The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease.
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.
Division of Human Immunology, Centre for Cancer Biology, Adelaide SA, Australia.
Timothy R
TR
Hercus
Daniel
D
Thomas
Mark A
MA
Guthridge
Paul G
PG
Ekert
Jack
J
King-Scott
Michael W
MW
Parker
Angel F
AF
Lopez
D000208:Acute Disease; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002908:Chronic Disease; D006706:Homeostasis; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor