title: Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5.
abstract: Fas (APO-1/CD95) and tumor necrosis factor receptor 1 (TNFR1) trigger apoptosis by recruiting the apoptosis initiator caspase-8 through the adaptor FADD. Fas binds FADD directly, whereas TNFR1 binds FADD indirectly, through TRADD. TRADD alternatively recruits the NF-kappaB-inducing adaptor RIP. The TNF homolog Apo2L/TRAIL triggers apoptosis through two distinct death receptors, DR4 and DR5; however, receptor over-expression studies have yielded conflicting results on the ligand's signaling mechanism. Apo2L/TRAIL induced homomeric and heteromeric complexes of DR4 and DR5 and stimulated recruitment of FADD and caspase-8 and caspase-8 activation in nontransfected cells. TRADD and RIP, which bound TNFR1, did not bind DR4 and DR5. Thus, Apo2L/TRAIL and FasL initiate apoptosis through similar mechanisms, and FADD may be a universal adaptor for death receptors.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Kischkel
authors.forename: D A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: A
authors.initials: A
authors.lastname: Chuntharapai
authors.forename: P
authors.initials: P
authors.lastname: Schow
authors.forename: K J
authors.initials: KJ
authors.lastname: Kim
authors.forename: A
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D018448:Models, Immunological; D011506:Proteins / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D047990:TNF Receptor-Associated Factor 1; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008024:Ligands; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D011506:Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases