Biology Reference
In-Depth Information
(
5
) separates the blood from the brain, strictly limiting the access
of blood born EPO into the brain. In the same manner BBB also
restricts the access of brain derived EPO into the circulating blood.
Therefore, under physiological conditions blood born EPO is
unlikely to exert any neurological effects. Due to its very limited
access and significantly lower concentration than circulating EPO
levels, brain derived EPO is more likely to act in an autocrine or
paracrine manner and is not likely to modulate hematopoiesis.
Similar to EPO regulation for hematopoiesis, intrinsic levels of
EPO in the brain are also regulated by HIF. As in the fetal liver and
adult kidney, hypoxia-induced regulation of EPO production in
the central nervous system depends mainly of HIF1. This is evi-
denced by the fact that in animal models with deficiency in HIF1
expression, HIF2 expression cannot substitute for absence of the
former (
6
).
The identification of circulating EPO as the activator for eryth-
ropoiesis initiated the search for its cellular target, the EPO-R. The
EPO-R is a transmembrane receptor consisting of 484 amino acids.
This glycoprotein has an extracellular domain with WSXWS-motif,
a single hydrophobic transmembrane section, and a cytoplasmic
domain (
7-9
). Homodimerization of two EPO-R's allows the
binding of a single EPO molecule. The latter is variable and changes
its confirmation upon activation by EPO, enabling the activation
of EPO-R-associated Janus Kinase-2 (JAK-2) (
10
) by autophos-
phorylation (
11
). Eight tyrosine residues within the cytoplasmic
section of the EPO-R are phosphorylated by the activation of
JAK-2 and subsequently attract signaling proteins containing Src
homology-2 (SH2) domains to phosphotyrosines. The variety of
recruited proteins containing SH2 domains determines the signal-
ing pathway activated and indicates the diversity of cellular responses
to EPO/EPO-R interaction. Among those are signal transducers
and activators of transcription (STAT-1, STAT-3, STAT-5), phos-
phatidyl-inositol 3-kinase (PI-3K), MAP-kinase, and p38 (
12
).
The “classical” EPO-induced anti-apoptotic pathway in eryth-
roid cells involves the activation of signal transducer and activator
of transcription 5 (STAT-5), which results in enhanced production
of Bcl-X
L
(
13
). In non-neuronal cells the upregulation of this anti-
apoptotic factor prevents programmed cell death of the immature
erythroid cells and is therefore essential for the production of
erythrocytes (
14
).
The other well-known main signaling pathway activated by
EPO/EPO-R and JAK-2 is the PI-3K pathway. This pathway is
also necessary to prevent apoptotic cell death of proerythrocytes.
PI-3K can bind to the EPO-R either directly at the tyrosine Y479
residue or indirectly via adaptors proteins, such as Grb2 and RAS.
Direct binding of PI-3K to EPO-R results in phosphorylation and
subsequent activation of AKT, a key element in pro-survival signal-
ing in many cell types. Activated AKT phosphorylates transcription
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