To die or not to die--the quest of the TRAIL receptors.

The last 18 months have witnessed the characterization of several new members of the tumor necrosis factor (TNF) receptor family. Among these are five receptors for the cytotoxic ligand TRAIL (TNF-related apoptosis-inducing ligand). Two of these receptors, TRAIL-R1 and TRAIL-R2, contain classical cytoplasmic death domains and are able to transduce an apoptotic signal. The others lack functional death domains and are not able to promote cell death. Indeed, one of the receptors for TRAIL, osteoprotegerin (OPG) is a soluble protein whose activities so far have been shown to be inhibition of osteoclastogenesis and increased bone density in vivo. The existence of multiple receptors for TRAIL suggests an unexpected complexity to TRAIL-mediated biological functions.