EPO-induced Jak-STAT pathway
Erythropoiesis is a major pathway by which a pluripotent hematopoietic stem cell gives
rise to mature end stage cells. Erythropoietin (EPO) is a
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 , which is 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 the receptor. These phosphorylated
tyrosine residues form docking sites for several molecules, including the signal
transducer and activator of transcription (STAT) transcription factors. The STAT
molecules are phosphorylated on a single tyrosine residue by JAK kinases, leading to
dimerization and subsequent translocation to the nucleus where they act as transcription
factors . STAT5 factors (STAT5A and STAT5B)
are the most prominent STAT proteins activated by EPO
receptor , .
STAT3 and STAT1 are also,
albeit to a lesser extent, activated by EPO stimulation
, , .
CrkL, an adapter protein that is activated by binding to
the EPO receptor, can directly
associate with STAT5A and inhibit its DNA binding activity
, . Kinases c-Src and
JAK2 cooperatively tyrosine-phosphorylate STAT5 .
EPO-induced activation of STATs is mainly involved in
cell survival via up-regulation of the expression of antiapopototic factors, such as
Pim-1, Bcl-2 and transcription
factor c-Myc , , , , .
Protein kinase Lyn directly associates with
EPO receptor, binds to
JAK2, and phosphorylates EPO
receptor and STAT5 at tyrosine
residues, thus playing a role in activation of
JAK2/STAT5 signaling .
Calcium-binding protein Calmodulin physically interacts
with EPO receptor and enhances
JAK2-mediated signaling .
EPO also activates the canonical kinase
cascade H-Ras - c-Raf-1-
MEK1/2 - ERK1/2 by recruiting
complex to the EPO receptor , .
Besides tyrosine phosphorylation of STAT3 by
JAK2, leading to nuclear translocation,
STAT3 proteins can be serine-phosphorylated by
MSK1 kinase, which is activated upon MEK1/2
- ERK1/2 signal transduction cascade. It was
demonstrated that serine phosphorylation of STAT3 augments
its transactivational potential in erythroid cells .
c-Fes tyrosine kinase is also involved in
EPO-induced activation of STAT3
Expression of suppressors of cytokine signaling proteins
SOCS1 and SOCS3 (, or
CISH (Cytokine-inducible SH2-containing protein) negatively
regulates EPO-mediated Jak-STAT signaling , . On the
other hand, SOCS3 binds to the GTPase activating protein
p120GAP that attenuates H-Ras
inhibition and activates MEK1/2
- ERK1/2 cascade
to ensure cell survival and proliferation .
The adaptor protein APS is tyrosine phosphorylated by
JAK2, followed by recruitment of the adaptor protein
c-Cbl into the EPO
receptor/JAK2 complex, which inhibits the
JAK-STAT pathway .
Protein tyrosine phosphatases SHP-1 and
SHP-2 are recruited to the EPO
receptor/JAK2 complex and dephosphorylate
JAK2, inhibiting JAK-STAT signaling , , . SHP-1 is critical in negative
regulation of STAT5 activation.
SHP-1 is recruited to EPO
receptor/JAK2 complex that results in the
recruitment of Grb2 and its associated protein
SOCS1. SOCS1 is targeted to
JAK2, leading to
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