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.
Hercus
Timothy R
TR
Division of Human Immunology, Centre for Cancer Biology, Adelaide SA, Australia.
Thomas
Daniel
D
Guthridge
Mark A
MA
Ekert
Paul G
PG
King-Scott
Jack
J
Parker
Michael W
MW
Lopez
Angel F
AF
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