Pathway maps

Immune response_Oncostatin M signaling via MAPK in human cells
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 [1].

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 [2].

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 [3], [4], [2]. Then, SHP-2 is activated by phosphorylation, for instance, by Janus kinase 1 ( JAK1 ) [5], [2]. 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 [2]

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 [6].

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 [2].

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 ) [7], [8], [9]. High EGR1 transcription in this case may be explained by autotranscription [10].

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 [11].

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 [12].

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 [13] ), thus inhibiting the adipogenesis [14].

Oncostatin M can also induce activation of Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ) and Mitogen-activated protein kinases 11 - 14 ( p38MAPK ) [15], [16], [17]. 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) ) [18], [15], [16].

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 [19], [20]. 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 ) [18], [15].

Oncostatin M participates in induction of epithelial-to-mesenchymal transition (EMT) of renal cells [21]. Induction of via ERK1/2 during this process modulates some EMT markers expression [22]. 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 [23], [24], [25]. [22], [26].


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