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

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

Authors

  • Liu C
  • Kato Y
  • Zhang Z
  • Do VM
  • Yankner BA
  • He X

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 25, 1999

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01GM 57603

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