Death receptor (Fas, TRAIL-R1, and TRAIL-R2) (TNFRSF6, TNFRSF10A, TNFRSF10B)

The Fas (CD95) and TRAIL (TNF-related apoptosis-inducing ligand) receptors, specifically TRAIL-R1 (DR4) and TRAIL-R2 (DR5), are transmembrane proteins belonging to the tumor necrosis factor receptor (TNFR) superfamily (UniProt P25445, O00220, O14763). These receptors are characterized by an intracellular death domain that is essential for transducing pro-apoptotic signals. Upon binding to their respective ligands, FasL or TRAIL, these receptors cluster and recruit the adapter protein FADD and pro-caspase-8 to form the death-inducing signaling complex (DISC) (PubMed 15771580). This activation triggers the extrinsic apoptotic pathway, leading to programmed cell death. In many cancers, these receptors are either downregulated or the signaling pathway is inhibited, allowing tumor cells to evade immune-mediated destruction (PubMed 24591361). Therapeutic strategies have focused on developing agonistic antibodies or recombinant ligands to reactivate these pathways in cancer cells (ClinicalTrials.gov). While TRAIL receptors are promising targets due to their preferential induction of apoptosis in malignant versus normal cells, Fas-targeted therapies have been limited by severe systemic toxicities, particularly in the liver (PubMed 11015116).

Other names

Tumor necrosis factor receptor superfamily member 6Tumor necrosis factor receptor superfamily member 10ATumor necrosis factor receptor superfamily member 10BCD95APO-1DR4DR5APO-2TRAIL-R1TRAIL-R2CD261CD262

Agonism of death receptors to induce extrinsic apoptosis via the formation of the death-inducing signaling complex (DISC) (PubMed 15771580).