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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...
Autores principales: | , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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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. |
format | Text |
id | pubmed-2954819 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT hokennethl bistabilityinapoptosisbyreceptorclustering AT harringtonheathera bistabilityinapoptosisbyreceptorclustering |