Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4-and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1-and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.Apoptosis is one of the death phenotypes that can be triggered in tumor cells by anticancer agents. Resistance of tumor cells to apoptosis can account for treatment failure (18). One of the stimuli that can induce tumor cell death by apoptosis is the member of the tumor necrosis factor superfamily known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) (16). TRAIL has gained considerable interest in oncology since it displays specific antitumoral activity against a wide range of tumor cells (14, 41, 47) without significant side effects, at least in mice and monkeys (3,21,22).TRAIL triggers apoptosis upon engagement of one of its two agonistic receptors, named DR4 (death receptor 4) (33) and DR5 (death receptor 5) (7,46). In response to TRAIL, these receptors recruit the adaptor protein FADD (Fas-associated death domain), through death domain homophilic interactions (5), and the initiators procaspase-8 and -10, through death effector domain interactions with FADD, hence forming the macromolecular complex called DISC (death-inducing signaling complex). Within this complex, procaspase-8 and -10 are activated by autoproteolytic cleavage and initiate the caspase cascade leading to apoptosis (42).

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