期刊
BLOOD
卷 114, 期 7, 页码 1289-1298出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-12-164004
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资金
- National Health and Medical Research Council of Australia ( Canberra, Australia)
- National Institutes of Health [RO1-AI50744-02]
- Australian Cancer Research Foundation ( Sydney, Australia)
- Cancer Council South Australia ( Adelaide, Australia)
- Leukemia Research Fund ( Melbourne, Australia)
- Children's Cancer Center Foundation ( Melbourne, Australia)
- Australian Research Council Federation Fellowship ( Canberra, Australia)
- Sylvia and Charles Viertel Senior Medical Fellowship ( Melbourne, 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. 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. (Blood. 2009; 114: 1289-1298)
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