FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2.
Humans
Cell Cycle Proteins
/ metabolism
F-Box-WD Repeat-Containing Protein 7
/ genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Proteasome Endopeptidase Complex
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Protein-Tyrosine Kinases
/ genetics
Dyrk Kinases
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
18 03 2023
18 03 2023
Historique:
received:
06
07
2022
accepted:
03
03
2023
revised:
28
02
2023
entrez:
19
3
2023
pubmed:
20
3
2023
medline:
22
3
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36934104
doi: 10.1038/s41419-023-05724-0
pii: 10.1038/s41419-023-05724-0
pmc: PMC10024693
doi:
Substances chimiques
Cell Cycle Proteins
0
F-Box-WD Repeat-Containing Protein 7
0
FBXW7 protein, human
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Ubiquitin-Protein Ligases
EC 2.3.2.27
Protein Serine-Threonine Kinases
EC 2.7.11.1
Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
202Informations de copyright
© 2023. The Author(s).
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