Cross-Talk in Cell Death Signaling

Apoptotic cell suicide can be initiated by a plethora of stimuli that generally feed into one of two known cell death signaling pathways (Fig. 1; for review see references 1 and 2). Both pathways share many features, including molecular devices that spark caspase activation by proenzyme recruitment, oligomerization, and proximity-induced autocatalytic activation. Beyond this, however, their activities are relatively (but not absolutely) distinct. The ‘intrinsic’ pathway feeds cell death signals through the mitochondrion, which appears to act as a generic damage sensor and monitor of metabolic status. With the assistance of cytochrome c, cell death is initiated by the formation of a macromolecular complex (the apoptosome), which utilizes apoptotic protease activating factor (APAF)-1 to mediate the activation of caspase-9. The ‘extrinsic’ pathway transduces the signals of extracellular ‘death ligands’ belonging to the TNF superfamily (e.g.,...