Dynamics within the CD95 death-inducing signaling complex decide life and death of cells.
This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-kappaB. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-kappaB signaling. Systematic model reduction resulted in a surprisingly simple model well approximating experimentally observed dynamics. The model postulates a new link between c-FLIP(L) cleavage in the death-inducing signaling complex (DISC) and the NF-kappaB pathway. We validated experimentally that CD95 stimulation resulted in an interaction of p43-FLIP with the IKK complex followed by its activation. Furthermore, we showed that the apoptotic and NF-kappaB pathways diverge already at the DISC. Model and experimental analysis of DISC formation showed that a subtle balance of c-FLIP(L) and procaspase-8 determines life/death decisions in a nonlinear manner. We present an integrated model describing the complex dynamics of CD95-mediated apoptosis and NF-kappaB signaling.
Neumann
Leo
L
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Pforr
Carina
C
Beaudouin
Joel
J
Pappa
Alexander
A
Fricker
Nicolai
N
Krammer
Peter H
PH
Lavrik
Inna N
IN
Eils
Roland
R
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D019070:Cell Lineage; D002470:Cell Survival; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D016328:NF-kappa B; D019014:fas Receptor; D051550:I-kappa B Kinase; D020169:Caspases