Pathway Map Details
Immune response_Oncostatin M signaling via MAPK in human cells
Object list (links open in MetaCore):
p38 MAPK, PPAR-gamma, JNK(MAPK8-10), GRB2, c-Raf-1, Stromelysin-1, ERK1/2, c-Fos, C/EBPbeta, AP-1, SHP-2, STAT1, SOS, c-Jun, JAK1, MEK2(MAP2K2), MEK4(MAP2K4), LIF receptor, MMP-13, H-Ras, ERK1 (MAPK3), gp130, ERK2 (MAPK1), MMP-1, Oncostatin M, Shc, OSM receptor, Rac1, LDLR, EGR1, MEK1(MAP2K1), TIMP1, LIFR, CCL2, OSMR, MEKK1(MAP3K1), MEK3(MAP2K3)
Oncostatin M signaling via MAPK in human cells
Oncostatin M is a multifunctional cytokine produced by activated T lymphocytes, monocytes and microglia. It is structurally and functionally related to the subfamily of hematopoietic and neurotrophic cytokines known as the Interleukin 6 (IL6)-type cytokine family .
Human Oncostatin M and mouse Oncostatin M signaling pathways are different. Human Oncostatin M signaling is mediated by its binding to two receptor complexes: the type I OSM receptor complex ( LIF receptor ) consisting of Interleukin 6 signal transducer ( gp130 ) and Leukemia inhibitory factor receptor subunits ( LIFR ), and the type II OSM receptor complex ( OSM receptor ) consisting of gp130 and OSM receptor beta ( OSMR ) subunits. Mouse Oncostatin M uses only one receptor complex: OSM receptor, but not LIF receptor .
Binding of Oncostatin M to its receptor subunits ( gp130 and OSMR (or LIFR )) induces MAPK signaling pathway via several routes, specifically Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 )-dependent and Src homology 2 domain containing transforming protein 1 ( Shc )-dependent Growth factor receptor-bound protein 2 ( GRB2 ) activation.
SHP-2 is recruited to LIFR and gp130 subunits of LIF receptor or OSM receptor , , . Then, SHP-2 is activated by phosphorylation, for instance, by Janus kinase 1 ( JAK1 ) , . Phosphorylated SHP-2 acts as a docking target for the adaptor protein GRB2, which provides a link to the v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) pathway of Mitogen-activated protein kinases 1-3 ( ERK1/2) activation 
Shc, in turn, is activated via OSMR subunit of OSM receptor. OSMR recruits Shc as a downstream signaling molecule and initiates MAPK cascade via GRB2 .
Activated GRB2 is bound with the GTP-exchange factor Son of sevenless homolog ( SOS ). SOS interacts with H-Ras, and H-Ras recruits v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ). Activated c-Raf-1 then transmits its signal via the Mitogen-activated protein kinase kinases ( MEK s)/ ERK1/2 cascade, leading to gene expression .
ERK1/2, in turn, activated by phosphorylation some transfactors.
Oncostatin M -induced ERK1/2 may activate transcription factor Early growth response 1 ( EGR1 ), which, along with CCAAT/enhancer binding protein beta ( C/EBPbeta ), stimulates transcription of lipid metabolism regulator - Low density lipoprotein receptor ( LDLR ) , , . High EGR1 transcription in this case may be explained by autotranscription .
Oncostatin M -induced ERK1/2 may participate in regulation of remodeling of the extracellular matrix. ERK1/2 activates transcription of TIMP metallopeptidase inhibitor 1 ( TIMP-1 ) and Matrix metallopeptidase 1 ( MMP-1 ). Activation of the ERK1/2 and Signal transducer and activator of transcription 1 ( STAT1 ), which leads to v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) expression and activation, is involved in transcription of TIMP-1 and MMP-1 .
Oncostatin M/ ERK1/2 pathway participates in regulation of inflammatory processes. For example, Oncostatin M induces Chemokine ligand 2 ( CCL2) expression in osteoblasts. Activation of the ERK1/2 and STAT1 pathways, which leads to c-Fos expression and activation, is also involved in the process .
In addition, Oncostatin M/ ERK1/2 pathway leads to down-regulation of Peroxisome proliferator-activated receptor gamma ( PPAR-gamma ) (e.g., via activation of STAT1  ), thus inhibiting the adipogenesis .
