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Immune response Oncostatin M signaling via MAPK in human cells

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Immune response Oncostatin M signaling via MAPK in human cells

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 ofhematopoietic and neurotrophic cytokines known as the Interleukin 6 (IL6)-type cytokinefamily [1].

Human Oncostatin M and mouse Oncostatin M signaling pathways aredifferent. Human Oncostatin M signaling is mediated by its binding to two receptorcomplexes: the type I OSM receptor complex ( LIF receptor ) consisting ofInterleukin 6 signal transducer ( gp130 ) and Leukemia inhibitory factor receptorsubunits ( LIFR ), and the type II OSM receptor complex ( OSM receptor )consisting of gp130 and OSM receptor beta ( OSMR ) subunits. MouseOncostatin M uses only one receptor complex: OSM receptor, but not LIFreceptor [2].

Binding of Oncostatin M to its receptor subunits ( gp130 and OSMR(or LIFR )) induces MAPK signaling pathway via several routes, specificallyProtein tyrosine phosphatase, non-receptor type 11 ( SHP-2 )-dependent and Srchomology 2 domain containing transforming protein 1 ( Shc )-dependent Growthfactor receptor-bound protein 2 ( GRB2 ) activation.

SHP-2 is recruited to LIFR and gp130 subunits of LIFreceptor 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 adocking target for the adaptor protein GRB2, which provides a link to thev-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) pathway ofMitogen-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 MAPKcascade 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-1murine leukemia viral oncogene homolog 1 ( c-Raf-1 ). Activated c-Raf-1then transmits its signal via the Mitogen-activated protein kinase kinases ( MEKs)/ 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 Earlygrowth response 1 ( EGR1 ), which, along with CCAAT/enhancer binding protein beta( C/EBPbeta ), stimulates transcription of lipid metabolism regulator - Lowdensity lipoprotein receptor ( LDLR ) [7], [8], [9]. High EGR1 transcription in this case may be explained byautotranscription [10].

Oncostatin M -induced ERK1/2 may participate in regulation of remodelingof the extracellular matrix. ERK1/2 activates transcription of TIMPmetallopeptidase inhibitor 1 ( TIMP-1 ) and Matrix metallopeptidase 1 (MMP-1 ). Activation of the ERK1/2 and Signal transducer and activator oftranscription 1 ( STAT1 ), which leads to v-fos FBJ murine osteosarcoma viraloncogene homolog ( c-Fos ) expression and activation, is involved in transcriptionof TIMP-1 and MMP-1 [11].

Oncostatin M/ ERK1/2 pathway participates in regulation of inflammatoryprocesses. 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 ofPeroxisome proliferator-activated receptor gamma ( PPAR-gamma ) (e.g., viaactivation of STAT1 [13]), thus inhibiting the adipogenesis [14].

Oncostatin M can also induce activation of Mitogen-activated protein kinases8-10 ( JNK(MAPK8-10) ) and Mitogen-activated protein kinases 11 - 14 (p38MAPK ) [15], [16], [17]. Signaltransduction pathways resulting in their activation, however, are poorly understood.Probably, Oncostatin M activates JNK(MAPK8-10) and p38MAPK viaGRB2/ 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) orMEK4(MAP2K4) ) [18], [15], [16].

Oncostatin M -induced p38MAPK and JNK(MAPK8-10) participate inregulation of remodeling of the extracellular matrix. For example, p38MAPK takespart 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 transcriptionof MMP-1, Matrix metallopeptidase 3 ( Stromelysin-1 ), and Matrixmetallopeptidase 13 ( MMP-13 ), possible, using transfactors STAT1and/or  Jun oncogene ( c-Jun ) [18], [15].