IDENTIFICATION AND MOLECULAR-CLONING OF 2 NOVEL RECEPTORS FOR THE CYTOTOXIC LIGAND TRAIL

A human receptor for the cytotoxic ligand TRAIL (TRAIL receptor-1, des ignated DR4) was identified recently as a member of the tumor necrosis factor receptor family. In this report we describe the identification of two additional human TRAIL receptors, TRAIL receptor-2 and TRAIL r eceptor-3, that belong to the tumor necrosis factor receptor family. I nterestingly, TRAIL receptor-g but not TRAIL receptor-3 contains a cyt oplasmic ''death domain'' necessary for induction of apoptosis and is hence designated death receptor-5 (DR5). Like DR4, DR5 engages the apo ptotic pathway independent of the adaptor molecule FADD/MORT1. Because of its lack of a death domain, TRAIL receptor-3 is not capable of ind ucing apoptosis. However, by competing for TRAIL, it is capable of inh ibiting TRAIL-induced apoptosis. Thus, TRAIL receptor-3 may function a s an antagonistic decoy receptor to attenuate the cytotoxic effect of TRAIL in most tissues that are TRAIL(+), DR4(+), and DR5(+).