Extrinsic pathway
The extrinsic pathway begins outside the cell through the activation of specific pro-apoptotic receptors on the cell surface. These are activated by specific molecules known as pro-apoptotic ligands (Figure 2.1). These ligands include Apo2L/TRAIL and CD95L/FasL and bind their cognate receptors DR4/DR5 and CD95/Fas, respectively.1-4 Unlike the intrinsic pathway, the extrinsic pathway triggers apoptosis independently of the p53 protein.5,6
Click here to view a PDF of this image.Figure 2.1. Elements of the extrinsic apoptotic pathway.
Adapted from Ashkenazi, 2002. Reproduced with permission from Nat Rev Cancer.
Ligand binding induces receptor clustering and recruitment of the adaptor protein Fas-associated death domain (FADD) and the initiator caspases 8 or 10 as procaspases, forming a death-inducing signaling complex (DISC).7-10 Formation of the DISC brings procaspase molecules into close proximity of one another, facilitating their autocatalytic processing and release into the cytoplasm where they activate effector caspases 3, 6, and/or 7, thereby converging on the intrinsic pathway (Figure 2.2).1,11-13 Dimerization may be crucial for caspase 8 activation, and clustering of the receptors and the associated DISC may enhance this activation.13 DISC formation is modulated by several inhibitory mechanisms, including c-FLICE inhibitory protein (c-FLIP), which exerts its effects on the DISC by interacting with FADD to block initiator caspase activation; and decoy receptors, which can block ligand binding or directly abrogate pro-apoptotic receptor stimulation.14 Upon DISC activation, the extrinsic pathway adopts the same effector caspase machinery as the intrinsic pathway.
It has been shown that activation of the extrinsic pathway through the binding of CD95L/FasL to CD95/Fas can result in 2 apoptotic programs, termed type I and type II. Type I cells are able to overcome the need for mitochondrial amplification of the death signal in CD95-mediated apoptosis by producing sufficient amounts of caspase 8 at the DISC to directly cleave and activate effector caspases and execute cell death.15 Because type I cells bypass mitochondrial involvement in CD95-mediated apoptosis, expression of Bcl-2 or Bcl-XL has no inhibitory effect on their apoptotic program. Conversely, type II cells produce minimal amounts of active caspase 8 at the DISC and require the mitochondrial amplification of the CD95 signal.15 This signal is probably through the pro-apoptotic BH3 domain, which only contains the Bcl-2 family member, Bid.15 The cleavage of Bid by caspase 8 results in its translocation to the mitochondria where it initiates the release of mitochondrial factors, which in turn augment cell death. Because type II cells rely on the apoptotic function of mitochondria, expression of Bcl-2/Bcl-XL does confer protection from CD95-mediated apoptosis.15 An explanation for the differences between type I and type II cells remains unclear, although differential expression of inhibitors of the death receptor signaling cascade, such as c-FLIP or X-linked inhibitor of apoptosis protein (XIAP), has been suggested to play a role.16
Click here to view a PDF of this image.Figure 2.2. FADD recruitment and caspase activation via the extrinsic pathway.
Adapted from Ashkenazi, 2002.1 Reproduced with permission from Nat Rev Cancer.