Apoptosis mediated by death receptors requires the FADD adaptor molecule. (A) Engagement of a Fas ligand trimer on a trimer of Fas leads to FADD adaptor molecule recruitment through homotypic DD interactions. FADD next binds initiator pro-caspase through DED interactions. This Fas/FADD/pro-caspase complex forms the Fas death-inducing signaling complex (DISC) since initiator pro-caspase activates a caspase cascade resulting in apoptotic death of the cell. Alternatively, c-FLIPs can promote cell survival by interacting with FADD through their respective DED, thus hindering recruitment and activation of initiator pro-caspase. (B) Signaling mediated by TNF-R1 implicates formation of two sequential complexes . The complex I (in blue) contains the TNF-R1, the adaptor TRADD, the receptor interacting kinase (RIP), and the TNF-receptor associated factor 2 (TRAF2). It assemblies rapidly following TNF-α stimulation and activates the NF-kB pathway which in turn induces expression of survival genes, including c-FLIP. Later on, complex I dissociates from the TNF-R1 and is internalized. FADD can then bind the liberated DD of TRADD and recruits initiator pro-caspase, forming complex II (in red) which is cytoplasmic. Activation of initiator pro-caspase 8/10 in complex II results in apoptosis of the cell. Red box: DD; hatched red box: DED.