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Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent ex...

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Detalles Bibliográficos
Autores principales: Ho, Kenneth L., Harrington, Heather A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954819/
https://www.ncbi.nlm.nih.gov/pubmed/20976242
http://dx.doi.org/10.1371/journal.pcbi.1000956
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author Ho, Kenneth L.
Harrington, Heather A.
author_facet Ho, Kenneth L.
Harrington, Heather A.
author_sort Ho, Kenneth L.
collection PubMed
description Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.
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spelling pubmed-29548192010-10-25 Bistability in Apoptosis by Receptor Clustering Ho, Kenneth L. Harrington, Heather A. PLoS Comput Biol Research Article Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering. Public Library of Science 2010-10-14 /pmc/articles/PMC2954819/ /pubmed/20976242 http://dx.doi.org/10.1371/journal.pcbi.1000956 Text en Ho, Harrington. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ho, Kenneth L.
Harrington, Heather A.
Bistability in Apoptosis by Receptor Clustering
title Bistability in Apoptosis by Receptor Clustering
title_full Bistability in Apoptosis by Receptor Clustering
title_fullStr Bistability in Apoptosis by Receptor Clustering
title_full_unstemmed Bistability in Apoptosis by Receptor Clustering
title_short Bistability in Apoptosis by Receptor Clustering
title_sort bistability in apoptosis by receptor clustering
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954819/
https://www.ncbi.nlm.nih.gov/pubmed/20976242
http://dx.doi.org/10.1371/journal.pcbi.1000956
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