Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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

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

Analysis of CD95 Threshold 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}

Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis.
B. B. Aldridge, S. Gaudet, D. A. Lauffenburger, and P. K. Sorger (2014)
Mol Syst Biol 7, 553
   Abstract »    Full Text »    PDF »
Dynamics within the CD95 death-inducing signaling complex decide life and death of cells.
L. Neumann, C. Pforr, J. Beaudouin, A. Pappa, N. Fricker, P. H. Krammer, I. N. Lavrik, and R. Eils (2014)
Mol Syst Biol 6, 352
   Abstract »    Full Text »    PDF »
Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes.
D. A. Flusberg, J. Roux, S. L. Spencer, and P. K. Sorger (2013)
Mol. Biol. Cell 24, 2186-2200
   Abstract »    Full Text »    PDF »
Systems Analysis of Cancer Cell Heterogeneity in Caspase-dependent Apoptosis Subsequent to Mitochondrial Outer Membrane Permeabilization.
J. Schmid, H. Dussmann, G. J. Boukes, L. Flanagan, A. U. Lindner, C. L. O'Connor, M. Rehm, J. H. M. Prehn, and H. J. Huber (2012)
J. Biol. Chem. 287, 41546-41559
   Abstract »    Full Text »    PDF »
Signaling Active CD95 Receptor Molecules Trigger Co-translocation of Inactive CD95 Molecules into Lipid Rafts.
I. Lang, A. Fick, V. Schafer, T. Giner, D. Siegmund, and H. Wajant (2012)
J. Biol. Chem. 287, 24026-24042
   Abstract »    Full Text »    PDF »
Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis.
M. W. Wynes, B. L. Edelman, A. G. Kostyk, M. G. Edwards, C. Coldren, S. D. Groshong, G. P. Cosgrove, E. F. Redente, A. Bamberg, K. K. Brown, et al. (2011)
J. Immunol. 187, 527-537
   Abstract »    Full Text »    PDF »
Modeling Reveals That Dynamic Regulation of c-FLIP Levels Determines Cell-to-Cell Distribution of CD95-mediated Apoptosis.
H. T. Toivonen, A. Meinander, T. Asaoka, M. Westerlund, F. Pettersson, A. Mikhailov, J. E. Eriksson, and H. Saxen (2011)
J. Biol. Chem. 286, 18375-18382
   Abstract »    Full Text »    PDF »
Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL.
N. Fricker, J. Beaudouin, P. Richter, R. Eils, P. H. Krammer, and I. N. Lavrik (2010)
J. Cell Biol. 190, 377-389
   Abstract »    Full Text »    PDF »
Real Time Analysis of Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Cycloheximide-induced Caspase Activities during Apoptosis Initiation.
C. T. Hellwig, B. F. Kohler, A.-K. Lehtivarjo, H. Dussmann, M. J. Courtney, J. H. M. Prehn, and M. Rehm (2008)
J. Biol. Chem. 283, 21676-21685
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882