Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family. This group of apoptosis induction pathways all work through protein interactions mediated by the intracellular death domain (DD), encoded within the cytoplasmic domain of the receptor. TRAIL selectively induces apoptosis through its interaction with the Fas-associated death domain protein (FADD) and caspase-8/10 (Wang S & el-Deiry WS 2003; Sprick MR et al. 2002). TRAIL and its receptors, TRAIL-R1 and TRAIL-R2, were shown to be rapidly endocytosed via clathrin-dependent and -independent manner in human Burkitt's lymphoma B cells (BJAB) (Kohlhaas SL et al. 2007). However, FADD and caspase-8 were able to bind TRAIL-R1/R2 in TRAIL-stimulated BJAB cells at 4oC (at which membrane trafficking is inhibited), suggesting that the endocytosis was not required for an assembly of the functional TRAIL DISC complex. Moreover, blocking of clathrin-dependent endocytosis did not interfere with the capacity of TRAIL to promote apoptosis (Kohlhaas SL et al. 2007).
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Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].
The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010].
Caspase-10 precursor is recruited to the TRAIL:TRAIL receptor-2:FADD complex (TNFSF10:TNFRSF10B:FADD) as well as TRAIL:TRAIL receptor-1:FADD complex (TNFSF10:TNFRSF10A:FADD) (Sprick et al. 2002) through interaction of death effector domains of caspase-10 and FADD (Wang et al. 2001).
TRAIL (TNF-related apoptosis-inducing ligand) binds TRAIL receptor-1 (TNFRSF10A) or TRAIL receptor-2 (TNFRSF10B) (Wiley et al. 1995, Pan et al. 1997, Walczak et al. 1997).
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