FLIPping the kill switch

I t's always wise to consult others before making a big decision, so a cell seeks input from a lot of different proteins before choosing between survival and death by apoptosis. Fricker et al. describe how one particular protein— cFLIP—can nudge a cell in either direction depending on the expression levels of its three different isoforms (1). Cells contemplate suicide in response to a number of stimuli, including activation of the CD95 death receptor by its ex-tracellular ligand CD95L (2). Receptor stimulation triggers the formation of a death-inducing signaling complex (DISC) at the plasma membrane containing inactive procaspase-8 molecules, which are converted by a series of self-cleavage events into active proteases that induce apoptosis (3). cFLIP, which exists as one long (cFLIP L) and two short (cFLIP S/R) splice variants, also localizes to the DISC and regulates the activation of procaspase-8. The short variants inhibit procaspase-8 cleavage and cell death, but the function of cFLIP L is more controversial: while some reports suggest cFLIP L is exclusively anti-apoptotic (4), others indicate that the longer isoform can promote apop-tosis under certain conditions (5). Inna Lavrik and colleagues at the Ger-man Cancer Research Center in Heidelberg decided to take a more quantitative approach to the problem. " Previous studies simply overexpressed or down-regulated cFLIP, " explains Lavrik. " Ours is the fi rst quantitative study to really show the conditions in which cFLIP L promotes apoptosis. " Fricker et al. found that cFLIP L could either block or accelerate procaspase-8 processing and cell death depending on its expression level and the strength of CD95 stimulation. The researchers then measured the absolute concentrations of all the important proteins known to function at the DISC in HeLa cells and generated a mathematical model describing how cFLIP in-fl uences the cell's life-and-death decision. The approach revealed a narrow window in which intermediate amounts of cFLIP L boost procaspase-8 cleavage and apoptosis. Nevertheless, says Lavrik, the results show that " the same molecule can have different functions in a signaling pathway, depending on its own concentration and the concentration of other proteins in the same pathway. " The reason for this seems to lie in two opposing properties of cFLIP L. Like its shorter variants, cFLIP L has a high affi nity for the DISC and competes with procas-pase-8 for recruitment to the death receptor complex. Thus, at high concentrations, all cFLIP isoforms block procas-pase-8's activation …