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A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1
Polo-like kinase 1 (PLK1) is a crucial regulator of cell cycle progression. It is established that the activation of PLK1 depends on the coordinated action of Aurora-A and Bora. Nevertheless, very little is known about the spatiotemporal regulation of PLK1 during G2, specifically, the mechanisms tha...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755526/ https://www.ncbi.nlm.nih.gov/pubmed/34759346 http://dx.doi.org/10.1038/s41388-021-02094-9 |
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author | Raab, Monika Matthess, Yves Raab, Christopher A. Gutfreund, Niklas Dötsch, Volker Becker, Sven Sanhaji, Mourad Strebhardt, Klaus |
author_facet | Raab, Monika Matthess, Yves Raab, Christopher A. Gutfreund, Niklas Dötsch, Volker Becker, Sven Sanhaji, Mourad Strebhardt, Klaus |
author_sort | Raab, Monika |
collection | PubMed |
description | Polo-like kinase 1 (PLK1) is a crucial regulator of cell cycle progression. It is established that the activation of PLK1 depends on the coordinated action of Aurora-A and Bora. Nevertheless, very little is known about the spatiotemporal regulation of PLK1 during G2, specifically, the mechanisms that keep cytoplasmic PLK1 inactive until shortly before mitosis onset. Here, we describe PLK1 dimerization as a new mechanism that controls PLK1 activation. During the early G2 phase, Bora supports transient PLK1 dimerization, thus fine-tuning the timely regulated activation of PLK1 and modulating its nuclear entry. At late G2, the phosphorylation of T210 by Aurora-A triggers dimer dissociation and generates active PLK1 monomers that support entry into mitosis. Interfering with this critical PLK1 dimer/monomer switch prevents the association of PLK1 with importins, limiting its nuclear shuttling, and causes nuclear PLK1 mislocalization during the G2-M transition. Our results suggest a novel conformational space for the design of a new generation of PLK1 inhibitors. |
format | Online Article Text |
id | pubmed-8755526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87555262022-01-26 A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 Raab, Monika Matthess, Yves Raab, Christopher A. Gutfreund, Niklas Dötsch, Volker Becker, Sven Sanhaji, Mourad Strebhardt, Klaus Oncogene Article Polo-like kinase 1 (PLK1) is a crucial regulator of cell cycle progression. It is established that the activation of PLK1 depends on the coordinated action of Aurora-A and Bora. Nevertheless, very little is known about the spatiotemporal regulation of PLK1 during G2, specifically, the mechanisms that keep cytoplasmic PLK1 inactive until shortly before mitosis onset. Here, we describe PLK1 dimerization as a new mechanism that controls PLK1 activation. During the early G2 phase, Bora supports transient PLK1 dimerization, thus fine-tuning the timely regulated activation of PLK1 and modulating its nuclear entry. At late G2, the phosphorylation of T210 by Aurora-A triggers dimer dissociation and generates active PLK1 monomers that support entry into mitosis. Interfering with this critical PLK1 dimer/monomer switch prevents the association of PLK1 with importins, limiting its nuclear shuttling, and causes nuclear PLK1 mislocalization during the G2-M transition. Our results suggest a novel conformational space for the design of a new generation of PLK1 inhibitors. Nature Publishing Group UK 2021-11-10 2022 /pmc/articles/PMC8755526/ /pubmed/34759346 http://dx.doi.org/10.1038/s41388-021-02094-9 Text en © The Author(s) 2021, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Raab, Monika Matthess, Yves Raab, Christopher A. Gutfreund, Niklas Dötsch, Volker Becker, Sven Sanhaji, Mourad Strebhardt, Klaus A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 |
title | A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 |
title_full | A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 |
title_fullStr | A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 |
title_full_unstemmed | A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 |
title_short | A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1 |
title_sort | dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of plk1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755526/ https://www.ncbi.nlm.nih.gov/pubmed/34759346 http://dx.doi.org/10.1038/s41388-021-02094-9 |
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