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.
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology
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Animals
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Apoptosis Regulatory Proteins / pharmacology*
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Caspase 8
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Caspases / physiology
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Cell Line, Tumor
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Chemokine CCL2 / metabolism
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Death Domain Receptor Signaling Adaptor Proteins
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Enzyme Activation / drug effects
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Fas-Associated Death Domain Protein
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Humans
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I-kappa B Kinase / metabolism
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Interleukin-8 / metabolism
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Kinetics
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MAP Kinase Kinase 4 / metabolism
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Membrane Glycoproteins / pharmacology*
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Mice
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Mice, Knockout
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NF-kappa B / physiology
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Phosphorylation
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Protein Kinases / metabolism*
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RNA, Small Interfering
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Signal Transduction / physiology
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TNF Receptor-Associated Factor 2 / physiology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / physiology
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Tumor Necrosis Factor-alpha / pharmacology*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Chemokine CCL2
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Death Domain Receptor Signaling Adaptor Proteins
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FADD protein, human
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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Interleukin-8
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Membrane Glycoproteins
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NF-kappa B
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RNA, Small Interfering
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TNF Receptor-Associated Factor 2
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Tumor Necrosis Factor-alpha
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Protein Kinases
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I-kappa B Kinase
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases