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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-07-2062.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2584-2590
HEMATOPOIESIS
Signaling mechanisms coupled to tyrosines in the granulocyte
colony-stimulating factor receptor orchestrate G-CSF-induced expansion
of myeloid progenitor cells
Mirjam H. A. Hermans,
Gert-Jan van de Geijn,
Claudia Antonissen,
Judith Gits,
Daphne van Leeuwen,
Alister C. Ward, and
Ivo P. Touw
From the Institute of Hematology, Erasmus University of
Rotterdam, the Netherlands; and Deakin University,
Burwood, Victoria, Australia.
Granulocyte colony-stimulating factor (G-CSF) is the
major regulator of neutrophil production. Studies in cell lines have established that conserved tyrosines Tyr704, Tyr729, Tyr744,
Tyr764 within the cytoplasmic domain of G-CSF receptor
(G-CSF-R) contribute significantly to G-CSF-induced proliferation,
differentiation, and cell survival. However, it is unclear whether
these tyrosines are equally important under more physiologic
conditions. Here, we investigated how individual G-CSF-R tyrosines
affect G-CSF responses of primary myeloid progenitors. We generated
G-CSF-R-deficient mice and transduced their bone marrow cells with
tyrosine "null" mutant (m0), single tyrosine
"add-back" mutants, or wild-type (WT) receptors. G-CSF-induced
responses were determined in primary colony assays, serial replatings,
and suspension cultures. We show that removal of all tyrosines had no
major influence on primary colony growth. However, adding back Tyr764
strongly enhanced proliferative responses, which was reverted by
inhibition of ERK activity. Tyr729, which we found to be associated
with the suppressor of cytokine signaling, SOCS3, had a negative effect
on colony formation. After repetitive replatings, the clonogenic
capacities of cells expressing m0 gradually dropped compared with WT.
The presence of Tyr729, but also Tyr704 and Tyr744, both involved in
activation of signal transducer and activator of transcription 3 (STAT3), further reduced replating efficiencies. Conversely, Tyr764
greatly elevated the clonogenic abilities of myeloid progenitors,
resulting in a more than 104-fold increase of
colony-forming cells over m0 after the fifth replating. These findings
suggest that tyrosines in the cytoplasmic domain of G-CSF-R, although
dispensable for G-CSF-induced colony growth, recruit signaling
mechanisms that regulate the maintenance and outgrowth of myeloid
progenitor cells.
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