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O-GlcNAcylation of MEK2 promotes the proliferation and migration of breast cancer cells.

Authors
  • Xu, Yaoyao1
  • Sheng, Xiangying1, 2
  • Zhao, Ting1
  • Zhang, Lei1
  • Ruan, Yuanyuan3, 4
  • Lu, Haojie1, 2, 3
  • 1 Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. , (China)
  • 2 Department of Chemistry, Fudan University, Shanghai 200433, China. , (China)
  • 3 NHC Key Laboratory of Glycoconjugates Research, Fudan University, Shanghai 200032, China. , (China)
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. , (China)
Type
Published Article
Journal
Glycobiology
Publisher
Oxford University Press
Publication Date
Jun 03, 2021
Volume
31
Issue
5
Pages
571–581
Identifiers
DOI: 10.1093/glycob/cwaa103
PMID: 33226073
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Mitogen-activated protein kinase kinases are an important part of evolutionary conserved signaling modules that are involved in a variety of cellular processes in response to environmental stimuli. Among them, mitogen-activated protein kinase kinase 2 (MEK2) is the most crucial upstream signaling pathway of ERK1/2 cascade as a therapeutic target for overcoming Ras-driven cancers. However, the mechanisms of MEK2 regulation during tumor progression remain not fully elucidated. Herein, we identified that MEK2 was post-translationally regulated by O-GlcNAcylation. We found that MEK2 associated with OGT and was modified by O-GlcNAc. Mass spectrometry analysis further verified that O-GlcNAcylation of MEK2 occurred at Thr13, which was in the docking domain for specifically identifying its target proteins. While total O-GlcNAcylation stimulated the protein stability and phosphorylation of MEK2, Thr13 O-GlcNAcylation of MEK2 specifically enhanced its Thr394 phosphorylation as well as downstream ERK1/2 activation. Genetic ablation of MEK2 O-GlcNAcylation at Thr13 abrogated its ability to promote the proliferation and migration of breast cancer cells. Together, our data demonstrate that O-GlcNAcylation of MEK2 might be a key regulatory mechanism during tumorigenesis and is a potential therapeutic target for tumor treatment. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]

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