2. Academic Validation
  3. Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7-mediated Vangl ubiquitination and endoplasmic reticulum-associated degradation

Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7-mediated Vangl ubiquitination and endoplasmic reticulum-associated degradation

  • Sci Adv. 2021 May 14;7(20):eabg2099. doi: 10.1126/sciadv.abg2099.
Di Feng 1 2,  Jin Wang 1 2,  Wei Yang 1 2,  Jingyu Li 3,  Xiaochen Lin 1,  Fangzi Zha 1,  Xiaolu Wang 1,  Luyao Ma 1,  Nga Ting Choi 1 2,  Yusuke Mii 4 5,  Shinji Takada 4,  Michael S Y Huen 1,  Yusong Guo 6,  Liang Zhang 3,  Bo Gao 7 2
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 2 The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China.
  • 3 Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong SAR, China.
  • 4 Exploratory Research Center on Life and Living Systems (ExCELLS) and National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Japan.
  • 5 Japan Science and Technology Agency, PRESTO, Kawaguchi, Japan.
  • 6 Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR, China.
  • 7 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. gaobo@hku.hk.
PMID: 33990333 DOI: 10.1126/sciadv.abg2099
Abstract

The four-pass transmembrane proteins Vangl1 and Vangl2 are dedicated core components of Wnt/planar cell polarity (Wnt/PCP) signaling that critically regulate polarized cell behaviors in many morphological and physiological processes. Here, we found that the abundance of Vangl proteins is tightly controlled by the ubiquitin-proteasome system through endoplasmic reticulum-associated degradation (ERAD). The key ERAD component p97/VCP directly binds to Vangl at a highly conserved VCP-interacting motif and recruits the E3 Ligase KBTBD7 via its UBA-UBX adaptors to promote Vangl ubiquitination and ERAD. We found that Wnt5a/CK1 prevents Vangl ubiquitination and ERAD by inducing Vangl phosphorylation, which facilitates Vangl export from the ER to the plasma membrane. We also provide in vivo evidence that KBTBD7 regulates convergent extension during zebrafish gastrulation and functions as a tumor suppressor in breast Cancer by promoting Vangl degradation. Our findings reveal a previously unknown regulatory mechanism of Wnt/PCP signaling through the p97/VCP-KBTBD7-mediated ERAD pathway.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12861
    99.90%, p97 AAA ATPase/VCP抑制剂
    p97
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