DR5

DR5, or death receptor 5, is a cell-surface receptor that plays a key role in the extrinsic pathway of apoptosis. In humans, it is encoded by the TNFRSF10B gene and is also known as TRAIL receptor 2 (TRAILR2). DR5 is a member of the tumor necrosis factor (TNF) receptor superfamily and is a type I transmembrane protein with an extracellular region that binds the ligand, a single transmembrane domain, and a cytoplasmic death domain that transmits apoptotic signals.

DR5 binds its ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which can be expressed as a membrane-bound or soluble form. Ligand binding induces receptor trimerization and formation of the death-inducing signaling complex (DISC), which recruits the adaptor protein FADD and initiator caspases such as caspase-8. Activation of these caspases drives the extrinsic apoptotic cascade, leading to programmed cell death. In addition to apoptosis, DR5 signaling can intersect with other pathways under certain conditions and may participate in non-apoptotic responses or necroptosis when caspase activity is inhibited.

Expression of DR5 is widespread, but sensitivity to TRAIL-induced apoptosis tends to differ among cell types. Many cancer cells show relatively higher susceptibility to DR5-mediated death compared to most normal cells, though resistance can arise through various mechanisms, including upregulation of anti-apoptotic proteins or decoy receptors that modulate TRAIL signaling.

DR5 has been a target of cancer research, with several DR5-agonist strategies explored in preclinical and clinical studies, including monoclonal antibodies and TRAIL-based therapeutics. Results have been mixed, with ongoing investigation into combinations and biomarkers to improve efficacy and safety. In non-oncologic contexts, DR5 remains part of the broader study of apoptosis and immune regulation.