Death receptor (DR) (DR)

Death receptors (DRs) are a distinct subset of the tumor necrosis factor receptor (TNFR) superfamily characterized by a conserved ~80 amino acid intracellular motif known as the "death domain" (DD) [Source: PMC3513710]. The most prominent members in oncology are DR4 (TRAIL-R1) and DR5 (TRAIL-R2), which trigger the extrinsic apoptotic pathway upon binding to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) [Source: Nature Reviews Cancer 2008]. Binding induces receptor trimerization and the recruitment of the adapter protein FADD and pro-caspase-8 to form the Death-Inducing Signaling Complex (DISC), which initiates a proteolytic cascade leading to cell death [Source: PubMed 15743924]. These receptors are highly attractive therapeutic targets because they are frequently overexpressed in various malignancies while being minimally expressed or functionally inactive in most normal tissues, potentially allowing for selective tumor cell killing [Source: PubMed 25113315]. However, clinical success has been limited by factors such as the short half-life of first-generation agonists, intrinsic or acquired resistance through the upregulation of anti-apoptotic proteins like c-FLIP, and sporadic reports of hepatotoxicity [Source: PubMed 21422400].

Other names

Tumor cell death receptorTumor necrosis factor receptor superfamilyTNFRSFPro-apoptotic receptorTRAIL receptorFAS (CD95)TNFR1DR4 (TNFRSF10A)DR5 (TNFRSF10B)

Agonism of the receptor induces the formation of the death-inducing signaling complex (DISC), activating the extrinsic apoptotic pathway via caspase-8 and caspase-10.