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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2001-12-0235.
Submitted December 12, 2001
Accepted April 12, 2002
Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors
Caroline A Evans, Shahrul Ariffin, Andrew Pierce, and Anthony D Whetton*
Biomolecular Sciences, UMIST, Manchester, United Kingdom
* Corresponding author; email: tony.whetton{at}umist.ac.uk.
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  subunits which interact with common ßc subunits. A chimeric receptor (hGM/ßc), comprising the extracellular domain of the hGM-CSF receptor subunit (hGM R) fused to the intracellular domain of hßc was generated to determine whether or not hßc activation is alone sufficient to promote differentiation. hGM-CSF activation of hGM/ßc, expressed in the presence and absence of the hßc subunit, promoted maintenance of primitive phenotype. This indicates that the cytosolic domain of the hGM R chain is required for differentiation mediated by activation of the hGM R, ßc receptor complex. We have previously demonstrated that the cytosolic domain confers signal specificity for IL-3 and GM-CSF receptors. Bioinformatic analysis of the IL-3 R and GM R 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 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 R promoted long-term proliferation and maintenance of primitive cell morphology whilst cytokine activation of the corresponding hIL-3 R mutant promoted myeloid differentiation. We have thus identified a region of the cytosolic domain that is of critical importance for defining receptor specificity.
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