The cell surface-bound receptor FAS (also called APO-1 or CD95) was originally discovered as the target of two monoclonal antibodies that trigger apoptotic cell death in certain human tumor derived cell lines in culture or as xeno-transplants in immuno-deficient mice. Cloning of the gene encoding FAS revealed that it is a member of the tumor necrosis factor receptor (TNF-R) family, which also includes the receptors for TNF, TRAIL (TNF-related apoptosis-inducing ligand) and those for other members of the TNF cytokine family. Accordingly, identification of the physiological ligand for FAS, called FAS ligand (FASL or CD95L), through expression cloning demonstrated that it belongs to the TNF cytokine family. FAS stimulation causes apoptosis because activators of FAS (agonistic antibodies or recombinantly produced forms of FASL) have been selected for this property and that we may therefore have overly emphasized this function of FASL-FAS signaling while under-estimating other activities, such as induction of cellular proliferation or differentiation. Ligation of FAS rapidly causes assembly of an intra-cellular ‘death inducing signaling complex’ (DISC), which was shown to contain the aspartate specific cysteine protease, caspase-8, its adaptor/activator FADD and its modulator c-FLIP (FLICE (i.e. caspase-8) inhibitory protein). Pharmacological modulation of the FASL-FAS signaling machinery may therefore be a useful strategy for therapeutic intervention in certain diseases.

References

1.Strasser A, et al. Immunity. 2009;30(2):180–192.