TRADD-TRAF2 AND TRADD-FADD INTERACTIONS DEFINE 2 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). T RADD is a TNFR1-associated signal transducer that is involved in activ ating both pathways. Here we show that TRADD directly interacts with T RAF2 and FADD, signal transducers that activate NF-kappa B and induce apoptosis, respectively. A TRAF2 mutant lacking its N-terminal RING fi nger 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-negat ive 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.