In the extrinsic pathway, ligand binding induces death receptors to recruit FADD, which recruits procaspase-8. Within this complex (DISC), procaspase-8 dimerizes and activates. Caspase-8 proteolytically activates procaspase-3, which cleaves cellular proteins causing cell death. In the intrinsic pathway, extracellular and intracellular stimuli signal to the mitochondria through a variety of BH3-only proteins (e.g., Bid) and through Bax, which translocates to and inserts into the outer mitochondrial membrane. Bax and Bak (not shown) stimulate the release of cytochrome c (cyt c) and other apoptogens. Once released, cytochrome c binds Apaf-1 along with dATP. This triggers oligomerization of Apaf-1 and recruitment of procaspase-9. Within this complex (apoptosome), procaspase-9 dimerizes and activates. Caspase-9 proteolytically activates procaspase-3. Caspase-8 also cleaves Bid, and its C-terminal fragment translocates to the mitochondria, where it activates Bax and Bak stimulating apoptogen release. FLIP binds and inhibits procaspase-8 in the DISC. ARC binds Fas, FADD, and procaspase-8, inhibiting DISC assembly. ARC, Ku-70, and Humanin bind Bax and inhibit its conformational activation and translocation. Bcl-2 and Bcl-x_L (not shown) inhibit mitochondrial apoptogen release. XIAP binds and inhibits activated caspase-9 and -3. Once cytoplasmic, the mitochondrial apoptogens Smac and HtrA2 bind XIAP, displacing and disinhibiting caspases. HtrA2 also has a serine protease activity that cleaves XIAP (not shown). AIF translocates to the nucleus and, in conjunction with a presumed endonuclease, mediates large-scale DNA fragmentation. A subset of intrinsic pathway death signals stimulate the ER, possibly through BH3-only proteins. This causes the release of intraluminal Ca²⁺ into the cytoplasm, which is mediated by Bax and Bcl-2 through the IP3R. Ca²⁺ translocates to the mitochondrial matrix and stimulates opening of the mitochondrial permeability transition pore in the inner membrane (not shown), which indirectly results in apoptogen release. The ER pathway may also activate procaspase-12, which can cleave and activate procaspase-9 independently of apoptosome formation (see text).