Abstract
Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transcription factors AP-1 and NF-kappaB through activation of the MAP kinases JNK and p38 and the IkappaB kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Gene Expression Regulation*
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HeLa Cells
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Humans
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I-kappa B Kinase
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Immunophilins / physiology
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Interleukin-1 / physiology
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1*
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Mitogen-Activated Protein Kinases*
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Protein Binding / physiology
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Protein Serine-Threonine Kinases / physiology*
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Proteins / physiology*
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Recombinant Fusion Proteins
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Signal Transduction*
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 6
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Tacrolimus Binding Proteins
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Transcriptional Activation
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Transfection
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Tumor Necrosis Factor-alpha / physiology
Substances
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Interleukin-1
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Proteins
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Recombinant Fusion Proteins
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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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 Kinase 1
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MAP3K1 protein, human
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Tacrolimus Binding Proteins
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Immunophilins