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Blood, 1 February 2002, Vol. 99, No. 3, pp. 879-887
HEMATOPOIESIS
Tyrosine residues of the granulocyte colony-stimulating factor
receptor transmit proliferation and differentiation signals in murine
bone marrow cells
Shiva Akbarzadeh,
Alister
C. Ward,
Dora O. M. McPhee,
Warren S. Alexander,
Graham J. Lieschke, and
Judith E. Layton
From the Ludwig Institute for Cancer Research,
Melbourne Tumour Biology Branch, and the Walter and Eliza Hall
Institute of Medical Research, Parkville, Victoria, Australia.
Granulocyte colony-stimulating factor (G-CSF) is the major
regulator of granulopoiesis and acts through binding to its specific receptor (G-CSF-R) on neutrophilic granulocytes. Previous studies of
signaling from the 4 G-CSF-R cytoplasmic tyrosine residues used model
cell lines that may have idiosyncratic, nonphysiological responses.
This study aimed to identify specific signals transmitted by the
receptor tyrosine residues in primary myeloid cells. To bypass the
presence of endogenous G-CSF-R, a chimeric receptor containing the
extracellular domain of the epidermal growth factor receptor in place
of the entire extracellular domain of the G-CSF-R was used. A series of
chimeric receptors containing tyrosine mutations to phenylalanine,
either individually or collectively, was constructed and expressed in
primary bone marrow cells from G-CSF-deficient mice. Proliferation and
differentiation responses of receptor-expressing bone marrow cells
stimulated by epidermal growth factor were measured. An increased 50%
effective concentration to stimulus of the receptor Ynull
mutant indicated that specific signals from tyrosine residues were
required for cell proliferation, particularly at low concentrations of
stimulus. Impaired responses by mutant receptors implicated G-CSF-R
Y764 in cell proliferation and Y729 in
granulocyte differentiation signaling. In addition, different
sensitivities to ligand stimulation between mutant receptors indicated
that G-CSF-R Y744 and possibly Y729 have an
inhibitory role in cell proliferation. STAT activation was not affected
by tyrosine mutations, whereas ERK activation appeared to depend, at
least in part, on Y764. These observations have suggested
novel roles for the G-CSF-R tyrosine residues in primary cells that
were not observed previously in studies in cell lines.
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