2.3 Exogenous death receptor pathway
Death receptor (DR) is a member of tumor necrosis factor receptor (TNFR) superfamily with extracellular Cys-rich domain and intracellular death domain (DD). When the death receptor combines with specific death ligand, it receives extracellular death signal, and activates the mechanism of apoptosis in cells, inducing apoptosis. The main death receptors- ligands known to date are Fas (APO-1, CD95)- FasL (CD95L), TNFR1 (DR1)- TNF, TRAILR1 (DR4)- TRAIL (APO-2L), TRAILR2 (DR5)- TRAIL (APO-2L), DR3 (APO-3, TRAMP)- TL1A and so on. Currently, there are 3 major apoptotic death receptor signaling pathways: Fas, TNFR1, TRAIL.
2.3.1 Fas signal pathway
When the FasL homotrimer complex binds to Fas, it initiates Fas-FasL- mediated apoptosis of the external death receptor pathway. In the process of signal transduction, the 3 Fas receptor molecules combine with ligand to form trimer and clustered intracellular DD recruits FADD, Daxx, FAP-1, FLIP and other related proteins. FADD recruits pro-caspase 8 through death effector domain DED to form death-inducing signaling complex (DISC), and pro-caspase8 in DISC self-cleaves into active Caspase8. FLIP contains DED which allows it to be integrated into the DISC of death receptor, FLIP in turn inhibits pro-caspase 8 activation by competitively binding DED on FADD or DED on Caspase8.
The pathways by which protein caspase8 activiates Caspase3 varies in different types of cells. In type I cells, the DISC complex activates a large number of Caspase8, Caspase8 activates Caspase3, and Caspase3 acts on various substrates that cause apoptosis, and lead to apoptosis finally; In type II cells, only a small amount of Caspase8 is activated. Actived Caspase8 can stimulate the transformation of Bid into tBid which is then recloated to the mitochondrial membrane, activitng the Bcl-2 family pro-apoptotic factors and inhibits the Bcl-2 family anti-apoptotic factors, which mediates apoptosis through the mitochondrial pathway. In addition, Daxx recruited by the DD domain of Fas can also activate JNK signaling pathway, and enhance the transcriptional expression of pro-apoptotic genes such as p53, Fas and FasL through mitochondrial pathway to mediate apoptosis.
2.3.2 TNFR1 signal pathway
TNF trimer binds to TNFR1 to induce the clustering of DD of TNFR1 to recruit adapter protein TRADD which recruits signaling molecules such as TRAF2, RIP and FADD. TRAF2 and RIP can activate signal pathways of NF-κB and JNK/AP, while FADD triggers caspase cascade, the survival of cells depends on the different adapter molecules recruited by TRADD.
FADD recruits and activates pro-caspase8 through DED to form active Caspase8 after binding to adapter protein TRADD. Caspase8 triggers Caspase cascade to mediate apoptosis, while FADD also can recruit FLIP to inhibit the release of active Caspase8. When the adapter protein TRADD binds to RIP by DD, it activates the TNFR related factor (TRAF-2) which binds to TRAF-1 and recruit cIAPs, the formed complex inhibits the activity and release of Caspase8, and thereby inhibiting apoptosis. In addition, TRAF-2 can activate NF-κB-inducing kinase (NIK), which in turn activates IκB kinase (IKK) through phosphorylation. IKK phosphorylates IκB and releases NF-κB, then translocates to the nucleus and activates anti-apoptotic genes such as cIAP, FLIP, Bcl-XL expression, and promote cell survival.
2.3.3 TRAIL signal pathway
TNF related apoptosis-inducing ligand (TRAIL) are type II transmembrane proteins. To date, at least 5 TRAIL receptors TRAILR1 (DR4), TRAILR2 (DR5), TRAILR3 (DcR1), TRAILR4 (DcR2), OPG have been found. TRAIL receptors can be divided into two categories, one is the decoy receptors like TRAILR3, TRAILR4, OPG, and the other one is the death receptors like TRAILR1, TRAILR2. Inducible receptors are mainly found in normal cells. When combined with ligand TRAIL, they can form to non-functional complexes and block apoptosis. The expression of TRAILR1 and TRAILR2 was significantly increased in cancer cells after binding with ligand TRAIL, pro-caspase8 was recruited by the combination of DD and FADD to form DISC, pro-caspase8 in DISC self-cleaves into active Caspase8 which mediates apoptosis by activating Caspase3 through a Caspase pathway similar to Fas and a mitochondria-dependent pathway.
Signal pathways of death receptors mediate apoptosis
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