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Differentiation-linked changes in tyrosine phosphorylation, functional
activity, and gene expression downstream from the granulocyte- macrophage
colony-stimulating factor receptor
PJ Roberts, A Khwaja, AK Lie, A Bybee, K Yong, NS Thomas and DC Linch
Department of Haematology, University College London Medical School, UK.
The HL-60 model of myeloid maturation was used to test whether changes in
signaling from the granulocyte-macrophage colony-stimulating factor
(GM-CSF) receptor accompany maturation-related changes in cellular
responses to GM-CSF. Receptor expression, tyrosine phosphorylation,
functional activity, and c-fos gene expression were measured. Functional
GM-CSF receptors were present throughout differentiation as both uninduced
and dimethyl sulfoxide (DMSO)-induced HL-60 cells responded to GM-CSF,
albeit in different ways. Uninduced promyelocytes proliferated in response
to GM-CSF, whereas DMSO-induced cells lost the capacity to proliferate but
did respond with increased expression of beta 2-integrins, enhanced
respiratory burst activity, and metabolism of arachidonic acid.
GM-CSF-stimulated upregulation of c-fos mRNA expression was not detected in
immature cells but developed after 2 to 4 days with DMSO in line with a
marked increase in responsiveness to stimulation with phorbol ester,
showing that increased expression of c- fos is predominantly a feature of
mature phagocytes. GM-CSF stimulated the tyrosine phosphorylation of a
broadly similar range of proteins in both uninduced and DMSO-treated HL-60
cells, but protein bands were more heavily phosphorylated in DMSO-induced
cells. Phosphorylation was rapid in onset and very transient in immature
cells. Phosphorylation of several proteins, in particular a 130-kD band,
was more sustained in DMSO-induced cells. These differences in signaling
were not because of numerical differences in receptors, because reduction
of GM-CSF concentration to trigger equivalent numbers of high-affinity
receptors delayed the onset of phosphorylation in DMSO-induced cells. We
conclude that there are maturation-related changes in signaling downstream
from the GM-CSF receptor.
Volume 84,
Issue 4,
pp. 1064-1073,
08/15/1994
Copyright © 1994 by The American Society of Hematology
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