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J. Biol. Chem. 282 (18): 13664-13671

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Analysis of CD95 Threshold Signaling

TRIGGERING OF CD95 (FAS/APO-1) AT LOW CONCENTRATIONS PRIMARILY RESULTS IN SURVIVAL SIGNALING*

Inna N. Lavrik{ddagger}, Alexander Golks{ddagger}1, Dagmar Riess{ddagger}, Martin Bentele§, Roland Eils§, , and Peter H. Krammer{ddagger}2

{ddagger}Division of Immunogenetics, Tumorimmunology Program, and the §Division of Theoretical Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

Abstract: Recently we generated a mathematical model (Bentele, M., Lavrik, I., Ulrich, M., Stosser, S., Heermann, D. W., Kalthoff, H., Krammer, P. H., and Eils, R. (2004) J. Cell Biol. 166, 839-851) of signaling in CD95(Fas/APO-1)-mediated apoptosis. Mathematical modeling in combination with experimental data provided new insights into CD95-mediated apoptosis and allowed us to establish a threshold mechanism of life and death. Here, we further assessed the predictability of the model experimentally by a detailed analysis of the threshold behavior of CD95 signaling. Using the model predictions for the mechanism of the threshold behavior we found that the CD95 DISC (death-inducing signaling 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 recruitment into the DISC. Given that death signaling does not occur upon CD95 stimulation at low (threshold) anti-APO-1 concentrations, we also analyzed survival signaling, focusing on mitogen-activated protein kinase activation. Interestingly, we found that mitogen-activated protein kinase activation takes place under threshold conditions. These findings show that triggering of CD95 can signal both life or death, depending on the strength of the stimulus.


Received for publication January 16, 2007. Revision received March 7, 2007.

* This work was supported by the Wilhelm Sander Stiftung SFB 405 and Tumorzentrum Heidelberg/Mannheim. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Present address: Novartis Pharma AG, CH-4002 Basel, Switzerland.

2 To whom correspondence should be addressed. E-mail:p.krammer{at}dkfz.de.


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