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J Biol Chem, Vol. 274, Issue 13, 8669-8677, March 26, 1999

A Cell Type-specific Constitutive Point Mutant of the Common -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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