TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1.
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.
Schultheiss
U
U
Institute for Clinical Molecular Biology and Tumor Genetics, Department of Gene Vectors, GSF-National Research Center for Environment and Health, Marchioninistrasse 25, D-81377 München, Germany.
Püschner
S
S
Kremmer
E
E
Mak
T W
TW
Engelmann
H
H
Hammerschmidt
W
W
Kieser
A
A
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002472:Cell Transformation, Viral; D003598:Cytoskeletal Proteins; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D018390:Gene Targeting; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D060588:LIM Domain Proteins; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System / Q000502:physiology*; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014443:Tyrosine / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D016328:NF-kappa B; C484380:PDLIM7 protein, human; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human