Analysis of CD95 threshold signaling: triggering of CD95 (FAS/APO-1) at low concentrations primarily results in survival signaling.
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.
Lavrik
Inna N
IN
Division of Immunogenetics, Tumorimmunology Program, Im Neuenheimer Feld, Heidelberg, Germany.
Golks
Alexander
A
Riess
Dagmar
D
Bentele
Martin
M
Eils
Roland
R
Krammer
Peter H
PH
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053181:Caspase 8 / Q000276:immunology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D018448:Models, Immunological; D019014:fas Receptor / Q000819:agonists / Q000276:immunology*
D000911:Antibodies, Monoclonal; D053418:Death Domain Receptor Signaling Adaptor Proteins; D019014:fas Receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D053181:Caspase 8