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Human granulocyte-macrophage colony-stimulating factor receptor signal
transduction requires the proximal cytoplasmic domains of the alpha and
beta subunits
M Weiss, C Yokoyama, Y Shikama, C Naugle, B Druker and CA Sieff
Division of Pediatric Hematology and Oncology, Dana-Farber Cancer
Institute, Boston, MA 02115.
Human granulocyte-macrophage colony-stimulating factor (GM-CSF) controls
the production, maturation, and function of cells in multiple hematopoietic
lineages. These effects are mediated by a cell-surface receptor (GM-R)
composed of alpha and beta subunits, each containing 378 and 881 amino
acids, respectively. Whereas the alpha subunit exists as several isoforms
that bind GM-CSF with low affinity, the beta common subunit (beta c) does
not bind GM-CSF itself, but acts as a high- affinity converter for GM-CSF,
interleukin-3 (IL-3), and IL-5 receptor alpha subunits. The cytoplasmic
region of GM-R alpha consists of a membrane-proximal conserved region
shared by the alpha 1 and alpha 2 isoforms and a C-terminal variable region
that is divergent between alpha 1 and alpha 2. The cytoplasmic region of
beta c contains membrane proximal serine and acidic domains. To investigate
the amino acid sequences that influence signal transduction by this
receptor complex, we constructed a series of cytoplasmic truncation mutants
of the alpha 2 and beta subunits. To study these truncations, we stably
transfected the IL-3-dependent murine cell line Ba/F3 with wild-type or
mutant cDNAs. We found that the wild-type and mutant alpha subunits
conferred similar low-affinity binding sites for human GM-CSF to Ba/F3, and
the wild-type or mutant beta subunit converted some of these sites to high-
affinity; the cytoplasmic domain of beta was unnecessary for this high-
affinity conversion. Proliferation assays showed that the membrane-
proximal conserved region of GM-R alpha and the serine-acidic domain of
beta c are required for both cell proliferation and ligand-dependent
phosphorylation of a 93-kD cytoplasmic protein. We suggest that these
regions may represent an important signal transduction motif present in
several cytokine receptors.
Volume 82,
Issue 11,
pp. 3298-3306,
12/01/1993
Copyright © 1993 by The American Society of Hematology
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