TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.
Tumor necrosis factor (TNF) can induce apoptosis and activate NF-kappa B through signaling cascades emanating from TNF receptor 1 (TNFR1). TRADD is a TNFR1-associated signal transducer that is involved in activating both pathways. Here we show that TRADD directly interacts with TRAF2 and FADD, signal transducers that activate NF-kappa B and induce apoptosis, respectively. A TRAF2 mutant lacking its N-terminal RING finger domain is a dominant-negative inhibitor of TNF-mediated NF-kappa B activation, but does not affect TNF-induced apoptosis. Conversely, a FADD mutant lacking its N-terminal 79 amino acids is a dominant-negative inhibitor of TNF-induced apoptosis, but does not inhibit NF-kappa B activation. Thus, these two TNFR1-TRADD signaling cascades appear to bifurcate at TRADD.
Hsu
H
H
Tularik, Incorporated, South San Francisco, California 94080, USA.
Shu
H B
HB
Pan
M G
MG
Goeddel
D V
DV
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D015533:Transcriptional Activation; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D002352:Carrier Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D007375:Interleukin-1; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; C481226:Tradd protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha