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Phase plane dynamics of ERK phosphorylation
The extracellular signal–regulated kinase (ERK) controls multiple critical processes in the cell and is deregulated in human cancers, congenital abnormalities, immune diseases, and neurodevelopmental syndromes. Catalytic activity of ERK requires dual phosphorylation by an upstream kinase, in a mecha...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616409/ https://www.ncbi.nlm.nih.gov/pubmed/37690685 http://dx.doi.org/10.1016/j.jbc.2023.105234 |
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author | Shvartsman, Stanislav Y. McFann, Sarah Wühr, Martin Rubinstein, Boris Y. |
author_facet | Shvartsman, Stanislav Y. McFann, Sarah Wühr, Martin Rubinstein, Boris Y. |
author_sort | Shvartsman, Stanislav Y. |
collection | PubMed |
description | The extracellular signal–regulated kinase (ERK) controls multiple critical processes in the cell and is deregulated in human cancers, congenital abnormalities, immune diseases, and neurodevelopmental syndromes. Catalytic activity of ERK requires dual phosphorylation by an upstream kinase, in a mechanism that can be described by two sequential Michaelis-Menten steps. The estimation of individual reaction rate constants from kinetic data in the full mechanism has proved challenging. Here, we present an analytically tractable approach to parameter estimation that is based on the phase plane representation of ERK activation and yields two combinations of six reaction rate constants in the detailed mechanism. These combinations correspond to the ratio of the specificities of two consecutive phosphorylations and the probability that monophosphorylated substrate does not dissociate from the enzyme before the second phosphorylation. The presented approach offers a language for comparing the effects of mutations that disrupt ERK activation and function in vivo. As an illustration, we use phase plane representation to analyze dual phosphorylation under heterozygous conditions, when two enzyme variants compete for the same substrate. |
format | Online Article Text |
id | pubmed-10616409 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-106164092023-11-01 Phase plane dynamics of ERK phosphorylation Shvartsman, Stanislav Y. McFann, Sarah Wühr, Martin Rubinstein, Boris Y. J Biol Chem Research Article The extracellular signal–regulated kinase (ERK) controls multiple critical processes in the cell and is deregulated in human cancers, congenital abnormalities, immune diseases, and neurodevelopmental syndromes. Catalytic activity of ERK requires dual phosphorylation by an upstream kinase, in a mechanism that can be described by two sequential Michaelis-Menten steps. The estimation of individual reaction rate constants from kinetic data in the full mechanism has proved challenging. Here, we present an analytically tractable approach to parameter estimation that is based on the phase plane representation of ERK activation and yields two combinations of six reaction rate constants in the detailed mechanism. These combinations correspond to the ratio of the specificities of two consecutive phosphorylations and the probability that monophosphorylated substrate does not dissociate from the enzyme before the second phosphorylation. The presented approach offers a language for comparing the effects of mutations that disrupt ERK activation and function in vivo. As an illustration, we use phase plane representation to analyze dual phosphorylation under heterozygous conditions, when two enzyme variants compete for the same substrate. American Society for Biochemistry and Molecular Biology 2023-09-09 /pmc/articles/PMC10616409/ /pubmed/37690685 http://dx.doi.org/10.1016/j.jbc.2023.105234 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Shvartsman, Stanislav Y. McFann, Sarah Wühr, Martin Rubinstein, Boris Y. Phase plane dynamics of ERK phosphorylation |
title | Phase plane dynamics of ERK phosphorylation |
title_full | Phase plane dynamics of ERK phosphorylation |
title_fullStr | Phase plane dynamics of ERK phosphorylation |
title_full_unstemmed | Phase plane dynamics of ERK phosphorylation |
title_short | Phase plane dynamics of ERK phosphorylation |
title_sort | phase plane dynamics of erk phosphorylation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616409/ https://www.ncbi.nlm.nih.gov/pubmed/37690685 http://dx.doi.org/10.1016/j.jbc.2023.105234 |
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