A cell type-specific constitutive point mutant of the common beta-subunit of the human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors requires the GM-CSF receptor alpha-subunit for activation
Bj. Jenkins et al., A cell type-specific constitutive point mutant of the common beta-subunit of the human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors requires the GM-CSF receptor alpha-subunit for activation, J BIOL CHEM, 274(13), 1999, pp. 8669-8677
The high affinity receptor for human granulocyte-macrophage colony-stimulat
ing factor (GM-CSF) consists of a cytokine-specific alpha-subunit (hGMR alp
ha) and a common signal-transducing beta-subunit (hpc) that is shared with
the interleukin-3 and -5 receptors, We have previously identified a constit
utively active extracellular point mutant of hpc, I374N, that can confer fa
ctor independence on murine FDC-P1 cells but not BAF-B03 or CTLL-2 cells (J
enkins, B. J., D'Andrea, R. J., and Gonda, T. J. (1995) EMBO J. 14, 4276-42
87), This restricted activity suggested the involvement of cell type-specif
ic signaling molecules in the activation of this mutant. We report here tha
t one such molecule is the mouse GMR alpha (mGMR alpha) subunit, since intr
oduction of mGMR alpha, but not hGMR alpha, into BAF-B03 or CTLL-2 cells ex
pressing the I374N mutant conferred factor independence, Experiments utiliz
ing mouse/human chimeric GMR alpha subunits indicated that the species spec
ificity lies in the extracellular domain of GMRa. Importantly, the requirem
ent for mGMR alpha correlated with the ability of I374N (but not wild-type
hpc) to constitutively associate with mGMRa. Expression of I374N in human f
actor-dependent UT7 cells also led to factor-independent proliferation, wit
h concomitant up-regulation of hGMR alpha surface expression. Taken togethe
r, these findings suggest a critical role for association with GMR alpha in
the constitutive activity of I374N.