IDENTIFICATION OF A NOVEL PATHWAY IMPORTANT FOR PROLIFERATION AND DIFFERENTIATION OF PRIMARY ERYTHROID PROGENITORS

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.