Biology Reference
In-Depth Information
Non-hematopoietic cells
Tissue protection
Hematopoietic cells
EPO
Erythropoiesis
Extracellular
EPO
Intracellular
Extracellular
Intracellular
NFkB
MMP/TIMP
PLC
Brain
Brain
STAT5
MAPK
PI3K/AKT
STAT
MAPK
PI3K/Akt/NO
Endothelium
Brain
Heart
Brain
Heart
Heart
Brain
JAK2
Endothelium
EPOR
Endothelium
Pancreas
CR
EPO
β
Fig. 1
Downstream pathways activated by Epo signaling in hematopoietic and non-hematopoietic cells. In
non-hematopoietic cells the
b
CR subunit makes a functional receptor with a classic EpoR. In the absence of
b
CR it is postulated that the homodimer configuration will occur. Note the similarities of the downstream
pathways activated by both hetero- and homodimers
protein kinase (MAPK) (
54, 55
). Although Epo can activate STAT1,
STAT3, and STAT5a/b, JAK2/STAT5 is the classical pathway acti-
vated in erythroid cells (summarized in Fig.
1
and reviewed in ref.
56
). Epo-mediated activation of this pathway leads to the upregula-
tion of the antiapoptotic Bcl2 and Bcl-X
L
gene, thereby protecting
precursors from apoptosis (
56, 57
).
The PI3K/Akt pathway has been shown to be necessary, but
not solely sufficient, for erythroid cell survival by protecting them
from apoptosis (
58
). The PI3K/Akt cascade phosphorylates serine
residue 310 of GATA-1 both in vitro and in erythroid cells thereby
enhancing GATA-1 transcriptional activity (
55
). GATA-1 binds to
a consensus GATA motif present in the
cis
-regulatory elements of
most erythroid genes and is a key transcription factor for antiapop-
totic Bcl-X
L
and erythroid-specific gene transcription, and terminal
differentiation of erythroid precursors into red blood cells (
59-
61
). Notably PI3K can also be indirectly recruited to EpoR by
other proteins such as Grb-2. PI3K-mediated Akt phosphorylation
inhibits cytochrome c release from mitochondria (
62
) and facili-
tates NFkB activation by enhancing inhibitor of NF-kappaB (IkB)
degradation (
63
). Additionally, Akt can inhibit activity of Foxo3A
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