Oncostatin M can also induce activation of Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ) and Mitogen-activated protein kinases 11 - 14 ( p38MAPK ) , , . Signal transduction pathways resulting in their activation, however, are poorly understood. Probably, Oncostatin M activates JNK(MAPK8-10) and p38MAPK via GRB2/ SOS/ Ras-related C3 botulinum toxin substrate 1 ( Rac-1 ) (or H-Ras )/ mitogen-activated protein kinase kinase kinase (e.g., MEKK1 )/ mitogen-activated protein kinase kinases (e.g., MEK3(MAP2K3) or MEK4(MAP2K4) ) , , .
Oncostatin M -induced p38MAPK and JNK(MAPK8-10) participate in regulation of remodeling of the extracellular matrix. For example, p38MAPK takes part in activation transcription of TIMP-1 via AP-1 transfactors (e.g., c-Fos and others) production in both cell types , . Oncostatin M -induced JNK(MAPK8-10) may activate transcription of MMP-1, Matrix metallopeptidase 3 ( Stromelysin-1 ), and Matrix metallopeptidase 13 ( MMP-13 ), possible, using transfactors STAT1 and/or Jun oncogene ( c-Jun ) , .
Oncostatin M participates in induction of epithelial-to-mesenchymal transition (EMT) of renal cells . Induction of via ERK1/2 during this process modulates some EMT markers expression . Normally, EMT seems to be a process, induced during wound healing after injury. And EMT can be a normal recovery process in renal cells, because proliferating myofibroblasts are produced during it. EMT of renal cells can lead to renal fibrosis progression , , . , .
- Tanaka M, Miyajima A
Oncostatin M, a multifunctional cytokine. Reviews of physiology, biochemistry and pharmacology. 2003;149:39-52
- Chen SH, Benveniste EN
Oncostatin M: a pleiotropic cytokine in the central nervous system. Cytokine & growth factor reviews 2004 Oct;15(5):379-91
- Schiemann WP, Bartoe JL, Nathanson NM
Box 3-independent signaling mechanisms are involved in leukemia inhibitory factor receptor alpha- and gp130-mediated stimulation of mitogen-activated protein kinase. Evidence for participation of multiple signaling pathways which converge at Ras. The Journal of biological chemistry 1997 Jun 27;272(26):16631-6
- Wang Y, Robledo O, Kinzie E, Blanchard F, Richards C, Miyajima A, Baumann H
Receptor subunit-specific action of oncostatin M in hepatic cells and its modulation by leukemia inhibitory factor. The Journal of biological chemistry 2000 Aug 18;275(33):25273-85
- Ahn S, Lisitza N, Warren WS
Intermolecular zero-quantum coherences of multi-component spin systems in solution NMR Journal of magnetic resonance (San Diego, Calif. : 1997) 1998 Aug;133(2):266-72
- Hermanns HM, Radtke S, Schaper F, Heinrich PC, Behrmann I
Non-redundant signal transduction of interleukin-6-type cytokines. The adapter protein Shc is specifically recruited to rhe oncostatin M receptor. The Journal of biological chemistry 2000 Dec 29;275(52):40742-8
- Li C, Kraemer FB, Ahlborn TE, Liu J
Induction of low density lipoprotein receptor (LDLR) transcription by oncostatin M is mediated by the extracellular signal-regulated kinase signaling pathway and the repeat 3 element of the LDLR promoter. The Journal of biological chemistry 1999 Mar 5;274(10):6747-53
- Zhang F, Ahlborn TE, Li C, Kraemer FB, Liu J
Identification of Egr1 as the oncostatin M-induced transcription activator that binds to sterol-independent regulatory element of human LDL receptor promoter. Journal of lipid research 2002 Sep;43(9):1477-85
- Zhou Y, Zhang F, Abidi P, Lin M, Thiel G, Liu J
Blockage of oncostatin M-induced LDL receptor gene transcription by a dominant-negative mutant of C/EBPbeta. The Biochemical journal 2006 Jul 1;397(1):101-8
- Sakamoto KM, Fraser JK, Lee HJ, Lehman E, Gasson JC
