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J. Biol. Chem., Vol. 269, Issue 48, 30173-30180, 12, 1994
M Eder, TJ Ernst, A Ganser, PT Jubinsky, R Inhorn, D Hoelzer and JD Griffin
The high affinity receptor for granulocyte-macrophage colony- stimulating
factor (GM-CSF) is composed of at least two subunits, an 85- kDa low
affinity GM-CSF-binding protein (alpha-GMR) and a 120-kDa beta- subunit
(beta-GMR) necessary for high affinity binding and signal transduction.
Previous studies have shown that deletion of the intracellular domain of
alpha-GMR inactivates the receptor's ability to support proliferation, but
has no effect on GM-CSF binding. Using anti- alpha-GMR- and
anti-beta-GMR-specific antibodies, we show that alpha- GMR and beta-GMR
coprecipitate only after GM-CSF binding, suggesting that binding of GM-CSF
induces stabilization or assembly of an activated receptor complex
involving recruitment of beta-GMR chains. To understand the contribution of
each subunit of this receptor to the generation of an activated receptor
complex, we attempted to construct minimal receptors with some or all of
the functions of the wild-type heterodimer. We found that a hybrid human
alpha/beta-GMR molecule in which the extracellular and transmembrane
segments are composed of alpha-GMR sequences and the intracellular segment
is composed of beta- GMR bound GM-CSF with low affinity, but activated
tyrosine kinase activity, induced receptor internalization, and supported
short- and long-term proliferation of transfected Ba/F3 cells. At least 1
ng/ml human GM-CSF was required for growth stimulation, and maximal
proliferation occurred at a concentration of 10 ng/ml. This was 10-100-
fold more than needed to stimulate growth of Ba/F3 cells expressing both
full-length human alpha-GMR and beta-GMR and 1000-fold less than needed to
stimulate growth of Ba/F3 cells expressing only human alpha- GMR. These
results indicate that the cytoplasmic domain of alpha-GMR is not required
to initiate a unique signaling event for proliferation in Ba/F3 cells, but
can be functionally replaced by the cytoplasmic domain of beta-GMR.
A low affinity chimeric human alpha/beta-granulocyte-macrophage colony- stimulating factor receptor induces ligand-dependent proliferation in a murine cell line
Department of Hematology, University of Frankfurt, Federal Republic of Germany.
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