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).