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 auto-catalytic activation. Beyond this, however, their activities are relatively (but not absolutely) distinct. The 'intrinsic' pathway feeds cell death signals through the mitochon-drion, which appears to act as a generic damage sensor and monitor of metabolic status. With the assistance of cyto-chrome c , cell death is initiated by the formation of a mac-romolecular complex (the apoptosome), which utilizes ap-optotic 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., TNF-␣ , Fas ligand [FasL]/Apo1L/ CD95L, Trail/Apo2L, Apo3L). The binding of these ligands to preassembled receptor complexes (3, 4) triggers the activation of caspase-8 through the adapter molecule Fas-associated death domain (FADD)/Mort1 (plus others in some cases). Once the activation of initiator caspases occurs by either of these two routes, the pathways converge on the effector caspases (caspase-3 and caspase-7), which are the proteolytic engines of cell death. Each of the two pathways is modulated, as might be expected, by regulatory polypeptides such as FLICE (FADD-like IL-1ß–converting enzyme) inhibitory protein (cFLIP)/usurpin ('extrinsic' pathway) or Bcl-2 family members ('intrinsic' pathway), and these molecules have been used to examine the relationship between the two pathways in vitro, and more recently in vivo. With the identification of these two distinct apoptotic pathways, controversy raged as reports demonstrating that Bcl-2 did not inhibit CD95-mediated apoptosis were matched by an equal number of reports demonstrating that it did (CD95, a.k.a. Fas/Apo1, being the archetypal extrin-sic death receptor). Then, in 1998, the group led by Peter Krammer and Marcus Peter (Scaffidi et al., reference 5) reported the existence of two distinct cell types that utilize distinct CD95 signaling pathways: type I cells undergo CD95-mediated apoptosis without the involvement of mi-tochondria, whereas type II cells require release of cyto-chrome c from mitochondria in order for CD95 to exert its apoptotic effects. At the molecular level, these two cell types differ principally in the amount of caspase-8 recruited to CD95 via the adapter molecule FADD/Mort1 to form the death-inducing signaling complex (DISC). Whereas type I cells contain large amounts of DISC in …