APOPTOSIS SIGNALING BY DEATH RECEPTORS

Death receptors have been recently identified as a subgroup of the TNF -receptor superfamily with a predominant function in induction of apop tosis. The receptors are characterized by an intracellular region, cal led the death domain, which is required for the transmission of the cy totoxic signal. Currently, five different such death receptors are kno wn including tumor necrosis factor (TNF) receptor-1, CD95 (Fas/ APO-1) , TNF-receptor-related apoptosis-mediated protein (TRAMP) and TNF-rela ted apoptosis-inducing ligand (TRAIL) receptor-1 and -2. The signaling pathways by which these receptors induce apoptosis are rather similar . Ligand binding induces receptor oligomerization, followed by the rec ruitment of an adaptor protein to the death domain through hemophilic interaction. The adaptor protein then binds a proximal caspase, thereb y connecting receptor signaling to the apoptotic effector machinery. I n addition, further pathways have been linked to death receptor-mediat ed apoptosis, such as sphingomyelinases, JNK kinases and oxidative str ess. These pro-apoptotic signals are counteracted by several mechanism s which inhibit apoptosis at different levels. This review summarizes the current and rapidly expanding knowledge about the biological funct ions of death receptors and the mechanisms to trigger or to counteract cell death.