TRAIL death receptors (DR4 and DR5) (DR4 (TRAIL-R1), DR5 (TRAIL-R2))

TRAIL death receptors (DR4 and DR5) are transmembrane proteins belonging to the tumor necrosis factor receptor superfamily. Their extracellular region contains cysteine-rich domains, and the intracellular portion contains a death domain necessary for initiating apoptosis. Binding of TRAIL ligand to DR4/DR5 trimerizes the receptors, leading to recruitment of adaptor proteins and activation of caspase-8, resulting in rapid and selective apoptosis of tumor cells. There are also decoy receptors (DcR1, DcR2, OPG) that bind TRAIL without triggering apoptosis, thus regulating the response. While these receptors are considered promising cancer therapy targets due to their tumor-selectivity, clinical responses have been limited by cancer cell resistance and variable receptor expression.

Other names

DR4 (TRAIL-R1, TNFRSF10A, CD261, APO2)DR5 (TRAIL-R2, TNFRSF10B, CD262, KILLER, TRICK2, ZTNFR9)TRAIL death receptors (“TRAIL-R1/DR4” and “TRAIL-R2/DR5”)

Agonists (TRAIL, antibodies) bind to DR4/DR5, induce receptor clustering, recruit adaptor proteins (FADD), activate caspase-8, and initiate the apoptotic cascade. Chemotherapy and radiation upregulate death receptor expression, sensitizing tumor cells to apoptosis.