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

Nat Cell Biol. 2006 Apr;8(4):348-57. doi: 10.1038/ncb1381. Epub 2006 Mar 19.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Blotting, Western
  • Carrier Proteins / physiology*
  • Cell Cycle Proteins / physiology*
  • Cell Line
  • Chromatography, Affinity
  • Cullin Proteins / physiology*
  • Dishevelled Proteins
  • Embryo, Nonmammalian / metabolism
  • Fluorescent Antibody Technique, Indirect
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kidney / cytology
  • Microscopy, Fluorescence
  • Phosphoproteins / metabolism*
  • Signal Transduction*
  • Ubiquitin
  • Ubiquitin-Protein Ligases / physiology*
  • Wnt Proteins / metabolism*
  • Xenopus Proteins / physiology*
  • Xenopus laevis / embryology
  • Zebrafish / embryology
  • Zebrafish Proteins / physiology*
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • CUL3 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cullin Proteins
  • Dishevelled Proteins
  • Intracellular Signaling Peptides and Proteins
  • KLHL12 protein, Xenopus
  • KLHL12 protein, zebrafish
  • Phosphoproteins
  • Ubiquitin
  • Wnt Proteins
  • Xenopus Proteins
  • Zebrafish Proteins
  • beta Catenin
  • Ubiquitin-Protein Ligases