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Extracellular truncations of h beta c, the common signaling subunit for
interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor
(GM-CSF), and IL-5, lead to ligand-independent activation
RJ D'Andrea, SC Barry, PA Moretti, K Jones, S Ellis, MA Vadas and GJ Goodall
Division of Human Immunology, Hanson Centre for Cancer Research, Adelaide,
Australia.
The hypothesis that extracellular truncation of the common receptor subunit
for interleukin-3 (IL-3), granulocyte-macrophage colony- stimulating
factor, and IL-5 (h beta c) can lead to ligand-independent activation was
tested by infecting factor-dependent hematopoietic cell lines with
retroviruses encoding truncated forms of h beta c. A truncation, resembling
that in v-Mpl, and retaining 45 h beta c-derived extracellular residues,
led to constitutive activation in the murine myeloid cell line, FDC-P1.
However, infection of cells with retrovirus encoding a more severely
truncated receptor, retaining only 7 h beta c- derived extracellular
residues, did not confer factor independence on these cells. These
experiments show that truncation activates the receptor and define a
37-amino acid segment of h beta c (H395-A431) which contains two motifs
conserved throughout the cytokine receptor superfamily (consensus Y/H XX
R/Q VR and WSXWS), as essential for factor-independent signaling. The
mechanism of activation was also investigated in less severe truncations. A
receptor that retains the entire membrane-proximal domain (domain 4) also
conferred factor independent growth on FDC-P1 cells; however, a retrovirus
encoding a truncated form of h beta c having two intact membrane proximal
domains did not have this ability, suggesting that domain 3 may have an
inhibitory role in h beta c. The ability of these receptors to confer
factor independence was cell specific as demonstrated by their inability to
confer factor-independent growth when introduced into the murine
IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a
model in which activation requires unmasking of an interactive receptor
surface in domain 4 and association with a myeloid- specific receptor or
accessory component. We suggest that in the absence of ligand
intramolecular interactions prevent inappropriate signaling.
Volume 87,
Issue 7,
pp. 2641-2648,
04/01/1996
Copyright © 1996 by The American Society of Hematology
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