Caspase signaling and its modulation. In the extrinsic pathway, DISC formation leads to caspase-8 activation. Two signaling pathways downstream from the receptor were established. In type I cells (shown in light blue) caspase-8 directly cleaves caspase-3, which starts the death cascade. In type II cells (shown in light red) an additional amplification loop is required, which involves tBid-mediated cytochrome c release from mitochondria followed by apoptosome formation. Initiation of the intrinsic pathway results in mitochondria-mediated apoptosome formation, followed by caspase-9 and -3 activation, leading to destruction of the cell. Caspase action can be modulated on several levels. Activation of caspases at the DISC is inhibited by c-FLIP proteins; activation of effector caspases is inhibited by IAPs (see text). Effector caspases are shown in light green; cellular caspase inhibitors are presented in yellow. The targets for pharmacological modulation are shown with an orange arrow.