U. Klingmuller et al., IDENTIFICATION OF A NOVEL PATHWAY IMPORTANT FOR PROLIFERATION AND DIFFERENTIATION OF PRIMARY ERYTHROID PROGENITORS, Proceedings of the National Academy of Sciences of the United Statesof America, 94(7), 1997, pp. 3016-3021
Homodimerization of the erythropoietin (EPO) receptor (EPO-R) in respo
nse to EPO binding transiently activates the receptor-associated prote
in tyrosine kinase JAK2. Tyrosine phosphorylation of the EPO-R creates
''docking sites'' for SH2 domain(s) in signaling molecules such as th
e protein tyrosine phosphatases SH-PTP1 and SH-PTP2, phosphoinositide
3-kinase (PI3 kinase), and STAT5. However, little Is known about tile
specific intracellular signals essential for proliferation and differe
ntiation of erythroid progenitors. Here we show that an EPO-R containi
ng only one cytosolic (phospho)tyrosine residue, Y479, induces a signa
l transduction pathway sufficient for proliferation and differentiatio
n of fetal liver progenitors of erythroid colony-forming units from EP
O-R(-/-) mice as well as for proliferation of cultured hematopoietic c
ells, This cascade involves sequential EPO-induced recruitment of PI3
kinase to the EPO-R and activation of mitogen-activated protein kinase
activity, independent of the Shc/Grb2-adapter pathway and of STAT5. P
rotein kinase C epsilon may be one of the mediators connecting PI3 kin
ase with the mitogen-activated protein kinase signaling cascade. Our r
esults identify a signaling cascade important in vivo for erythroid ce
ll proliferation and differentiation.