Biology Reference
In-Depth Information
Erythropoietin receptor signaling processes
Saghi Ghaffari,
1,2
Lily Jun-shen Huang,
1
Jing Zhang
1
, and Harvey F. Lodish
1,3
1
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
2
Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
3
Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4307, USA
Introduction
Activation of erythropoietin receptor (EPOR) by erythropoietin (EPO) is
essential for the survival, proliferation, and differentiation of red blood cells,
as has been demonstrated definitively by the generation of EPO and EPOR-
deficient mice [1-3]. Signaling by other cytokine receptors cannot replace
EPO since EPO and EPOR-deficient mice die of severe anemia at days 13 to
15 (E13-E15) of embryogenesis due to lack of differentiation of their mature
erythroid progenitors (erythroid colony-forming units [CFU-E]) [1-3]. Fetal
livers of EPO
-/-
and EPOR
-/-
animals contain normal numbers of primitive
(erythroid burst-forming units [BFU-E]) and mature CFU-E progenitors indi-
cating that EPO signaling is not required for lineage determination and com-
mitment, but is essential for terminal maturation of red blood cells. EPO bind-
ing induces conformational changes of an already dimerized EPOR on the cell
surface and triggers the transphosphorylation and activation of receptor-asso-
ciated JAK-2, a member of Janus protein tyrosine kinase family (Fig.1).
JAK-2 phosphorylates several tyrosine residues on EPOR, providing docking
sites for binding of intracellular signaling proteins and initiating EPOR sig-
naling pathways. (See Chapter 3 by Osslund for further information.) These
pathways converge presumably on a common set of targets resulting in cell
proliferation, differentiation, and survival. It is not known, however, whether
any signal emanating from EPOR specifically regulates transcription of genes
required for red cell differentiation and maturation.
For historical and physiological reasons, EPOR signaling has been well
studied in red cell progenitors and erythroblasts. It has become clear more
recently that EPOR is expressed in many organs including brain, heart,
endothelium, and ovaries and may have physiological roles in these organs
[4-9]. In particular, it has been suggested that EPOR signaling may be
required for survival of neuronal cells [5, 10]. Although studies have begun
[11] to establish the role of EPOR signaling in these organs, it is becoming
increasingly apparent that red cells are not the only targets of EPO.
