Oncostatin M signaling via MAPK in human
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
(MEKs)/ ERK1/2 cascade,
leading to gene expression .
ERK1/2, in turn, activated by phosphorylation some
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
(JNK(MAPK8-10)) and Mitogen-activated protein
(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
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 , , . , .
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