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The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.

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.

Pubmed ID: 16547521


  • Angers S
  • Thorpe CJ
  • Biechele TL
  • Goldenberg SJ
  • Zheng N
  • MacCoss MJ
  • Moon RT


Nature cell biology

Publication Data

April 11, 2006

Associated Grants

  • Agency: NCRR NIH HHS, Id: P41 RR011823

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Blotting, Western
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Chromatography, Affinity
  • Cullin Proteins
  • Embryo, Nonmammalian
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Kidney
  • Microscopy, Fluorescence
  • Phosphoproteins
  • Signal Transduction
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Wnt Proteins
  • Xenopus Proteins
  • Xenopus laevis
  • Zebrafish
  • Zebrafish Proteins
  • beta Catenin