Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Timothy R. Hercus1,
  2. Daniel Thomas1,
  3. Mark A. Guthridge1,
  4. Paul G. Ekert2,
  5. Jack King-Scott3,
  6. Michael W. Parker3, and
  7. Angel F. Lopez1
  1. 1Division of Human Immunology, Centre for Cancer Biology, Adelaide;
  2. 2The Murdoch Children's Research Institute, Royal Children's Hospital, Parkville; and
  3. 3St Vincent's Institute for Medical Research, Fitzroy, Australia

Abstract

Already 20 years have passed since the cloning of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α-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.

  • Submitted December 23, 2008.
  • Accepted April 17, 2009.
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