The KLHL12–Cullin-3 ubiquitin ligase negatively regulates the Wnt–β-catenin pathway by targeting Dishevelled for degradation
Abstract
Dishevelled is a conserved protein that interprets signals received by Frizzled receptors. Using a tandem-affinity purification strategy and mass spectrometry we have identified proteins associated with Dishevelled, including a Cullin-3 ubiquitin ligase complex containing the Broad Complex, Tramtrack and Bric à Brac (BTB) protein Kelch-like 12 (KLHL12). This E3 ubiquitin ligase complex is recruited to Dishevelled in a Wnt-dependent manner that promotes its poly-ubiquitination and degradation. Functional analyses demonstrate that regulation of Dishevelled by this ubiquitin ligase antagonizes the Wnt-beta-catenin pathway in cultured cells, as well as in Xenopus and zebrafish embryos. Considered with evidence that the distinct Cullin-1 based SCF(beta-TrCP)complex regulates beta-catenin stability, our data on the stability of Dishevelled demonstrates that two distinct ubiquitin ligase complexes regulate the Wnt-beta-catenin pathway.
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KLHL12 can induce degradative polyubiquitylation of dishevelled.
“KLHL12 can induce degradative polyubiquitylation of dishevelled 89”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [89]
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References 48 · Cited by 364
- Authors
- Angers, S., Thorpe, C. J., Biechele, T. L., Goldenberg, S. J., Zheng, N., MacCoss, M. J., & Moon, R. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- Corresponding author
- Moon, Randall T.
- Venue
- Nature Cell Biology
- Published
- 2006-03-19
- Volume
- 8
- Issue
- 4
- Pages
- 348-357
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1495670272
- Cited by
- 364
- References
- 48
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 13 · 2020: 28 · 2019: 19 · 2018: 16 · 2017: 11 · 2016: 14 · 2015: 12 · 2014: 22 · 2013: 30 · 2012: 28
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (P41RR011823)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- CUL3, E3 ubiquitin ligase, Dishevelled, Wnt/β-catenin signaling, protein degradation, polyubiquitination, Frizzled receptors, protein stability, Xenopus embryo, zebrafish embryos
- MeSH terms
- Dishevelled Proteins, Animals, Carrier Proteins, Cell Line, Chromatography, Affinity, Embryo, Nonmammalian, Humans, Kidney, Microscopy, Fluorescence, Phosphoproteins, Xenopus laevis, Zebrafish, Blotting, Western, Signal Transduction, Cell Cycle Proteins, Fluorescent Antibody Technique, Indirect, Ubiquitin, Xenopus Proteins, Zebrafish Proteins, Ubiquitin-Protein Ligases, Cullin Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Wnt Proteins, beta Catenin
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