FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2

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  • dc.contributor.author Jiménez-Izquierdo, Rafael
  • dc.contributor.author Morrugares, Rosario
  • dc.contributor.author Suanes-Cobos, Lucía
  • dc.contributor.author Correa-Sáez, Alejandro
  • dc.contributor.author Garrido-Rodríguez, Martín
  • dc.contributor.author Cerero-Tejero, Laura
  • dc.contributor.author Khan, Omar M.
  • dc.contributor.author Luna, Susana de la
  • dc.contributor.author Sancho, Rocío
  • dc.contributor.author Calzado, Marco A.
  • dc.date.accessioned 2023-06-07T06:14:56Z
  • dc.date.available 2023-06-07T06:14:56Z
  • dc.date.issued 2023
  • dc.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.
  • dc.description.sponsorship This work was funded by the Spanish Ministerio de Ciencia e Innovación (MICINN, PID2021-124314OB-I00 to MAC and PID2019-107185GB-I00 to SdlL), Junta de Andalucía-Consejería de Conocimiento, Investigación y Universidad (P20_00470 to MAC) and University of Cordoba (1380920-R to MAC) grants. ACS and LCS were supported by an FPU fellowship (FPU18/ 00845 and FPU20/02699, respectively) from the Spanish Ministerio de Educación y Formación Profesional.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Jiménez-Izquierdo R, Morrugares R, Suanes-Cobos L, Correa-Sáez A, Garrido-Rodríguez M, Cerero-Tejero L, et al. FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2. Cell Death Dis. 2023 Mar 18;14(3):202. DOI: 10.1038/s41419-023-05724-0
  • dc.identifier.doi http://dx.doi.org/10.1038/s41419-023-05724-0
  • dc.identifier.issn 2041-4889
  • dc.identifier.uri http://hdl.handle.net/10230/57085
  • dc.language.iso eng
  • dc.publisher Springer
  • dc.relation.ispartof Cell Death Dis. 2023 Mar 18;14(3):202
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-124314OB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-107185GB-I00
  • dc.rights © The Author(s) 2023. 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/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cell signalling
  • dc.subject.keyword Kinases
  • dc.subject.keyword Mechanisms of disease
  • dc.subject.keyword Post-translational modifications
  • dc.subject.keyword Tumour-suppressor proteins
  • dc.title FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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