Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL
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Cellular FADD-like interleukin-1β–converting enzyme inhibitory proteins (c-FLIPs; isoforms c-FLIP long [c-FLIPL], c-FLIP short [c-FLIPS], and c-FLIP Raji [c-FLIPR]) regulate caspase-8 activation and death receptor (DR)–induced apoptosis. In this study, using a combination of mathematical modeling, imaging, and quantitative Western blots, we present a new mathematical model describing caspase-8 activation in quantitative terms, which highlights the influence of c-FLIP proteins on this process directly at the CD95 death-inducing signaling complex. We quantitatively define how the stoichiometry of c-FLIP proteins determines sensitivity toward CD95-induced apoptosis. We show that c-FLIPL has a proapoptotic role only upon moderate expression in combination with strong receptor stimulation or in the presence of high amounts of one of the short c-FLIP isoforms, c-FLIPS or c-FLIPR. Our findings resolve the present controversial discussion on the function of c-FLIPL as a pro- or antiapoptotic protein in DR-mediated apoptosis and are important for understanding the regulation of CD95-induced apoptosis, where subtle differences in c-FLIP concentrations determine life or death of the cells.
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c-FLIPS inhibits and c-FLIPL activates CASP8 by modulating CASP8 oligomerization.
“Compelling evidence indicates that the short variant of c-FLIP (c-FLIPS) and its long counterpart (c-FLIPL) inhibit and activate CASP8, respectively, by modulating CASP8 oligomerization [298–301].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [299]
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- Authors
- Fricker, N., Beaudouin, J., Richter, P., Eils, R., Krammer, P. H., & Lavrik, I. N.
- Affiliations
- German Cancer Research Center (DE)
- Division of Immunogenetics 1 and 2
- Corresponding author
- Lavrik, Inna N.
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2010-08-09
- Volume
- 190
- Issue
- 3
- Pages
- 377-389
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2922645
- OpenAlex
- W2089552619
- Cited by
- 154
- References
- 45
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 11 · 2022: 7 · 2021: 12 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 3 · 2016: 9 · 2015: 14 · 2014: 15 · 2013: 19 · 2012: 18
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- c-FLIP, Fas, caspase-8 activation, death receptor signaling, apoptosis, stoichiometry, anti-apoptotic proteins, pro-apoptotic proteins
- MeSH terms
- Algorithms, Computer Simulation, HeLa Cells, Humans, Models, Biological, Blotting, Western, Signal Transduction, Apoptosis, fas Receptor, Protein Isoforms, Caspase 8, CASP8 and FADD-Like Apoptosis Regulating Protein
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