title: Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand.
abstract: Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) mainly activates programmed cell death through caspases. By contrast, TNF primarily induces gene transcription through the inhibitor of kappaB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Apo2L/TRAIL also can stimulate these kinases, albeit less strongly; however, the underlying mechanisms of this stimulation and its relation to apoptosis are not well understood. Here we show that Apo2L/TRAIL activates kinase pathways by promoting the association of a secondary signaling complex, subsequent to assembly of a primary, death-inducing signaling complex (DISC). The secondary complex retained the DISC components FADD and caspase-8, but recruited several factors involved in kinase activation by TNF, namely, RIP1, TRAF2, and NEMO/IKKgamma. Secondary complex formation required Fas-associated death domain (FADD), as well as caspase-8 activity. Apo2L/TRAIL stimulation of JNK and p38 further depended on RIP1 and TRAF2, whereas IKK activation required NEMO. Apo2L/TRAIL induced secretion of interleukin-8 and monocyte chemoattractant protein-1, augmenting macrophage migration. Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways. One function of kinase stimulation by Apo2L/TRAIL may be to promote phagocytic engulfment of apoptotic cells.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Varfolomeev
authors.forename: Heather
authors.initials: H
authors.lastname: Maecker
authors.forename: Darcie
authors.initials: D
authors.lastname: Sharp
authors.forename: David
authors.initials: D
authors.lastname: Lawrence
authors.forename: Mark
authors.initials: M
authors.lastname: Renz
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D053181:Caspase 8; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004789:Enzyme Activation / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007700:Kinetics; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018932:Chemokine CCL2; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases