FBXW7是F-box蛋白家族的成员，它作为SCF E3泛素连接酶的底物识别组分发挥作用。由于其能够控制c-Jun、c-Myc、Cyclin E1、mTOR和Notch1-IC等几种癌基因蛋白的蛋白酶体介导降解，因此FBXW7是主要的肿瘤抑制因子。FBXW7在人类癌症中的失活是由某个体突变或其蛋白水平的下调引起的。这项工作描述了一种新的FBXW7调节机制，该机制依赖于丝氨酸/苏氨酸蛋白激酶DYRK2。我们展示了DYRK2与FBXW7相互作用并磷酸化FBXW7，导致其经蛋白酶体介导降解。DYRK2依赖的FBXW7不稳定性独立于其泛素连接酶活性。功能分析证明了DYRK2依赖的调节机制的存在，用于重要的FBXW7底物。最后，我们提供证据表明，DYRK2依赖的FBXW7蛋白积累调节贡献于对多柔比星或紫杉醇等化疗药剂在结肠癌细胞系和BET抑制剂在T细胞急性淋巴细胞白血病细胞系中产生的细胞毒性效应。总的来说，这项工作揭示了一种新的调节轴DYRK2/FBXW7，这有助于我们理解这两种蛋白在肿瘤进展和DNA损伤应答中的作用。© 2023. 作者（们）。

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.© 2023. The Author(s).