Analysis of CD95 Threshold Signaling TRIGGERINGOF CD95 (FAS/APO-1) AT LOWCONCENTRATIONS PRIMARILY RESULTS IN SURVIVAL SIGNALING*

signaling in CD95(Fas/APO-1)-mediated apoptosis.Mathemat-ical modeling in combination with experimental data provided new insights into CD95-mediated apoptosis and allowed us to establish a thresholdmechanism of life and death. Here, we fur-ther assessed the predictability of themodel experimentally by a detailed analysis of the threshold behavior of CD95 signaling. Using themodel predictions for themechanismof the threshold behavior we found that the CD95 DISC (death-inducing signal-ing complex) is formed at the cell membrane upon stimulation with low concentrations of agonistic anti-APO-1 monoclonal antibodies; however, activation of procaspase-8 at the DISC is blocked due to high cellular FLICE-inhibitory protein recruit-ment into the DISC. Given that death signaling does not occur upon CD95 stimulation at low (threshold) anti-APO-1 concen-trations, we also analyzed survival signaling, focusing on mito