Fas and TRAIL receptors (Fas/TRAIL-R)

Fas (CD95) and TRAIL receptors (DR4 and DR5) are transmembrane proteins belonging to the death receptor subfamily of the tumor necrosis factor receptor (TNFR) superfamily [2.1.1, 2.3.2]. They play a critical role in the extrinsic apoptosis pathway by transducing signals from their respective ligands, FasL and TRAIL, to initiate programmed cell death [2.1.4, 2.4.2]. Upon ligand binding or engagement by agonistic antibodies, these receptors trimerize and recruit the adaptor protein FADD and pro-caspase-8/10 to form the death-inducing signaling complex (DISC), which activates the downstream caspase cascade [2.4.3, 3.2.5]. In oncology, these receptors are targeted by recombinant ligands and agonistic antibodies to selectively eliminate tumor cells, which often express these receptors at higher levels than normal tissues [2.2.1, 3.2.3]. However, therapeutic development has been hindered by severe toxicities, such as hepatotoxicity with Fas agonists, and the emergence of resistance through mechanisms like c-FLIP overexpression or decoy receptor competition [2.2.2, 2.4.4]. Additionally, these receptors can trigger non-apoptotic pathways, including NF-κB and MAPK signaling, which may paradoxically promote tumor survival, migration, and inflammation in certain contexts [2.3.1, 2.3.5].

Other names

Death receptorsCD95 and DR4/DR5Tumor necrosis factor receptor superfamily member 6 and 10A/10BApo-1 and Apo-2 receptorsTNFRSF6TNFRSF10ATNFRSF10B

Agonism of the receptors leads to receptor trimerization and the formation of the death-inducing signaling complex (DISC), which recruits FADD and pro-caspase-8/10 to initiate the extrinsic apoptotic cascade.