In contrast to growth factors which promote cell proliferation, FAS ligand (FAS-L) and the tumor necrosis factors (TNFs) rapidly induce apoptosis. Cellular response to FAS-L and TNF is mediated by structurally related receptors containing a conserved "death domain" and belonging to the TNF receptor superfamily. TRADD, FADD and RIP are FAS/TNF-R1 interacting proteins that contain a death domain homologous region (DDH). TRADD (TNF-R1-associated death domain) and FADD (FAS-associated death domain) associate with the death domains of both FAS and TNF-R1 via their DDH regions. Overexpression of TRADD leads to NFkB activation and apoptosis in the absence of TNF. Overexpression of FADD causes apoptosis, which can be blocked by the cow pox protein CrmA, suggesting that FADD lies upstream of ICE and possibly other serine proteases. The receptor interacting protein, RIP, associates with FAS exclusively via its DDH and this association is abrogated in lpr mutants. Unlike TRADD and FADD, RIP contains a putative amino terminal kinase domain.