Abstract
Tumor necrosis factor (TNF)-induced activation of the c-jun N-terminal kinase (JNK, also known as SAPK; stress-activated protein kinase) requires TNF receptor-associated factor 2 (TRAF2). The apoptosis signal-regulating kinase 1 (ASK1) is activated by TNF and stimulates JNK activation. Here we show that ASK1 interacts with members of the TRAF family and is activated by TRAF2, TRAF5, and TRAF6 overexpression. A truncated derivative of TRAF2, which inhibits JNK activation by TNF, blocks TNF-induced ASK1 activation. A catalytically inactive mutant of ASK1 is a dominant-negative inhibitor of TNF- and TRAF2-induced JNK activation. In untransfected mammalian cells, ASK1 rapidly associates with TRAF2 in a TNF-dependent manner. Thus, ASK1 is a mediator of TRAF2-induced 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
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line
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Enzyme Activation
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Humans
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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Mammals
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Mitogen-Activated Protein Kinases*
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Tumor Necrosis Factor / metabolism
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Recombinant Proteins / metabolism
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Signal Transduction
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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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Transfection
Substances
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Proteins
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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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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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases