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

Michael B. Major, Nathan D. Camp, Jason D. Berndt, Xianhua Yi, Seth J. Goldenberg, Charlotte Hubbert, Travis L. Biechele, Anne Claude Gingras, Ning Zheng, Michael J. MacCoss, Stephane Angers, Randall T. Moon

Research output: Contribution to journalArticlepeer-review

324 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)1043-1046
Number of pages4
JournalScience
Volume316
Issue number5827
DOIs
StatePublished - May 18 2007

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