Tumor necrosis factor-related apoptosis-inducing ligand death receptor 5 (DR5)

Tumor necrosis factor-related apoptosis-inducing ligand death receptor 5 (DR5) is a cell surface receptor belonging to the TNF receptor superfamily. It comprises a signal peptide, cysteine-rich extracellular domains, a transmembrane domain, and an intracellular death domain. DR5 binds to TRAIL (TNF-related apoptosis-inducing ligand), leading to trimerization and formation of the death-inducing signaling complex (DISC). This process recruits the FADD adaptor protein and ultimately activates caspase 8 and 10, resulting in caspase-dependent apoptosis. DR5 is typically expressed at low levels in normal tissues but is highly upregulated in many cancers, making it a critical target for selective tumor cell apoptosis. Several clinical-stage drugs and antibodies target DR5, though therapeutic resistance and on-target toxicity are notable challenges for clinical application. Alternative splicing generates isoforms with distinct sequences, but both forms activate apoptotic signaling upon TRAIL binding. DR5 also plays roles in other diseases including inflammation and autoimmunity, but its predominant therapeutic focus remains cancer.

Other names

Death receptor 5TRAIL receptor 2 (TRAIL-R2)Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)CD262Apo2Killer/Ly98TRICK2A (short isoform)TRICK2B (long isoform)

Agonist binding: Activation by monoclonal antibodies or TRAIL mimetics leads to receptor trimerization and DISC formation, recruiting FADD adaptor and caspases 8/10, triggering apoptosis in target (often tumor) cells. Inhibition: Molecules (such as extracellular vesicles displaying DR5) can potentially sequester TRAIL, leading to resistance or inhibition of apoptosis.