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Published on: June 17, 2014

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

Michael B Major1, Nathan D Camp, Jason D Berndt

  • 1Howard Hughes Medical Institute, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.

Science (New York, N.Y.)
|May 19, 2007
PubMed

Insights

WTX protein interacts with the beta-catenin destruction complex, promoting beta-catenin ubiquitination and degradation. This action antagonizes WNT/beta-catenin signaling, explaining WTX’s tumor suppressor activity in diseases like colorectal cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Aberrant WNT signal transduction is implicated in various diseases, including colorectal cancer and melanoma.
  • Mutations in the beta-catenin degradation complex lead to its stabilization and activation of transcription, driving tumorigenesis.

Purpose of the Study:

  • To define the protein interaction network of the beta-catenin destruction complex.
  • To investigate the role of WTX protein in WNT/beta-catenin signaling.

Main Methods:

  • Tandem-affinity protein purification and mass spectrometry were employed to identify protein interactions.
  • Functional analyses were conducted in cultured cells, Xenopus, and zebrafish.

Main Results:

  • WTX (a gene mutated in Wilms tumors) was found to form a complex with beta-catenin, AXIN1, beta-transducin repeat-containing protein 2 (beta-TrCP2), and adenomatous polyposis coli (APC).
  • WTX was demonstrated to promote beta-catenin ubiquitination and degradation.
  • WTX antagonizes WNT/beta-catenin signaling.

Conclusions:

  • WTX functions as a negative regulator of WNT/beta-catenin signaling by promoting beta-catenin degradation.
  • These findings offer a mechanistic explanation for the tumor suppressor role of WTX.

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