Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors

Caroline A. Evans, Shahrul Hisham Zainal Ariffin, Andrew Pierce, Anthony D. Whetton

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Activation of human interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors, ectopically expressed in FDCP-mix multi-potent 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.

Original languageEnglish
Pages (from-to)3164-3174
Number of pages11
JournalBlood
Volume100
Issue number9
DOIs
Publication statusPublished - 1 Nov 2002
Externally publishedYes

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Colony-Stimulating Factor Receptors
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Interleukin-3
Chemical activation
Maintenance
Computational Biology
Proline
Bioinformatics
Cytokines
Phenotype
Survival

ASJC Scopus subject areas

  • Hematology

Cite this

Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors. / Evans, Caroline A.; Zainal Ariffin, Shahrul Hisham; Pierce, Andrew; Whetton, Anthony D.

In: Blood, Vol. 100, No. 9, 01.11.2002, p. 3164-3174.

Research output: Contribution to journalArticle

Evans, Caroline A. ; Zainal Ariffin, Shahrul Hisham ; Pierce, Andrew ; Whetton, Anthony D. / Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors. In: Blood. 2002 ; Vol. 100, No. 9. pp. 3164-3174.
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