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Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.

Aberrant WNT signal transduction is involved in many diseases. In colorectal cancer and melanoma, mutational disruption of proteins involved in the degradation of beta-catenin, the key effector of the WNT signaling pathway, results in stabilization of beta-catenin and, in turn, activation of transcription. We have used tandem-affinity protein purification and mass spectrometry to define the protein interaction network of the beta-catenin destruction complex. This assay revealed that WTX, a protein encoded by a gene mutated in Wilms tumors, forms a complex with beta-catenin, AXIN1, beta-TrCP2 (beta-transducin repeat-containing protein 2), and APC (adenomatous polyposis coli). Functional analyses in cultured cells, Xenopus, and zebrafish demonstrate that WTX promotes beta-catenin ubiquitination and degradation, which antagonize WNT/beta-catenin signaling. These data provide a possible mechanistic explanation for the tumor suppressor activity of WTX.

Pubmed ID: 17510365

Authors

  • Major MB
  • Camp ND
  • Berndt JD
  • Yi X
  • Goldenberg SJ
  • Hubbert C
  • Biechele TL
  • Gingras AC
  • Zheng N
  • Maccoss MJ
  • Angers S
  • Moon RT

Journal

Science (New York, N.Y.)

Publication Data

May 18, 2007

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • Animals
  • Axin Protein
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus
  • Cytoplasm
  • Genes, Wilms Tumor
  • Humans
  • Kidney Neoplasms
  • Protein Binding
  • Protein Interaction Mapping
  • Proteomics
  • RNA Interference
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Signal Transduction
  • Transduction, Genetic
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Wilms Tumor
  • Wnt Proteins
  • Xenopus Proteins
  • Zebrafish
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins