title: Caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation.
abstract: Stimulation of CD95/Fas/APO-1 results in the induction of both apoptotic and non-apoptotic signaling pathways. The processes regulating these two opposing pathways have not been thoroughly elucidated to date. In this study, using quantitative immunoblots, imaging, and mathematical modeling, we addressed the dynamics of the DED proteins of the death-inducing signaling complex (DISC), procaspase-8, and cellular FLICE inhibitory proteins (c-FLIPs) to the onset of CD95-mediated ERK1/2 and p38 mitogen-activated protein kinase (MAPK) activation. We found that CD95 DISC-induced caspase-8 activity is important for the initiation of ERK1/2 and p38 MAPK activation. The long c-FLIP isoform, c-FLIP(L), and the short c-FLIP isoform, c-FLIP(R), inhibited MAPK induction by blocking caspase-8 processing at the DISC. Furthermore, we built a mathematical model describing CD95 DISC-mediated MAPK activation and apoptosis. The model quantitatively defined the dynamics of DED proteins, procaspase-8, and c-FLIP, which lead to caspase-8 activation and induction of apoptotic and non-apoptotic signaling pathways. In conclusion, the combination of biochemical analysis with mathematical modeling provides evidence for an important role of caspase-8 in CD95-mediated activation of MAPKs, while c-FLIP exerts a regulatory function in this process.
authors.affiliation: Division of Immunogenetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: A M M
authors.initials: AM
authors.lastname: Kober
authors.forename: S
authors.initials: S
authors.lastname: Legewie
authors.forename: C
authors.initials: C
authors.lastname: Pforr
authors.forename: N
authors.initials: N
authors.lastname: Fricker
authors.forename: R
authors.initials: R
authors.lastname: Eils
authors.forename: P H
authors.initials: PH
authors.lastname: Krammer
authors.forename: I N
authors.initials: IN
authors.lastname: Lavrik
mesh_terms: D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019014:fas Receptor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8