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 Blood, 13 August 2009, Vol. 114, No. 7, pp. 1289-1298.
Prepublished online as a Blood First Edition Paper on May 12, 2009; DOI 10.1182/blood-2008-12-164004.

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REVIEW ARTICLE

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

Timothy R. Hercus1, Daniel Thomas1, Mark A. Guthridge1, Paul G. Ekert2, Jack King-Scott3, Michael W. Parker3, and Angel F. Lopez1

1 Division of Human Immunology, Centre for Cancer Biology, Adelaide; 2 The Murdoch Children's Research Institute, Royal Children's Hospital, Parkville; and 3 St Vincent's Institute for Medical Research, Fitzroy, Australia

Already 20 years have passed since the cloning of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor {alpha}-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, and allergic disease. The molecular 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.


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