Drug Resistance Group, Centre for Cancer Research, Cell Biology, Queens University Belfast, Belfast, Northern Ireland
The short form c-FLIPS is composed of 221 amino acids and has the same structure as vFLIP proteins, except that in addition to the two DEDs of cFLIPS, a carboxy-terminal tail composed of approximatively 20 amino acids is present that seems to be crucial for its ubiquitinylation and subsequent proteasomal degradation (Poukkula et al., 2005).
The short form c-FLIPR is composed of 213 amino acids, contains two DEDs and lacks the additional carboxy terminal amino acids present in c-FLIPS (Golks et al., 2005).
When the death receptors are stimulated by their corresponding ligand, they recruit the adapter molecule FADD. FADD can then recruit DED containing proteins, e.g. caspase-8, and form a DISC. c-FLIP inhibits caspase-8 activation at the DISC. c-FLIPL and c-FLIPS have been shown to block death receptor-mediated apoptosis by forming a proteolytically inactive heterodimer with procaspase-8 (Golks et al., 2005; Krueger et al., 2001). However, cleavage is blocked at different stages. For c-FLIPS and c-FLIPR, both cleavage steps required for procaspase-8 activation are completely blocked. In contrast, c-FLIPL allows partial cleavage of procaspase-8 at the DISC (Figure 3). When a molecule of procaspase-8 and c-FLIPL come into contact at the DISC, a conformational change in the two molecules occurs. This leads to the autocatalytic cleavage of the p10 subunit from procaspase-8. c-FLIPL is also partially cleaved by the procaspase-8 molecule to generate a p12 subunit. However, cleavage is stopped at this stage and no p18 subunit is generated from caspase-8. It has been hypothesised that the second reciprocal trans-catalytic cleavage step cannot occur because of the lack of the cysteine residue at the active site of c-FLIPL (Micheau, 2002). The resulting cleavage products are p41/43- and p10-caspase-8 products; and p43- and p12-c-FLIPL intermediates. Furthermore, Kreuger et al demonstrated that the p41/43-caspase-8 and p43-c-FLIPL intermediates remain bound at the DISC (Krueger et al., 2001). Recently, it has been proposed that the DISC-bound caspase 8/FLIP complex has catalytic activity that is not capable of generating a pro-apoptotic signal, but that can cleave local substrates such as RIP (receptor-interacting protein) (Micheau, 2002).
Christophe Le Clorennec ; Daniel B Longley ; Timothy Wilson
CFLAR (CASP8 and FADD-like apoptosis regulator)
Atlas Genet Cytogenet Oncol Haematol. 2008-09-01
Online version: http://atlasgeneticsoncology.org/gene/40065/cflar-(casp8-and-fadd-like-apoptosis-regulator)