein3727 (Entrez Gene)
PRKCEProtein5581 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
PRKCBProtein5579 (Entrez Gene)
FOSProtein2353 (Entrez Gene)
PRKCAProtein5578 (Entrez Gene)
CDKN1BProtein1027 (Entrez Gene)
IL6STProtein3572 (Entrez Gene)
PRKCDProtein5580 (Entrez Gene)
MAP2K2Protein5605 (Entrez Gene)
RICTORProtein253260 (Entrez Gene)
STAT3Protein6774 (Entrez Gene)
LDLRRna3949 (Entrez Gene)
STAT1Protein6772 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
JAK1Protein3716 (Entrez Gene)
CASP7Protein840 (Entrez Gene)
HIF1AGeneProductENSG00000100644 (Ensembl)
SHC1Protein6464 (Entrez Gene)
VEGFAGeneProductENSG00000112715 (Ensembl)
SRCProtein6714 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
HRASProtein3265 (Entrez Gene)
JAK3Protein3718 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
TYK2Protein7297 (Entrez Gene)
PXNProtein5829 (Entrez Gene)
RELAProtein5970 (Entrez Gene)
CDK2Protein1017 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
CEBPBProtein1051 (Entrez Gene)
SOCS3Protein9021 (Entrez Gene)
JUNBProtein3726 (Entrez Gene)
OSMRProtein9180 (Entrez Gene)
MTORProtein2475 (Entrez Gene)
PTPN11Protein5781 (Entrez Gene)
TP53Rna7157 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
CREB1Protein1385 (Entrez Gene)
PIAS3Protein10401 (Entrez Gene)
EGR1Rna1958 (Entrez Gene)
STAT5BProtein6777 (Entrez Gene)
CCL2Rna6347 (Entrez Gene)
CASP3Protein836 (Entrez Gene)
MMP3Rna4314 (Entrez Gene)
OSMProtein5008 (Entrez Gene)
NFKBIAProtein4792 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
TIMP3Rna7078 (Entrez Gene)
GRB2Protein2885 (Entrez Gene)
CASP9Protein840 (Entrez Gene)
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