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thereby downregulating target proteins having antiproliferative or
proapoptotic functions ( 64, 65 ).
Another important Epo-mediated signaling pathway is the
MAPK pathway. MAPKs are serine/threonine kinases activated by
extracellular signals of which there are at least three distinct types:
the classical ERK1/ERK2 kinases, the p38MAPKs (p38), and the
stress-activated protein kinase/Jun kinase (SAPK/JNK) subfamily.
All play important roles in Epo-induced differentiation or apoptosis
( 66-70 ).
Soon after stimulation of the receptor by its ligand, mechanisms
integral to downregulation of these signaling pathways are also acti-
vated, returning signaling proteins to their basal levels. This process
is crucial to prevent hyperstimulation and, consequently, the dysregu-
lation of cellular machinery (reviewed in ref. 63 ). Notably, EpoR is
also synthesized in a soluble form (sEpoR) that corresponds to the
extracellular domain of the complete receptor as a result of alternative
splicing of EpoR mRNA ( 71 ). The sEpoR is secreted into the extra-
cellular fluid and acts as a sink, sequestering Epo and preventing its
ability to activate EpoR and downstream signaling cascades (see
Fig. 2 , pathway 8). The presence of sEpoR has been reported in
plasma and several tissues including liver, spleen, kidney, heart, brain,
and bone marrow ( 15, 72 ).
4
Epo and EpoR Signaling in Non-hematopoietic Tissues
Production of Epo and expression of the EpoR has been detected
in non-hematopoietic tissues and emerging evidence suggests that
Epo exerts cytoprotective effects on non-erythroid cells. Notably,
a tissue-specific degree of Epo regulation has been reported.
Depending on the severity of hypoxia, Epo mRNA levels can
increase up to 20-fold in the brain in contrast to 200-fold in the
kidney ( 5 ) and remain high much longer ( 73 ). Also brain Epo,
purified from primary neuronal cell cultures, was shown to have
lower molecular weight and be more active than recombinant Epo
and serum Epo at low concentrations ( 74 ). Importantly, tissue
protection in vivo and in vitro appears to require nanomolar con-
centrations of Epo that are not normally reached in the circulation,
in contrast to low picomolar concentrations required for erythro-
poiesis ( 75 ) underlining the fact that paracrine/autocrine signaling
likely results in high local concentrations of Epo. The EpoR
expressed by PC12 cells also had lower affinity than EpoR on
erythroid cells and required different accessory proteins compared
to erythrocyte precursors ( 4 ). Lower binding affinities of EpoR
expressed by non-erythroid cells was also reported in vivo ( 76 ).
Thus, differential activity and affinity allows specific activation of
erythroid and non-hematopoietic receptors thus preventing cross-
talk between the endocrine and paracrine systems of Epo.
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