Figure 1.
The TRAIL apoptotic pathway. Simplified and schematic representation of the pathway. Binding of TRAIL or generated agonistic agents to the TRAIL receptors results in the recruitment of FADD and procaspase-8, also known as the DISC. Subsequently, caspase-8 cleavage in the DISC can activate downstream caspase-3, leading to the induction of apoptosis (extrinsic pathway). The caspase-8 analog cFLIP can compete for FADD binding and inhibit DISC formation. Caspase-8 can also cleave the Bcl-2 family member Bid into tBid engaging the intrinsic pathway by binding to Bax, causing mitochondrial membrane permeabilization and the release of apoptogenic factors such as cytochrome c. Pro-survival Bcl-2 family members can prevent mitochondrial permeabilization. IAPs, such as XIAP, can bind to caspases and inhibit apoptosis. Necroptosis, a regulated form of caspase-independent necrotic cell death, can also be activated through TRAIL receptors under specific conditions. This involves the activation of RIP1 and RIP3 in a complex that has not been precisely clarified as yet. See text for more details