Extrinsic pathway
The extrinsic pathway begins outside the cell through the activation of specific pro-apoptotic receptors on the cell surface by specific molecules known as pro-apoptotic ligands (Figure 2.7). These ligands include Apo2L/TRAIL (receptors DR4, DR5), and CD95L/FasL (receptor CD95/Fas).1,8,19,20 Unlike the intrinsic pathway, the extrinsic pathway triggers apoptosis independently of the p53 protein.21,22
Figure 2.7. The extrinsic apoptosis pathway.Click here to view a PDF of this image. Adapted from Ashkenazi 2002. Reproduced with permission from Nature Reviews Cancer.
Once activated by extracellular ligand binding (Figure 2.8 parts 1 and 2), the intracellular domains of these receptors, known as the 'death domains', bind to the adaptor protein Fas-associated death domain (FADD), leading to the assembly of the death-inducing signaling complex, or DISC, and recruitment and assembly of initiator caspases 8 and 10.23-26 Caspases 8 and 10 are stimulated and undergo self processing, releasing active enzyme molecules into the cytosol, where they activate caspases 3, 6, and 7, thereby converging on the intrinsic pathway (Figure 2.8).1,2,4
Figure 2.8. FADD recruitment and caspase activation via the extrinsic pathway.Click here to view a PDF of this image.