Granulocyte-macrophage colony-stimulating factor and interleukin-3 signaling pathways converge on the CREB-binding site in the human egr-1 promoter. Molecular and cellular biology 1994 Sep;14(9):5975-85
- Korzus E, Nagase H, Rydell R, Travis J
The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression. The Journal of biological chemistry 1997 Jan 10;272(2):1188-96
- Lin SK, Kok SH, Yeh FT, Kuo MY, Lin CC, Wang CC, Goldring SR, Hong CY
MEK/ERK and signal transducer and activator of transcription signaling pathways modulate oncostatin M-stimulated CCL2 expression in human osteoblasts through a common transcription factor. Arthritis and rheumatism 2004 Mar;50(3):785-93
- Hogan JC, Stephens JM
The identification and characterization of a STAT 1 binding site in the PPARgamma2 promoter. Biochemical and biophysical research communications 2001 Sep 21;287(2):484-92
- Miyaoka Y, Tanaka M, Naiki T, Miyajima A
Oncostatin M inhibits adipogenesis through the Ras/ERK and STAT5 signaling pathways. The Journal of biological chemistry 2006 Oct 6;
- Li WQ, Dehnade F, Zafarullah M
Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 2001 Mar 1;166(5):3491-8
- Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F
Principles of interleukin (IL)-6-type cytokine signalling and its regulation. The Biochemical journal 2003 Aug 15;374(Pt 1):1-20
- Boing I, Stross C, Radtke S, Lippok BE, Heinrich PC, Hermanns HM
Oncostatin M-induced activation of stress-activated MAP kinases depends on tyrosine 861 in the OSM receptor and requires Jak1 but not Src kinases. Cellular signalling 2006 Jan;18(1):50-61
- Faris M, Ensoli B, Stahl N, Yancopoulos G, Nguyen A, Wang S, Nel AE
Differential activation of the extracellular signal-regulated kinase, Jun kinase and Janus kinase-Stat pathways by oncostatin M and basic fibroblast growth factor in AIDS-derived Kaposi's sarcoma cells. AIDS (London, England) 1996 Apr;10(4):369-78
- Tong L, Smyth D, Kerr C, Catterall J, Richards CD
Mitogen-activated protein kinases Erk1/2 and p38 are required for maximal regulation of TIMP-1 by oncostatin M in murine fibroblasts. Cellular signalling 2004 Oct;16(10):1123-32
- Weiss TW, Kvakan H, Kaun C, Zorn G, Speidl WS, Pfaffenberger S, Maurer G, Huber K, Wojta J
The gp130 ligand oncostatin M regulates tissue inhibitor of metalloproteinases-1 through ERK1/2 and p38 in human adult cardiac myocytes and in human adult cardiac fibroblasts: a possible role for the gp130/gp130 ligand system in the modulation of extracellular matrix degradation in the human heart. Journal of molecular and cellular cardiology 2005 Sep;39(3):545-51
- Nightingale J, Patel S, Suzuki N, Buxton R, Takagi KI, Suzuki J, Sumi Y, Imaizumi A, Mason RM, Zhang Z
Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation. Journal of the American Society of Nephrology : JASN 2004 Jan;15(1):21-32
- Pollack V, Sarkozi R, Banki Z, Feifel E, Wehn S, Gstraunthaler G, Stoiber H, Mayer G, Montesano R, Strutz F, Schramek H
Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling. American journal of physiology. Renal physiology 2007 Nov;293(5):F1714-26
- Sun DF, Fujigaki Y, Fujimoto T, Yonemura K, Hishida A
Possible involvement of myofibroblasts in cellular recovery of uranyl acetate-induced acute renal failure in rats. The American journal of pathology 2000 Oct;157(4):1321-35
- Strutz F, Muller GA
Transdifferentiation comes of age. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2000 Nov;15(11):1729-31
- Poulsom R, Alison MR, Cook T, Jeffery R, Ryan E, Forbes SJ, Hunt T, Wyles S, Wright NA
Bone marrow stem cells contribute to healing of the kidney. Journal of the American Society of Nephrology : JASN 2003 Jun;14 Suppl 1:S48-54
- Li MX, Liu BC
Epithelial to mesenchymal transition in the progression of tubulointerstitial fibrosis. Chinese medical journal 2007 Nov 5;120(21):1925-30