SIGNALING BY PROTEOLYSIS - DEATH RECEPTORS INDUCE APOPTOSIS

Apoptosis, or programmed cell death, is a genetically regulated mechan ism with a central role in both metazoan development and homeostasis. Death receptors (Fas, TNFR-2, DR3, and TRAIL receptors) induce apoptos is upon ligation to cognate ligands or ectopic expression. The assembl y of a death-inducing signalling complex occurs in a hierarchical mann er upon receptor activation. The death domain of the receptor binds to the corresponding domain of the adapter molecule FADD, which in turn recruits the zymogen form of the death protease FLICE (MACH/caspase-8) . Upon approximation, FLICE ''zymogens'' attain a sufficient concentra tion to self-activate and to trigger the apoptotic pathway. For the fi rst time, a transmembrane receptor directly engaging a protease at the signalling complex and subsequently triggering a proteolytic signalli ng cascade is described.