The 55 kDa receptor for tumor necrosis factor (TNF-R55) has become a paradigm for membrane receptors that are devoid of intrinsic enzymatic activity. The initiation of intracellular signaling events observed in TNF-stimulated cells appears to depend on protein intermediates that interact with specific cytoplasmic domains of TNF-R55. By use of TNF-R55 deletion mutants, we have defined a novel domain of TNF-R55 (NSD) distinct from the death domain which is specifically required for activation of neutral sphingomyelinase (N-SMase). In addition, using the yeast interaction trap system, we have identified one protein (FAN) that binds to the NSD and mediates activation of N-SMase as well as seventeen other potential interaction partners of TNF-R55. These candidate interactors include the adaptor protein Grb2-linking TNF-R55 to the Ras pathway-as well as the enzyme phosphoglycerate mutase, suggesting a role of TNF-R55 in glycolysis/ energy metabolism of cells.