title: Analysis of CD95 threshold signaling: triggering of CD95 (FAS/APO-1) at low concentrations primarily results in survival signaling.
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.
authors.affiliation: Division of Immunogenetics, Tumorimmunology Program, Im Neuenheimer Feld, Heidelberg, Germany.
authors.forename: Inna N
authors.initials: IN
authors.lastname: Lavrik
authors.forename: Alexander
authors.initials: A
authors.lastname: Golks
authors.forename: Dagmar
authors.initials: D
authors.lastname: Riess
authors.forename: Martin
authors.initials: M
authors.lastname: Bentele
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
mesh_terms: 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*
chemical_list: D000911:Antibodies, Monoclonal; D053418:Death Domain Receptor Signaling Adaptor Proteins; D019014:fas Receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D053181:Caspase 8