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beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation.

http://www.ncbi.nlm.nih.gov/pubmed/10339577

Regulation of beta-catenin stability is essential for Wnt signal transduction during development and tumorigenesis. It is well known that serine-phosphorylation of beta-catenin by the Axin-glycogen synthase kinase (GSK)-3beta complex targets beta-catenin for ubiquitination-degradation, and mutations at critical phosphoserine residues stabilize beta-catenin and cause human cancers. How beta-catenin phosphorylation results in its degradation is undefined. Here we show that phosphorylated beta-catenin is specifically recognized by beta-Trcp, an F-box/WD40-repeat protein that also associates with Skp1, an essential component of the ubiquitination apparatus. beta-catenin harboring mutations at the critical phosphoserine residues escapes recognition by beta-Trcp, thus providing a molecular explanation for why these mutations cause beta-catenin accumulation that leads to cancer. Inhibition of endogenous beta-Trcp function by a dominant negative mutant stabilizes beta-catenin, activates Wnt/beta-catenin signaling, and induces axis formation in Xenopus embryos. Therefore, beta-Trcp plays a central role in recruiting phosphorylated beta-catenin for degradation and in dorsoventral patterning of the Xenopus embryo.

Pubmed ID: 10339577 RIS Download

Mesh terms: Animals | Axin Protein | Body Patterning | Cadherins | Calcium-Calmodulin-Dependent Protein Kinases | Carrier Proteins | Cytoskeletal Proteins | Embryo, Nonmammalian | GTP-Binding Proteins | Glycogen Synthase Kinase 3 | Humans | Microtubule-Associated Proteins | Phosphorylation | Proteins | Recombinant Fusion Proteins | Repressor Proteins | Signal Transduction | Trans-Activators | Transcription, Genetic | Xenopus Proteins | Xenopus laevis | beta Catenin | beta-Transducin Repeat-Containing Proteins

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01GM 57603

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