Abstract
Tumor necrosis factor-alpha (TNF), a major inflammatory cytokine, generates a wide variety of cellular responses via key cytoplasmic adaptor molecules named TNF receptor-associated factors (TRAFs). We report that TRAF2, TRAF5 and TRAF6 associate with apoptosis signal-regulating kinase 1 (ASK1), and a catalytically-inactive ASK1 mutant blocks stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) activation by these TRAFs. A truncated derivative of TRAF2, which inhibits SAPK activation by TNF, blocks TNF-induced ASK1 activation. Furthermore, protection from TNF-induced cell death conferred by an ASK1 mutant is dependent upon TRAF2. Hence, ASK1 is a common mediator of TRAF-regulated SAPK and apoptosis signaling, and the TRAF2 - ASK1 connection completes the signaling cascade from TNF to SAPK/JNK activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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COS Cells
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Cells, Cultured
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Enzyme Activation
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases / biosynthesis
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / physiology*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Peptide Mapping
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Proteins / metabolism*
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction / physiology*
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 5
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha
Substances
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Proteins
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 5
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases
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Map3k5 protein, mouse