Death receptor 4 and Death receptor 5 (DR4 and DR5)

Death receptor 4 (DR4) and death receptor 5 (DR5) are cell surface receptors that belong to the tumor necrosis factor receptor superfamily and are activated by binding TRAIL, a protein that induces apoptosis. Only DR4 and DR5 contain a cytoplasmic death domain needed to activate downstream apoptotic signaling[1][5][6]. These receptors, when ligated by TRAIL or agonist antibodies, recruit the adaptor protein FADD and subsequently activate caspase-8, initiating apoptosis preferably in tumor cells, making them attractive therapeutic targets[9][5]. In addition to canonical apoptosis, DR5 has additional roles in necroptosis, autophagy, and perhaps pyroptosis[2]. Both DR4 and DR5 play natural roles in immune surveillance and maintaining tissue homeostasis, and their expression or activation is implicated in cancer, neurodegeneration (including Alzheimer's disease), and potentially other diseases[7][1][8]. Numerous drugs—TRAIL mimics, monoclonal antibodies, and receptor peptidomimetics—have been developed to target these receptors, with ongoing clinical and preclinical efforts in cancer therapy[9][5][6]. If further structural or isoform-specific information is required, note that DR5 has at least two isoforms (DR5a and DR5b), though their function is not yet fully characterized[5]. Both DR4 and DR5 commonly serve as biomarkers and therapeutic targets, but their precise expression and activity may vary by cancer type, tumor microenvironment, and other factors[4][8].

Other names

TRAIL receptor 1TRAIL-R1TNFRSF10ACD261Apo2TRAIL receptor 2TRAIL-R2TNFRSF10BCD262Killer/Ly98TRICK2ATRICKB

Ligand (TRAIL) or antibody binding triggers receptor trimerization, recruitment of adaptor proteins (like FADD), and activation of caspase-8, leading to apoptosis. Some drugs sensitize cancer cells to apoptosis by upregulating DR4 or DR5 surface expression. Antibodies or derivatives directly agonize DR4 or DR5, causing receptor aggregation and downstream apoptotic signaling.