Fig. 2.

Death receptor pathway. TNF family death ligands (e.g., TNF, FAS, TRAIL) bind to their cognate receptors and initiate the formation of the death inducing signaling complex (DISC). All of the TNF family receptors which induce apoptosis contain a highly conserved death domain (DD) in their cytoplasmic tails. The adaptor protein FADD contains an N-terminal death effector domain (DED) and a C-terminal DD. FADD is recruited to the activated receptor by homotypic interations between the C-terminal DD of FADD and the DD of the receptor. Inactive caspase 8 and caspase 10 zymogens are recruited to the DISC by homotypic interactions between the N-terminal DED domains of the caspases and FADD. cFLIP can be recruited to the DISC and prevents recruitment of caspase 8 or 10. The recruitment of caspase 8 or caspase 10 to the DISC results in activation of the caspases and auto-processing into the active forms of the caspase (reviewed in Riedl and Shi, 2004). Activated caspase 8 or caspase 10 can directly activate effector caspases (e.g., caspases 3, 6, and 7). Activated caspase 8 or caspase 10 also can cleave the BH3 only protein Bid. Cleaved Bid (tBid) translocates to the mitochondria where it activates the extrinsic pathway.