2.2 The extrinsic pathway
The extrinsic apoptotic pathway is mediated by specific death receptors
(DRs) on the cell membrane, the DRs are members of the TNF (tumor
necrosis factor) superfamily(Locksley,
Killeen, & Lenardo, 2001). The death domain (DD) of DRs transmits
death signals from the cell surface to the intracellular signaling
pathway. So far, ligands and corresponding death receptors include
FasL/Fas, TNF-α/TNFR1, Apo3L/DR3, Apo2L/DR4 and Apo2L/DR5. When the
ligand binds to the receptor, it recruits cytoplasmic linker protein and
binds to the receptor through death
domain(Rubio-Moscardo et al., 2005;
Suliman, Lam, Datta, & Srivastava,
2001). Taking the FasL/Fas model as an example, the binding of FasL
(Fas ligand) to Fas can recruit the linker protein FADD (Fas-associated
protein with death domain) through the death
domain(Wajant, 2002) (Figure 4). Then
FADD combined with procaspase-8/10 through the dimerization of the death
effector domain (DED) to form a death-inducing signaling complex (DISC),
leading to autoproteolytic cleavage of
procaspase-8/10(Kischkel et al., 1995).
The activated caspase-8/10 have enzymatic activity and can hydrolyze
caspase-3/6/7 to induce
apoptosis(Ashkenazi, 2008). There is a
related cross-connection between the death receptor (extrinsic) pathway
and the mitochondrial (intrinsic) pathway. In certain cells, activated
caspase-8 cleaves the pro-apoptotic protein Bid to create truncated Bid
(tBid), thereby activating the mitochondria-mediated apoptosis signaling
pathway(K. Huang et al., 2016). TNFR1 is
activated by the binding of its respective ligand TNF. TNFR1 recruits
TRADD, an adaptor protein that can bind to TNF receptor-associated
factors (TRAFs),
receptor-interacting protein
kinase (RIP1) and cellular IAPs to form an initial membrane complex
(complex I), which stimulates the NF-κB pathway to facilitate cell
apoptosis(Mahmood & Shukla, 2010). The
initially formed TRADD-RIP1-TRAFs complex I then assembles into the
cytoplasmic apoptotic complex (complex II). There are two types of
cytoplasmic complex II, TRADD recruits FADD and caspase-8 to form
TRADD-dependent complex IIA, RIP1 recruits FADD and caspase-8 to form
complex IIB, and cIAPs can negatively regulate complex IIB. Both complex
IIA and IIB can trigger apoptosis by activating
caspase-8(Galluzzi, Kepp, & Kroemer,
2012; Pobezinskaya & Liu, 2012).