EPO-induced MAPK pathway
Erythropoiesis is the main pathway of pluripotent hematopoietic stem cell development
into mature end stage cells. Erythropoietin (Epo) is a major
lineage-specific hematopoietic growth factor required for survival, proliferation and
differentiation of committed erythroid progenitor cells , , .
Epo exerts its effect by binding to the Epo
receptor , composed of two identical subunits. Upon ligand
binding, the two subunits dimerize and Janus kinase JAK2 is
recruited to the receptor complex resulting in the phosphorylation of several tyrosine
residues on Epo receptor , , . Activated JAK2 initiates Epo-induced
JAK/STAT signaling .
Once phosphorylated Epo receptor recruits and activates a
number of downstream adaptors and effectors including MAPK (mitogen-activated protein
kinase) cascade and JNK (Jun N-terminal Kinases) pathway .
Activated Epo receptor complex recruits adapter proteins
Shc and GRB2, leading to
activation of the classical Shc /
MEK/ ERK cascade, which is
involved in cell proliferation .
Epo receptor, adapter protein
Shc and phosphatidyl-inositol polyphosphate 5-phosphatase
SHIP form a complex in hematopoietic cells, and SHIP
in Epo-induced signaling as an adapter
protein , .
Transmembrane receptor c-Kit is the receptor for mast
cell growth factor (MGF).
c-Kit can interact with and phosphorylate the
Epo receptor, resulting in enhanced erythroid cell
differentiation and proliferation .
Epo receptor transduces signals by activating physically
associated tyrosine kinases, mainly JAK2 and
Lyn, and, thereby, inducing tyrosine phosphorylation of
various substrates including the Epo receptor itself,
adapter proteins CrkL and c-Cbl
and tyrosine kinases Syk and
Btk , , , . CrkL associates with
Shc and c-Cbl in hematopoietic
cells. CrkL is constitutively associated with guanine
nucleotide exchange factor C3G, that also binds
Shc . C3G
modulates activity of the Ras family GTPases, such as RAP-1A
, which, in turn, inhibits c-Raf-1 kinase
Phospholipase C (PLC-gamma 1) is an adapter protein which
is rapidly tyrosine phosphorylated (e.g. by Btk kinase) upon
Epo stimulation. PLC-gamma 1
interacts with GRB2 and SOS2,
leading to activation of the ERK pathway .
Phosphorylated by Btk, Syk
and Lyn, phospholipase
PLC-gamma also triggers activation of several isoforms of
protein kinase C, including PKC-alpha and
PKC-epsilon, via diacylglycerol
(DAG) production and
Ca(2+) influx , , , . PKC isoforms, in turn, can phosphorylate
c-Raf-1 kinase, leading to MAPK cascade activation , .
In primary human erythroid progenitor cells, phosphatidylinositol-3 kinase,
PI3K-gamma, is activated by low concentration of Epo.
MEK1 and ERK1/2 kinases,
through a Raf-independent signaling pathway, are signal mediators of
PI3K-gamma . PI3K-gamma
is activated, probably, by H-Ras  and/or G-proteins beta/gamma .
Epo stimulation activates guanine nucleotide exchange
factor VAV-1 .
VAV-1 is involved in proliferative signals in hematopoietic
cells via activation of small GTPase Rac1 that stimulates
both JNK1-3 kinases and MEK (MEK1
and MEK2)/ERK1/2 cascade , , , , , . JNK1-3
and ERK1/2 kinases, in turn, phosphorylate
transcription factors Elk-1,
c-Jun and c-Fos that are
crucial for cell proliferation , , .
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