Epo is best known for its role in red blood cell formation. While Epo is not a lineage
commitment factor, it inhibits apoptosis and induces burst forming unit-erythroid
(BFU-E) differentiation into colony forming unit-erythroid (CFU-E), and the subsequent
proliferation and maturation of CFU-E into early normoblasts (10, 15, 16). Apart from its role
in erythropoiesis, Epo also acts on various non-hematopoietic cells to function as a viability
and proliferation factor. Epo can stimulate myoblast proliferation while suppressing its
differentiation, resulting in the expansion of the progenitor cell population (17). Epo is a tissueprotective factor that protects against ischemic and toxic injuries to neuronal, cardiovascular
and renal tissues (18, 19). Epo has also been shown to promote angiogenesis in various
physiologic and pathologic conditions (20, 21).
Epo binds and signals via the high-affinity preformed homodimeric Epo receptor (Epo R) that is
composed of two Epo R subunits. Each Epo R subunit is a type I transmembrane glycoprotein
that belongs to the type I cytokine receptor superfamily (18, 22-24). Its extracellular domain
contains the characteristic two fibronectin type III domains and a WSxWS motif near the
plasma membrane (24, 25). Binding of Epo to the Epo R homodimer results in conformational
change and phosphorylation and activation of the non-receptor protein kinase JAK2, which
activates the downstream signaling cascade (26). An alternative Epo heteromeric receptor
complex that transduces cell-protective signals and containing the beta common receptor ( beta CR)
subunit in addition to the Epo R subunit has been described. beta CR also belongs to the
type I cytokine receptor superfamily and is a subunit that is shared by the heteromeric IL-3,
IL-5 and GM-CSF receptor complexes. Epo binds with lower affinity to the heteromeric receptor
consisting of a Epo R subunit and a beta CR homodimer (18).
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