FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2

Jiménez-Izquierdo, Rafael; Morrugares, Rosario; Suanes-Cobos, Lucía; Correa-Sáez, Alejandro; Garrido-Rodríguez, Martín; Cerero-Tejero, Laura; Khan, Omar M.; Luna, Susana de la; Sancho, Rocío; Calzado, Marco A.

doi:http://dx.doi.org/10.1038/s41419-023-05724-0

FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2

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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

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.