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Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL
Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Biochemistry and Molecular Biology
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316727/ https://www.ncbi.nlm.nih.gov/pubmed/22213832 http://dx.doi.org/10.1074/mcp.M111.013730 |
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author | Szegezdi, Eva van der Sloot, Almer M. Mahalingam, Devalingam O'Leary, Lynda Cool, Robbert H. Muñoz, Inés G. Montoya, Guillermo Quax, Wim J. de Jong, Steven Samali, Afshin Serrano, Luis |
author_facet | Szegezdi, Eva van der Sloot, Almer M. Mahalingam, Devalingam O'Leary, Lynda Cool, Robbert H. Muñoz, Inés G. Montoya, Guillermo Quax, Wim J. de Jong, Steven Samali, Afshin Serrano, Luis |
author_sort | Szegezdi, Eva |
collection | PubMed |
description | Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity |
format | Online Article Text |
id | pubmed-3316727 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-33167272012-04-10 Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL Szegezdi, Eva van der Sloot, Almer M. Mahalingam, Devalingam O'Leary, Lynda Cool, Robbert H. Muñoz, Inés G. Montoya, Guillermo Quax, Wim J. de Jong, Steven Samali, Afshin Serrano, Luis Mol Cell Proteomics Special Issue: Prospects in Space and Time Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity The American Society for Biochemistry and Molecular Biology 2012-03 2012-01-02 /pmc/articles/PMC3316727/ /pubmed/22213832 http://dx.doi.org/10.1074/mcp.M111.013730 Text en © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Special Issue: Prospects in Space and Time Szegezdi, Eva van der Sloot, Almer M. Mahalingam, Devalingam O'Leary, Lynda Cool, Robbert H. Muñoz, Inés G. Montoya, Guillermo Quax, Wim J. de Jong, Steven Samali, Afshin Serrano, Luis Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL |
title | Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL |
title_full | Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL |
title_fullStr | Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL |
title_full_unstemmed | Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL |
title_short | Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity: Apoptosis Induction by TRAIL |
title_sort | kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by trail |
topic | Special Issue: Prospects in Space and Time |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316727/ https://www.ncbi.nlm.nih.gov/pubmed/22213832 http://dx.doi.org/10.1074/mcp.M111.013730 |
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