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Redundant and Selective Roles for Erythropoietin Receptor
Tyrosines in Erythropoiesis In Vivo
Gregory D. Longmore,
Yun You,
Jaime Molden,
Kathleen D. Liu,
Aki Mikami,
Stephen Y. Lai,
Pamela Pharr, and
Mark A. Goldsmith
From the Departments of Medicine and Cell Biology, Washington
University School of Medicine, St Louis, MO; the Gladstone Institute of
Virology and Immunology, San Francisco, CA; the Department of Medicine,
School of Medicine, University of California, San Francisco; and Ralph
H. Johnson Department of Veterans Affairs Medical Center and Department
of Medicine, Medical University of South Carolina, Charleston.
Cytokine receptors have been shown in cell culture systems to use
phosphotyrosine residues as docking sites for certain signal transduction intermediates. Studies using various cellular backgrounds have yielded conflicting information about the importance of such residues. The present studies were undertaken to determine whether or
not tyrosine residues within the erythropoietin receptor (EPOR) are
essential for biologic activity during hematopoiesis in vivo. A variant
of the EPOR was constructed that contains both a substitution (R129C)
causing constitutive receptor activation as well as replacement of all
eight cytoplasmic tyrosines by phenylalanines (cEPORYF). A comparison
between animals exposed to recombinant retroviruses expressing cEPOR
and cEPORYF showed that efficient red blood cell (RBC) development in
vivo is dependent on the presence of tyrosine residues in the
cytoplasmic domain of the EPOR. In addition, an inefficient EPOR
tyrosine independent pathway supporting RBC development was detected.
Tyrosine add-back mutants showed that multiple individual tyrosines
have the capacity to restore full erythropoietic potential to the EPOR
as determined in whole animals. The analysis of primary erythroid
progenitors transduced with the various cEPOR tyrosine mutants and
tyrosine add-backs showed that only tyrosine 343 (Y1) and tyrosine 479 (Y8) were capable of supporting immature burst-forming unit-erythroid
progenitor development. Thus, this receptor is characterized by
striking functional redundancy of tyrosines in a biologically relevant
context. However, selective tyrosine residues may be uniquely important
for early signals supporting erythroid development.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 870-878
© 1998 by The American Society of Hematology.
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