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Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation
BACKGROUND: Phosphorylation-dephosphorylation cycles (PDCs) mediated by kinases and phosphatases are common in cellular signalling. Kinetic modelling of PDCs has shown that these systems can exhibit a variety of input-output (dose-response) behaviors including graded response, ultrasensitivity and b...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583237/ https://www.ncbi.nlm.nih.gov/pubmed/22531112 http://dx.doi.org/10.1186/1752-0509-6-26 |
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author | Szomolay, Barbara Shahrezaei, Vahid |
author_facet | Szomolay, Barbara Shahrezaei, Vahid |
author_sort | Szomolay, Barbara |
collection | PubMed |
description | BACKGROUND: Phosphorylation-dephosphorylation cycles (PDCs) mediated by kinases and phosphatases are common in cellular signalling. Kinetic modelling of PDCs has shown that these systems can exhibit a variety of input-output (dose-response) behaviors including graded response, ultrasensitivity and bistability. In addition to proteins, there are a class of lipids known as phosphoinositides (PIs) that can be phosphorylated. Experimental studies have revealed the formation of an antagonistic kinase-phosphatase complex in regulation of phosphorylation of PIs. However, the functional significance of this type of complex formation is not clear. RESULTS: We first revisit the basic PDC and show that partial asymptotic phosphorylation of substrate limits ultrasensitivity. Also, substrate levels are changed one can obtain non-monotonic bell-shaped dose-response curves over a narrow range of parameters. Then we extend the PDC to include kinase-phosphatase complex formation. We report the possibility of robust bell-shaped dose-response for a specific class of the model with complex formation. Also, we show that complex formation can produce ultrasensitivity outside the Goldbeter-Koshland zero-order ultrasensitivity regime through a mechanism similar to competitive inhibition between an enzyme and its inhibitor. CONCLUSIONS: We conclude that the novel PDC module studied here exhibits new dose-response behaviour. In particular, we show that the bell-shaped response could result in transient phosphorylation of substrate. We discuss the relevance of this result in the context of experimental observations on PI regulation in endosomal trafficking. |
format | Online Article Text |
id | pubmed-3583237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35832372013-03-11 Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation Szomolay, Barbara Shahrezaei, Vahid BMC Syst Biol Research Article BACKGROUND: Phosphorylation-dephosphorylation cycles (PDCs) mediated by kinases and phosphatases are common in cellular signalling. Kinetic modelling of PDCs has shown that these systems can exhibit a variety of input-output (dose-response) behaviors including graded response, ultrasensitivity and bistability. In addition to proteins, there are a class of lipids known as phosphoinositides (PIs) that can be phosphorylated. Experimental studies have revealed the formation of an antagonistic kinase-phosphatase complex in regulation of phosphorylation of PIs. However, the functional significance of this type of complex formation is not clear. RESULTS: We first revisit the basic PDC and show that partial asymptotic phosphorylation of substrate limits ultrasensitivity. Also, substrate levels are changed one can obtain non-monotonic bell-shaped dose-response curves over a narrow range of parameters. Then we extend the PDC to include kinase-phosphatase complex formation. We report the possibility of robust bell-shaped dose-response for a specific class of the model with complex formation. Also, we show that complex formation can produce ultrasensitivity outside the Goldbeter-Koshland zero-order ultrasensitivity regime through a mechanism similar to competitive inhibition between an enzyme and its inhibitor. CONCLUSIONS: We conclude that the novel PDC module studied here exhibits new dose-response behaviour. In particular, we show that the bell-shaped response could result in transient phosphorylation of substrate. We discuss the relevance of this result in the context of experimental observations on PI regulation in endosomal trafficking. BioMed Central 2012-04-24 /pmc/articles/PMC3583237/ /pubmed/22531112 http://dx.doi.org/10.1186/1752-0509-6-26 Text en Copyright © 2012 Szomolay and Shahrezaei; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Szomolay, Barbara Shahrezaei, Vahid Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
title | Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
title_full | Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
title_fullStr | Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
title_full_unstemmed | Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
title_short | Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
title_sort | bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583237/ https://www.ncbi.nlm.nih.gov/pubmed/22531112 http://dx.doi.org/10.1186/1752-0509-6-26 |
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