TRADD–TRAF2 and TRADD–FADD Interactions Define Two Distinct TNF Receptor 1 Signal Transduction Pathways

• Published in: Cell Vol. 84; no. 2; pp. 299 - 308
• Main Authors: Hsu, Hailing, Shu, Hong-Bing, Pan, Ming-Gui, Goeddel, David V
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.01.1996
• Subjects: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Antigens, CD - metabolism; Antigens, CD - physiology; Apoptosis - physiology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Fas-Associated Death Domain Protein; Humans; Interleukin-1 - pharmacology; Mice; Molecular Sequence Data; NF-kappa B - physiology; Proteins; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor - physiology; Receptors, Tumor Necrosis Factor, Type I; Sequence Deletion; Signal Transduction - physiology; TNF Receptor-Associated Death Domain Protein; TNF Receptor-Associated Factor 1; TNF Receptor-Associated Factor 2; Transcriptional Activation; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80984-8

Tumor necrosis factor (TNF) can induce apoptosis and activate NF-κB 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-κB and induce apoptosis, respectively. A TRAF2 mutant lacking its N-terminal RING finger domain is a dominant-negative inhibitor of TNF-mediated NF-κB 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-κB activation. Thus, these two TNFR1–TRADD signaling cascades appear to bifurcate at TRADD.