Signalling by proteolysis: death receptors induce apoptosis.
Apoptosis, or programmed cell death, is a genetically regulated mechanism with a central role in both metazoan development and homeostasis. Death receptors (Fas, TNFR-2, DR3, and TRAIL receptors) induce apoptosis upon ligation to cognate ligands or ectopic expression. The assembly of a death-inducing signalling complex occurs in a hierarchical manner upon receptor activation. The death domain of the receptor binds to the corresponding domain of the adapter molecule FADD, which in turn recruits the zymogen form of the death protease FLICE (MACH/caspase-8). Upon approximation, FLICE "zymogens" attain a sufficient concentration to self-activate and to trigger the apoptotic pathway. For the first time, a transmembrane receptor directly engaging a protease at the signalling complex and subsequently triggering a proteolytic signalling cascade is described.
Muzio
M
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Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D015398:Signal Transduction / Q000502:physiology*
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; C105190:TNFRSF10A protein, human; C506033:TNFRSF25 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases