The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease

Timothy R Hercus, Daniel Thomas, Mark Andrew Guthridge, Paul G Ekert, Jack King-Scott, Michael W Parker, Angel F Lopez

Research output: Contribution to journalArticleResearchpeer-review

195 Citations (Scopus)

Abstract

Already 20 years have passed since the cloning of the granulocyte- macrophage colony-stimulating factor (GM-CSF) receptor a-chain, the first member of the GM-CSF/interleukin (IL)-3/IL-5 family of hemopoietic cytokine receptors to be molecularly characterized. The intervening 2 decades have uncovered a plethora of biologic functions transduced by the GM-CSF receptor (pleiotropy) and revealed distinct signaling networks that couple the receptor to biologic outcomes. Unlike other hemopoietin receptors, the GM-CSF receptor has a significant nonredundant role in myeloid hematologic malignancies, macrophage-mediated acute and chronic inflammation, pulmonary homeostasis, andallergic disease.Themolecular mechanisms underlying GM-CSF receptor activation have recently been revealed by the crystal structure of the GM-CSF receptor complexed to GM-CSF, which shows an unexpected higher order assembly. Emerging evidence also suggests the existence of intracellular signosomes that are recruited in a concentration-dependent fashion to selectively control cell survival, proliferation, and differentiation by GM-CSF. These findings begin to unravel the mystery of cytokine receptor pleiotropy and are likely to also apply to the related IL-3 and IL-5 receptors as well as other heterodimeric cytokine receptors. The new insights in GM-CSF receptor activation have clinical significance as the structural and signaling nuances can be harnessed for the development of new treatments for malignant and inflammatory diseases. ? 2009 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)1289 - 1298
Number of pages10
JournalBlood
Volume114
Issue number7
DOIs
Publication statusPublished - 2009
Externally publishedYes

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