Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors
- 1 November 2002
- journal article
- Published by American Society of Hematology in Blood
- Vol. 100 (9) , 3164-3174
- https://doi.org/10.1182/blood-2001-12-0235
Abstract
Activation of human interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors, ectopically expressed in FDCP-mix multipotent cells, stimulates self-renewal or myeloid differentiation, respectively. These receptors are composed of unique α subunits that interact with common βc subunits. A chimeric receptor (hGM/βc), comprising the extracellular domain of the hGM-CSF receptor α subunit (hGM Rα) fused to the intracellular domain of hβc, was generated to determine whether hβc activation is alone sufficient to promote differentiation. hGM-CSF activation of hGM/βc, expressed in the presence and absence of the hβc subunit, promoted maintenance of primitive phenotype. This indicates that the cytosolic domain of the hGM Rα chain is required for differentiation mediated by activation of the hGM Rα, βc receptor complex. We have previously demonstrated that the α cytosolic domain confers signal specificity for IL-3 and GM-CSF receptors. Bioinformatic analysis of the IL-3 Rα and GM Rα subunits identified a tripeptide sequence, adjacent to the conserved proline-rich domain, which was potentially a key difference between them. Cross-exchange of the equivalent tripeptides between the α subunits altered receptor function compared to the wild-type receptors. Both the mutant and the corresponding wild-type receptors promoted survival and proliferation in the short-term but had distinct effects on developmental outcome. The mutated hGM Rα promoted long-term proliferation and maintenance of primitive cell morphology, whereas cytokine activation of the corresponding hIL-3 Rα mutant promoted myeloid differentiation. We have thus identified a region of the α cytosolic domain that is of critical importance for defining receptor specificity.Keywords
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