Abstract
The oncogenic latent membrane protein 1 (LMP1) of the Epstein-Barr virus recruits tumor necrosis factor-receptor (TNFR)-associated factors (TRAFs), the TNFR-associated death domain protein (TRADD) and JAK3 to induce intracellular signaling pathways. LMP1 serves as the prototype of a TRADD-binding receptor that transforms cells but does not induce apoptosis. Here we show that TRAF6 critically mediates LMP1 signaling to p38 mitogen-activated protein kinase (MAPK) via a MAPK kinase 6-dependent pathway. In addition, NF-kappaB but not c-Jun N-terminal kinase 1 (JNK1) induction by LMP1 involves TRAF6. The PxQxT motif of the LMP1 C-terminal activator region 1 (CTAR1) and tyrosine 384 of CTAR2 together are essential for full p38 MAPK activation and for TRAF6 recruitment to the LMP1 signaling complex. Dominant-negative TRADD blocks p38 MAPK activation by LMP1. The data suggest that entry of TRAF6 into the LMP1 complex is mediated by TRADD and TRAF2. In TRAF6-knockout fibroblasts, significant induction of p38 MAPK by LMP1 is dependent on the ectopic expression of TRAF6. We describe a novel role of TRAF6 as an essential signaling mediator of a transforming oncogene, downstream of TRADD and TRAF2.
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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Adaptor Proteins, Signal Transducing
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Amino Acid Motifs
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Carrier Proteins / physiology*
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Cell Line
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Cell Transformation, Viral
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Cytoskeletal Proteins
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Enzyme Induction / drug effects
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Fibroblasts / metabolism
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Gene Targeting
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HeLa Cells
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Herpesvirus 4, Human / physiology
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Humans
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Intracellular Signaling Peptides and Proteins
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Kidney
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LIM Domain Proteins
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MAP Kinase Kinase 6
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MAP Kinase Signaling System / physiology*
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Macromolecular Substances
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Membrane Proteins / metabolism
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases / biosynthesis
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / physiology
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Models, Biological
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NF-kappa B / physiology
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Phosphorylation
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Protein Processing, Post-Translational
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Proteins / genetics
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Proteins / physiology*
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Structure-Activity Relationship
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 6
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Tyrosine / chemistry
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p38 Mitogen-Activated Protein Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cytoskeletal Proteins
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Intracellular Signaling Peptides and Proteins
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LIM Domain Proteins
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Macromolecular Substances
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Membrane Proteins
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NF-kappa B
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PDLIM7 protein, human
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Proteins
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 6
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Tyrosine
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 6
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MAP2K6 protein, human