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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2662-2672.
Prepublished online as a Blood First Edition Paper on December 6, 2005; DOI 10.1182/blood-2005-02-0684.
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Submitted February 17, 2005
Accepted November 9, 2005
Core erythropoietin receptor signals for late erythroblast development
Madhu P Menon, Jing Fang, and Don M Wojchowski*
Maine Medical Center Research Institute and Program in Stem Cell Biology & Regenerative Medicine, Scarborough, Maine, USA; Molecular Medicine Program, The Pennsylvania State University, University Park, Pennsylvania, USA
Maine Medical Center Research Institute and Program in Stem Cell Biology & Regenerative Medicine, Scarborough, Maine, USA
* Corresponding author; email: wojchd{at}mmc.org.
Critical signals for erythroblast formation are transduced by activated, tyrosine-phosphorylated erythropoietin receptor (EpoR) complexes. Nonetheless, steady-state erythropoiesis is supported effectively by EpoR alleles that are deficient in cytoplasmic phosphotyrosine sites. To better define core EpoR action mechanisms, signaling capacities of minimal PY-null (EpoR-HM) and PY343-retaining (EpoR-H) alleles were analyzed for the first time in bone marrow-derived erythroblasts. Jak2 activation via each allele was comparable. Stat5 (and several Stat5- response genes) were induced via EpoR-H but not via EpoR-HM. Stat1 and -3 activation was nominal for all EpoR forms. For both EpoR-HM and EpoR-H, Akt and p70S6-kinase activation was decreased multi-fold, and JNK activation was minimal. ERKs, however, were hyperactivated uniquely via EpoR-HM. In vivo, Epo expression in EpoR-HM mice was elevated, while Epo-induced reticulocyte production was diminished. In vitro, EpoR-HM erythroblast maturation also was attenuated (based on DNA content, forward-angle light-scatter and hemoglobinization). These EpoR-HM-specific defects were corrected not only upon PY343 site restoration in EpoR-H, but also upon MEK1,2 inhibition. Core EpoR PY site-independent signals for erythroblast formation therefore appear to be Stat-5,-1,-3, p70S6-kinase- and JNK-independent, but ERK-dependent. Wild-type signaling capacities, however, depend further upon signals provided via an EpoR/PY343/Stat5 axis.
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