2. Academic Validation
  3. Neddylation is essential for β-catenin degradation in Wnt signaling pathway

Neddylation is essential for β-catenin degradation in Wnt signaling pathway

  • Cell Rep. 2022 Mar 22;38(12):110538. doi: 10.1016/j.celrep.2022.110538.
Bojun Wang 1,  Tiantian Wang 1,  Huimin Zhu 1,  Rong Yan 1,  Xinru Li 1,  Chengqian Zhang 2,  Wanyu Tao 2,  Xisong Ke 3,  Piliang Hao 4,  Yi Qu 5
Affiliations

Affiliations

  • 1 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200, Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 3 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200, Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: xisongke@shutcm.edu.cn.
  • 4 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Electronic address: haopl@shanghaitech.edu.cn.
  • 5 Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, No.1200, Cailun Road, Shanghai 201203, P.R. China; Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: yiqu@shutcm.edu.cn.
PMID: 35320710 DOI: 10.1016/j.celrep.2022.110538
Abstract

β-catenin is a central component in the Wnt signaling pathway; its degradation has been tightly connected to ubiquitylation, but it is rarely examined by loss-of-function assays. Here we observe that endogenous β-catenin is not stabilized upon ubiquitylation depletion by a ubiquitylation inhibitor, TAK-243. We demonstrate that N-terminal phosphorylated β-catenin is quickly and strongly stabilized by a specific neddylation inhibitor, MLN4924, in all examined cell types, and that β-catenin and TCF4 interaction is strongly enhanced by inhibition of neddylation but not ubiquitylation. We also confirm that the E3 ligase β-TrCP2, but not β-TrCP1, is associated with neddylation and destruction of β-catenin. GSK3β and adenomatous polyposis coli (APC) are not required for β-catenin neddylation but essential for its subsequent degradation. Our findings not only clarify the process of β-catenin modification and degradation in the Wnt signaling pathway but also highlight the importance of reassessing previously identified ubiquitylation substrates.

Keywords

CP; CP: Molecular Biology; Molecular Biology; Wnt signaling pathway; neddylation; stabilization; ubiquitylation; β-TrCP2; β-catenin.

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