FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2
Abstract FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05724-0 |
| _version_ | 1797863414435938304 |
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| author | Rafael Jiménez-Izquierdo Rosario Morrugares Lucía Suanes-Cobos Alejandro Correa-Sáez Martín Garrido-Rodríguez Laura Cerero-Tejero Omar M. Khan Susana de la Luna Rocío Sancho Marco A. Calzado |
| author_facet | Rafael Jiménez-Izquierdo Rosario Morrugares Lucía Suanes-Cobos Alejandro Correa-Sáez Martín Garrido-Rodríguez Laura Cerero-Tejero Omar M. Khan Susana de la Luna Rocío Sancho Marco A. Calzado |
| author_sort | Rafael Jiménez-Izquierdo |
| collection | DOAJ |
| description | Abstract FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses. |
| first_indexed | 2024-04-09T22:35:13Z |
| format | Article |
| id | doaj.art-9aee63207e8647eaa6ccbe6db4bdeada |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T22:35:13Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9aee63207e8647eaa6ccbe6db4bdeada2023-03-22T12:32:04ZengNature Publishing GroupCell Death and Disease2041-48892023-03-0114311410.1038/s41419-023-05724-0FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2Rafael Jiménez-Izquierdo0Rosario Morrugares1Lucía Suanes-Cobos2Alejandro Correa-Sáez3Martín Garrido-Rodríguez4Laura Cerero-Tejero5Omar M. Khan6Susana de la Luna7Rocío Sancho8Marco A. Calzado9Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Hamad Bin Khalifa University, College of Health and Life Sciences Qatar Foundation, Education CityCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)Centre for Stem Cells and Regenerative Medicine, King’s College LondonInstituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)Abstract FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.https://doi.org/10.1038/s41419-023-05724-0 |
| spellingShingle | Rafael Jiménez-Izquierdo Rosario Morrugares Lucía Suanes-Cobos Alejandro Correa-Sáez Martín Garrido-Rodríguez Laura Cerero-Tejero Omar M. Khan Susana de la Luna Rocío Sancho Marco A. Calzado FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 Cell Death and Disease |
| title | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_full | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_fullStr | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_full_unstemmed | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_short | FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2 |
| title_sort | fbxw7 tumor suppressor regulation by dualspecificity tyrosine regulated kinase 2 |
| url | https://doi.org/10.1038/s41419-023-05724-0 |
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