Tumor necrosis factor (TNF) is a pleiotropic cytokine whose function is mediated through two distinct cell surface receptors (1,2). These receptors, designated TNF-R1 and TNF-R2, are expressed on most cell types (1,3). The majority of TNF functions are primarily mediated through TNF-R1 (1,4). FAN (for factor associated with neutral sphingomyelinase (N-SMase) activation) is an intermediate protein that interacts with TNF-R1 to initiate TNF signaling events. FAN binds to TNF-R1 at the cytoplasmic NSD (N-SMase activating domain), which results in the initiation of the N-SMase pathway (5). N-SMase has been shown to be involved in TNF-induced Raf-1 activation (6). FAN contains four carboxy-terminal WD-repeat domains which appear to be involved in protein-protein interaction. The FAN WD-repeats may mediate the interaction between FAN and TNF-R1 (5).