Pasquini et al: Sensitivity and resistance of human cancer cells to TRAIL
Figure 2. Outline of the signalling cascade triggered by TRAIL-R2. The binding of one homotrimeric TRAIL molecule to the TRAILR2 determines its trimerization with consequent binding of a FADD molecule to its cytoplasmic tail through a DD/DD interaction. FADD through its DED domain recruits pro-caspase-8. Caspase-8 activation is controlled by DED-containing FLICE inhibitory proteins (c-FLIPs) that exert an inhibitory activity on this process. In type I cells the activation of caspase-8 is sufficient to induce the activation of caspase-3 with subsequent induction of apoptosis. In type II cells, the amplification of the apoptotic signal through the mitochondrial pathway is required for induction of apoptosis: in this pathway Bid is cleaved by caspase-8; in turn, truncated Bid activates Bax and Bakmediated release of cytochrome C and SMAC/DIABLO from mitochondria with consequent induction of apoptosis. In addition to death signalling, TRAIL-R2 is also able to activate survival signals via the TRADD-mediated activation of the NF-#B transcription factor. However, it is important to note that usually the TRAIL-R2-mediated activation of NF-#B is weak and not able to counteract the death signalling activity induced by the activation of this receptor.
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