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Prepublished online as a Blood First Edition Paper on July 17, 2003; DOI 10.1182/blood-2003-01-0078.
Submitted January 10, 2003
Accepted June 28, 2003
Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells
Ke Li, Madhu P Menon, Vinit G Karur, Shailaja Hegde, and Don M Wojchowski*
Immunobiology Program, The Pennsylvania State University, University Park, PA, USA
* Corresponding author; email: dmw1{at}psu.edu.
Signals provided by the Epo receptor (EpoR) are required for erythroid development beyond the CFUe stage, and are propagated via the EpoR tethered Janus kinase, JAK2. JAK2 functions, in part, to phosphorylate eight conserved EpoR PY sites for the binding of a diverse set of signaling factors. However, recent studies in transgenic and knock-in mouse mice have demonstrated substantial bioactivity for PY-null EpoR forms. Presently, the activities of a PY-null EpoR-HM form in primary progenitor cells from knock-in mice were further assessed using optimized Epo dose-dependent proliferation, survival and differentiation assays. As compared to the wt-EpoR, EpoR-HM activity was compromised several fold in each context when Epo was limited to physiological concentrations. Possible compensatory increases in serum growth factor levels also were investigated, and as assayed using ES cell derived erythroid G1E2 cells, activities in serum from EpoR-HM mice were substantially elevated. In addition, when challenged with phenylhydrazine-induced anemia, EpoR-HM mice failed to respond with efficient splenic stress erythropoiesis. Thus, the function of this JAK2-coupled but minimal PY-null EpoR-HM form appears to be attenuated in several contexts, and to be assisted in vivo by compensatory mechanisms. Roles normally played by EpoR PY sites and distal domains therefore should receive continued attention.
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