Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates differentiation, survival, and proliferation of colony-forming unit-granulocyte-macrophage progenitor cells. The biologic actions of GM-CSF are mediated by binding to a specific receptor consisting of two chains designated as alpha and beta subunits. We have demonstrated that the murine FDC-P1-derived cell line WT-19 transfected with the human GM-CSF receptor alpha and beta subunits (GM-CSFRalpha and beta) can be induced to differentiate by the addition of human GM-CSF (hGM-CSF). By expressing a series of GM-CSFRalpha mutants in WT19 cells, we have determined the amino acid domains of the GM-CSFRalpha cytoplasmic domain that regulate cell differentiation, proliferation, and survival. We found that the membrane proximal proline-rich domain and adjacent 16 residues are essential for both hGM-CSF-dependent cell proliferation and differentiation. In contrast, the C-terminal region of the GM-CSFRalpha cytoplasmic domain was not necessary for cell differentiation mediated by hGM-CSF, but the removal of this region severely impaired the ability of hGM-CSF to support cell survival. While the activation of JAK2, Shc, Erk, and STAT5 proteins correlated with hGM-CSF-mediated cell growth, cellular differentiation occurred in the absence of activation of these signal transduction pathways.
Highlights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates differentiation, survival, and proliferation of colony-forming unit-granulocyte-macrophage progenitor cells
We find that when the wild type human GM-CSFR a and b subunits are both transfected into WT19 cells, these cells respond to the addition of human GM-CSF by undergoing differentiation
When the WT19 cells were incubated with murine GM-CSF (mGM-CSF), the expression of both these markers was significantly increased, suggesting that the cells differentiated toward monocytic lineage (Fig. 1A)
Summary
17450 –17459, 1997 Printed in U.S.A. The Cytoplasmic Domain of Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Receptor a Subunit Is Essential for Both GM-CSF-mediated Growth and Differentiation*. Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates differentiation, survival, and proliferation of colony-forming unit-granulocyte-macrophage progenitor cells. We have demonstrated that the murine FDC-P1-derived cell line WT-19 transfected with the human GM-CSF receptor a and b subunits (GM-CSFRa and b) can be induced to differentiate by the addition of human GM-CSF (hGMCSF). The C-terminal region of the GM-CSFRa cytoplasmic domain was not necessary for cell differentiation mediated by hGM-CSF, but the removal of this region severely impaired the ability of hGM-CSF to support cell survival. To identify the residues of GM-CSFRa cytoplasmic domain necessary for the induction of cell differentiation, WT19 cell lines were established which express mutated cytoplasmic domains of the a subunit along with the wild type b subunit. Our results suggest that cell survival and differentiation are controlled by different signal transduction pathways regulated by varying portions of the GM-CSFRa
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