Jiménez-Izquierdo, RafaelMorrugares, RosarioSuanes-Cobos, LucíaCorrea-Sáez, AlejandroGarrido-Rodríguez, MartínCerero-Tejero, LauraKhan, Omar M.Luna, Susana de laSancho, RocíoCalzado, Marco A.2023-06-072023-06-072023Jiménez-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/s41419-023-05724-02041-4889http://hdl.handle.net/10230/57085FBXW7 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41419-023-05724-0Cell signallingKinasesMechanisms of diseasePost-translational modificationsTumour-suppressor proteinsinfo:eu-repo/semantics/openAccess