(A) Intrinsic apoptosis pathways. Upon activation, BAK and BAX undergo conformational changes and oligomerization, forming pores in the MOM and causing irreversible MOM permeabilization (MOMP), the critical step for intrinsic apoptosis (3), allowing release of cytochrome c and SMAC. Cytochrome c and dATP join APAF-1 and the initiator protein procaspase-9 to form the apoptosome, while SMAC interacts with IAPs (see below). Within the apoptosome, procaspase-9 is cleaved into active caspase-9, which cleaves and activates the apoptosis effector proteins caspase-3, -6, and -7 (3). (B) Extrinsic apoptosis pathway. Upon ligand binding, DR4 and DR5 trimerize and aggregate within the cell membrane, a process known as capping. This is followed by recruitment of the adaptor protein FADD, which has a death effector domain (DED). Initiator procaspase-8 and -10 also have DEDs that bind to FADD at its DED, forming the DISC. Procaspase-8 and -10 are activated within the DISC and in turn cleave and activate executioner caspase-3, -6, and -7. Activation of procaspase-8/10 is negatively regulated by c-FLIP. c-FLIP competes directly with procaspase-8 for binding to FADD through homotypic DED interactions, thus inhibiting procaspase-8 recruitment and activation at the DISC (9-12). Activated caspase-8 also cleaves the BH3 subfamily member BID to active form truncated-BID (tBID). tBID translocates to the MOM and initiates apoptosis through its interactions with proapoptotic effector proteins BAK and BAX. BID cleavage and translocation to the mitochondria link the extrinsic cell death pathway to the intrinsic apoptotic pathway and amplify the apoptotic response. This amplification mechanism is required for effective apoptosis in certain cells, denoted as type II cells for their mechanism of apoptosis, in contrast with type I cells, which undergo extrinsic apoptosis independently of intrinsic apoptosis pathway induction (13, 14).