Pro-apoptotic death receptors (Fas, DR4, and DR5) (Fas/DR4/DR5)

The pro-apoptotic death receptors, specifically Fas (CD95), Death Receptor 4 (DR4), and Death Receptor 5 (DR5), are transmembrane proteins belonging to the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) (UniProt: P25445, O00220, O14763). These receptors are defined by a conserved intracellular sequence known as the death domain (DD), which is essential for transmitting cytotoxic signals. Upon binding to their respective ligands—Fas ligand (FasL) for Fas, and TRAIL (TNF-related apoptosis-inducing ligand) for DR4 and DR5—these receptors cluster and recruit adapter proteins like FADD to initiate the extrinsic apoptosis pathway (PubMed: 11071201). In cancer therapy, these receptors are targeted by agonistic antibodies or recombinant ligands to selectively trigger cell death in malignant cells. While promising, therapeutic progress has been hindered by challenges such as severe hepatotoxicity, particularly with Fas agonists, and the development of resistance mechanisms in tumor cells, such as the upregulation of anti-apoptotic proteins like c-FLIP (PubMed: 10491145, PubMed: 25135528).

Other names

CD95TNFRSF6Apo-1TNFRSF10ATRAIL-R1Apo2TNFRSF10BTRAIL-R2KillerTRICK2Death Receptor 4Death Receptor 5Fas receptor

Agonism of the receptors leads to the recruitment of the Fas-associated death domain (FADD) protein and pro-caspase-8, forming the death-inducing signaling complex (DISC) and triggering the extrinsic apoptotic pathway (PubMed: 11071201).