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The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease Hercus TR; Thomas D; Guthridge MA; Ekert PG; King-Scott J; Parker MW; Lopez AFBlood 2009[Aug]; 114 (7): 1289-98Already 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.|*Signal Transduction[MESH]|Acute Disease[MESH]|Animals[MESH]|Cell Differentiation[MESH]|Cell Proliferation[MESH]|Cell Survival[MESH]|Chronic Disease[MESH]|Homeostasis[MESH]|Humans[MESH]|Hypersensitivity/*metabolism[MESH]|Inflammation/metabolism[MESH]|Leukemia, Myeloid/*metabolism[MESH]|Lung/metabolism[MESH]|Macrophages/metabolism[MESH]|Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/*metabolism[MESH]|Structure-Activity Relationship[MESH] |
