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Updated: Aug 6, 2025
Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
Published on: May 10, 2022
FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2
Rafael Jiménez-Izquierdo1,2,3, Rosario Morrugares1,2,3, Lucía Suanes-Cobos1,2,3
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
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.
Insights
The serine/threonine protein kinase DYRK2 targets the tumor suppressor FBXW7 (F-box and WD repeat domain-containing 7) for degradation, impacting cancer progression and chemotherapy response.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- FBXW7 (F-box and WD repeat domain-containing 7) is a crucial tumor suppressor regulating oncoprotein degradation.
- FBXW7 inactivation via mutation or downregulation is common in human cancers.
- Understanding FBXW7 regulation is vital for cancer therapy.
Purpose of the Study:
- To elucidate a novel regulatory mechanism controlling FBXW7 protein levels.
- To investigate the role of serine/threonine protein kinase DYRK2 in FBXW7 regulation.
- To explore the implications of the DYRK2/FBXW7 axis in cancer and DNA damage responses.
Main Methods:
- Co-immunoprecipitation to assess protein interactions.
- Western blotting to evaluate protein levels and phosphorylation.
- Cell-based assays to determine functional consequences in cancer cell lines.
Main Results:
- DYRK2 directly interacts with and phosphorylates FBXW7.
- DYRK2 promotes proteasomal degradation of FBXW7, independent of its ligase activity.
- DYRK2 regulates key FBXW7 substrates and influences cellular responses to chemotherapy and BET inhibitors.
Conclusions:
- A novel DYRK2/FBXW7 regulatory axis is identified, impacting tumor suppressor function.
- DYRK2-mediated FBXW7 degradation influences sensitivity to chemotherapy and BET inhibitors.
- This axis offers potential therapeutic targets for colorectal and T-cell acute lymphoblastic leukemia.
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