Intrinsic and extrinsic pathways of apoptosis. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Various intermediary signaling molecules (many of whose functions are not completely defined) and proteins inhibiting the apoptotic cascade are also shown. Apaf-1, apoptosis-activating factor 1; Bak, bacille Calmette–Guérin; Bax, BCL-2-associated × protein; Bid, proapoptotic Bcl-2 family member; Bim, proapoptotic Bcl-2 family member; DIABLO, direct IAP binding protein with low PI; FADD, Fas-associated death domain protein; IAP, inhibitors of apoptosis; Smac, second mitochondria-derived activator of caspase; tBid, truncated beta interaction domain.