Figure 1.

The extrinsic and intrinsic pathways to apoptosis. The extrinsic pathway is initiated when death receptor ligands (e.g., first apoptosis signal ligand [FAS-L], tumor necrosis factor (TNF)) bind to their cognate death receptors (e.g., first apoptosis signal [FAS], TNF receptor [TNFR]) on the plasma membrane, resulting in activation of caspase 8 via FAS-associated death domain protein (FADD) with or without TNFR-associated death domain protein (TRADD). The intrinsic pathway is triggered when diverse stress signals (e.g., DNA damage, growth factor deprivation) activate pro-apoptotic BH3-only proteins, which carry out their pro-apoptotic function by neutralizing pro-survival B-cell lymphoma 2 (BCL2) family proteins or, when these pro-survival proteins are saturated or absent, by directly activating BCL-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK), causing mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of a range of apoptogenic factors, including cytochrome c, from the intermembrane space of the mitochondria into the cytoplasm. In the cytoplasm, cytochrome c binds to apoptotic protease activating factor 1 (APAF1) to form the apoptosome, which mediates the activation of caspase 9. The extrinsic and intrinsic pathways converge with initiator caspases (e.g., caspase 8, caspase 9) activating executioner caspases (e.g., caspase 3, caspase 7, caspase 6), which mediate cellular destruction.