Figure 1.

Schematic representation of death receptor signaling. Engagement of death receptors by their cognate ligands triggers the recruitment of different adaptor proteins. Distinct pathways originate from the adaptor proteins. A classic proapoptotic pathway is initiated when the adaptor proteins recruit large amounts of the initiator caspases 8 and 10, resulting in their autoactivation. Active caspases 8 and 10 initiate a signaling cascade that results in activation of the effector caspases (caspases 3, 6, and 7) either by directly processing the effector caspases themselves or by engaging the mitochondrial death pathway mediated by the cleavage of the BH3-only protein Bid. The release of proapoptotic proteins from the mitochondria, such as cytochrome c and Smac/DIABLO, ultimately promotes effector caspase activation and apoptosis. Several noncytotoxic signaling pathways can also originate from the association of adaptor proteins with the receptor, which generally results in the activation of MAPK- and/or NF-κB-mediated survival signals.