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J Biol Chem, Vol. 274, Issue 13, 8669-8677, March 26, 1999
-Subunit of the Human Granulocyte-Macrophage Colony-stimulating
Factor (GM-CSF), Interleukin (IL)-3, and IL-5 Receptors Requires the
GM-CSF Receptor 
-Subunit for Activation
From the Hanson Centre for Cancer Research and Division of Human
Immunology, Institute of Medical and Veterinary Science, Frome Road,
Adelaide, South Australia 5000, Australia
The high affinity receptor for human
granulocyte-macrophage colony-stimulating factor (GM-CSF) consists of a
cytokine-specific 
-subunit (hGMR) and a common signal-transducing
-subunit (hc) that is shared with the interleukin-3 and -5 receptors. We have previously identified a constitutively active
extracellular point mutant of hc, I374N, that can confer factor
independence on murine FDC-P1 cells but not BAF-B03 or CTLL-2 cells
(Jenkins, B. J., D'Andrea, R. J., and Gonda, T. J. (1995) EMBO J. 14, 4276-4287). This restricted activity
suggested the involvement of cell type-specific signaling molecules in
the activation of this mutant. We report here that one such molecule is
the mouse GMR (mGMR) subunit, since introduction of mGMR, but
not hGMR, into BAF-B03 or CTLL-2 cells expressing the I374N mutant
conferred factor independence. Experiments utilizing mouse/human
chimeric GMR subunits indicated that the species specificity lies in
the extracellular domain of GMR. Importantly, the requirement for
mGMR correlated with the ability of I374N (but not wild-type hc)
to constitutively associate with mGMR. Expression of I374N in human
factor-dependent UT7 cells also led to factor-independent
proliferation, with concomitant up-regulation of hGMR surface
expression. Taken together, these findings suggest a critical role for
association with GMR in the constitutive activity of I374N.
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