Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)
Cellular FLICE-inhibitory protein (c-FLIP) was originally identified as an inhibitor of caspase-8 (previously known as FLICE, for FADD-like IL-1 converting enzyme). cFLIP is a catalytically inactive caspase-8/-10 homolog (63–64). There are three cFLIP isoforms expressed from distinct mRNA splice variants: cFLIPL , cFLIPS , and cFLIPR (Figure 30.6). Similar to the Nterminus of caspase-8, all three cFLIP isoforms contain two tandem DED motifs that serve to recruit cFLIP to the DISC, thereby competing with caspase-8. Unlike cFLIPS and cFLIPR, which contain only the DEDs, cFLIPL is a full-length mimic of caspase-8 equipped with a caspase-8 cleavage site at the linker region between large and small subunits, but lacks the caspase active site (65).
When over-expressed, all three cFLIP isoforms inhibit extrinsic apoptosis by blocking caspase-8 binding sites at the DISC (66). However, there was conflicting evidence regarding whether cFLIPL is antior pro-apoptotic. Later studies revealed that cFLIPL has a dual function in regulating caspase-8 activation, depending on its expression level (67). At higher expression levels, cFLIPL can be recruited to the DISC where it binds to FADD or TRADD and competes away caspase-8. Consistent with this model, deregulation of cFLIP is associated with some cancers.
In contrast, at lower expression levels, cFLIPL is reported to promote caspase-8 activation at the DISC by forming heterodimers with caspase-8, even though only one partner in this duo can be enzymatically activated (68). In this scenario, cFLIPL is processed by caspase-8 at the inter-subunit linker to stimulate cFLIP-caspase-8 heterodimerization and subsequent activation of caspase-8 (69). As described above, active dimerized/uncleaved caspase-8 can inhibit RIP1-dependent necrotic cell death. Thus, caspases can have pro-survival functions as well. Perhaps the best way of linking the proliferation of lymphocytes in response to a new infection to the eventual elimination of the same lymphocytes following recovery from infection is to use the same molecules for both tasks.
Figure 30.6. Decoy receptors. Decoy receptors mimic death receptors by binding to the death ligands FasL, TWEAK, and TRAIL to inhibit cell-death signaling.
Figure 30.7. Different isoforms of cFLIP modulate death-receptor signaling. Like caspase-8, cFLIP isoforms contain two tandem DED motifs that recruit cFLIP to the DISC, thereby competing with caspase-8 recruitment. cFLIPL is a full-length mimic of caspase-8 equipped with a caspase-8 cleavage site between large and small subunits, but lacks the protease active site.
cFLIPL also regulates non-apoptotic signaling pathways such as cell survival and proliferation (70). In certain contexts, cFLIPL only activates caspase-8 to a moderate level, which is sufficient to cleave cFLIPL , but not sufficient to trigger apoptosis. Processed cFLIPL then recruits specific proteins to activate alternative signaling pathways (71–73).