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Keywords:

  • erythropoiesis;
  • colony-forming unit-erythroid;
  • erythropoietin-receptor;
  • signal transduction;
  • inositolphospholipid 3-kinase;
  • Janus kinase 2;
  • signal transducer activator of transcription;
  • mitogen-activated protein kinase;
  • KIT

Abstract

  1. Top of page
  2. Abstract
  3. References

Red blood cells arise continuously from pluripotent stem cells which mature and become functionally specialized upon commitment to the erythroid lineage. In mammals, the key regulator of this process is the hormone erythropoietin (EPO). Hormone binding to the cognate receptor, the erythropoietin receptor (EPO-R), causes receptor homodimerization and transiently triggers tyrosine phosphorylation within target cells. Although the EPO-R lacks intrinsic enzymatic activity it couples, presumably sequentially, to the protein tyrosine kinase receptor c-KIT and the cytosolic protein tyrosine kinase JAK2. Signaling through the EPO-R is promoted by tyrosine phosphorylation of the cytosolic domain and the recruitment of secondary signaling molecules such as the lipid kinase inositolphospholipid 3-kinase (phosphatidylinositol 3-kinase) and protein tyrosine phosphatase SHP-2 to the activated receptor. Complex formation of the activated EPO-R with the protein tyrosine phosphatase SHP-1 terminates signaling. In primary fetal liver cells redundant signals emanating from phosphotyrosine residues in the EPO-R support formation of erythroid colonies in vitro. However, since the last tyrosine residue in the cytosolic domain of the EPO-R, Y479, uniquely supports in the absence of other tyrosine residues an almost normal level of colony-forming unit-erythroid (CFU-E) colony formation, Y479 represents one of the key residues required in vivo for erythroid proliferation and differentiation. The signal emanating from Y479 involves sequential EPO-induced recruitment of phosphoinositol lipid 3-kinase to the EPO-R and activation of mitogen-activated-protein(MAP)kinase activity. The MAP-kinase signaling cascade could serve as an intracellular switch integrating signals mediated by several phosphotyrosine residues in the cytosolic domain of the EPO-R and provide a possible explanation for partial redundancy in signaling.

Abbreviation
EPO

erythropoietin

EPO-R

erythropoietin receptor

MAP

mitogen-activated protein

MEK

mitogen-activated-protein-kinase kinase

JAK

Janus kinase

SHP

SH2 domain containing protein tyrosine phosphatase

CFU-E

colony-forming unit-erythroid

BFU-E

burst-forming unit-erythroid

IL-3

interleukin-3

GM-CSF

granulocyte/macrophage colony-stimulating factor

SCF

stem cell factor

SH2

domain src homology 2 domain

SH3

domain src homology 3 domain

STAT

signal transducer activator of transcription

PTB

phosphotyrosine binding domain

SOS

son of the sevenless

GST

glutathione S -transferase

PLC-γ

phospholipase Cγ

PKC

protein kinase C

PDGF

plateletderived growth factor

rh

recombinant human

InsP3

inositol 1,4,5-trisphosphate

References

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  2. Abstract
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