It's not over until the FAT lady sings.

The death receptors FAS, TRAIL-Rs and TNFR1 play critical roles in programmed cell death, particularly in the immune system. Upon ligation of death receptors, caspase-8 is activated within the so-called ‘Death Induced Signalling Complex’ (DISC) but the mechanisms that mediate and modulate the activation of caspase-8 are still not fully understood. This is an important issue because caspase-8 is essential for apoptosis induced by death receptors. In this issue of The EMBO Journal, Kranz and Boutros (2014) describe their findings from a whole genome siRNA screen for the identification of novel regulators of death receptor induced apoptosis signalling. They identified the atypical cadherin FAT1 as a negative regulator of TRAIL-R-mediated caspase-8 activation and consequent induction of apoptosis, although it had no impact on NF-κB activation. The authors also show that FAT1 depletion substantially increased TRAIL-induced killing of glioblastomaderived cell lines, suggesting a potential novel approach for treatment of this highly aggressive cancer.