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Receptors that induce erythroid differentiation of Ba/F3 cells: structural
requirements and effect on STAT5 binding
M Pless, K Norga, M Carroll, MH Heim, AD D'Andrea and B Mathey-Prevot
Division of Pediatric Oncology and Hematology, Dana-Farber Cancer
Institute, Children's Hospital, Boston, MA 02115, USA.
Ectopic expression of the erythropoietin receptor (EpoR) in the
interleukin-3 (IL-3)-dependent cell line Ba/F3 results in growth and
partial erythroid differentiation in Epo. In contrast, introduction and
activation of the interleukin-5 receptor (IL-5R) or of the granulocyte-
macrophage colony-stimulating factor receptor (GM-CSFR) results in
proliferation only. As this effect is specific to the EpoR, the role of its
extracellular or cytoplasmic domain in differentiation was tested after
construction of two chimeric receptors. One receptor contained the
extracellular domain of EpoR fused to the endodomain of IL-3R beta- chain
(E/beta), while the other contained the EpoR cytoplasmic region fused to
the extracellular domain of GM-CSFR alpha-chain (GMER). Surprisingly, both
receptors induced differentiation ruling out a strict specificity of the
extracellular or cytoplasmic region of EpoR in this process. Instead the
ability to signal differentiation correlated with structural features
shared by the EpoR, GMER, and E/beta receptors. Dimerization of all three
receptors results in the pairing of two signal transducing chains in the
cytoplasm, in contrast to the mitogenic receptors IL-3R, IL-5R, GM-CSFR,
which assemble as alphabeta heterodimers. Two new chimeric receptors that
fulfilled the structural requirement exemplified by EpoR, but lacked any
part of EpoR, were designed to consolidate this model. They consisted of
the ectodomains of the GMR-alpha and IL-5R alpha, respectively, fused to
the endodomain of IL-3R beta-chain. Both receptors were as effective as
EpoR in signaling differentiation in response to their cognate ligand.
Another property of receptors fulfilling these structural requirements is
that they cause a marked delay in signal transducers and activators of
transcription 5 (STAT5) activation on ligand stimulation. Taken together
our studies show that structural assembly of receptors dictates their
potential to signal erythroid differentiation in Ba/F3 cells, that
differentiation can take place in the absence of Epo and that a delay in
STAT5 activation is highly predictive of this process.
Volume 89,
Issue 9,
pp. 3175-3185,
05/01/1997
Copyright © 1997 by The American Society of Hematology
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