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 RIS Download
Adaptor Proteins, Signal Transducing | Animals | Blotting, Western | Carrier Proteins | Cell Cycle Proteins | Cell Line | Chromatography, Affinity | Cullin Proteins | Dishevelled 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