Death receptors TRAIL-R1, TRAIL-R2, and Fas (TRAIL-R/Fas)

Death receptors, specifically TRAIL-R1 (DR4), TRAIL-R2 (DR5), and Fas (CD95), are transmembrane proteins belonging to the tumor necrosis factor receptor (TNFR) superfamily that mediate programmed cell death (PMID: 30333116). These receptors are characterized by a conserved intracellular death domain (DD) which, upon activation by ligands such as TRAIL (TNF-related apoptosis-inducing ligand) or FasL, recruits adapter proteins like FADD to initiate the extrinsic apoptotic cascade (UniProt P50591, O14763). In oncology, these receptors are significant therapeutic targets because many cancer cells exhibit higher sensitivity to death receptor-mediated apoptosis compared to normal cells, or overexpress these receptors on their surface (PMID: 18611160). Therapeutic interventions have primarily focused on developing recombinant TRAIL variants (e.g., dulanermin) or agonistic monoclonal antibodies (e.g., mapatumumab, conatumumab) to selectively trigger tumor cell death. However, clinical progress has been hampered by challenges such as the short half-life of ligands, the presence of decoy receptors (DcR1 and DcR2) that compete for ligand binding without signaling, and significant safety concerns like hepatotoxicity, which is particularly severe for Fas-targeted therapies (PMID: 24639238).

Other names

TNFRSF10ATNFRSF10BTNFRSF6CD95APO-1Death receptor 4Death receptor 5DR4DR5Fas receptorTRAIL-R1TRAIL-R2

Agonism of death receptors to trigger the extrinsic apoptotic pathway via the formation of the death-inducing signaling complex (DISC), recruitment of FADD, and activation of initiator caspases 8 and 10 (PMID: 30333116).