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Science 316 (5827): 1043-1046

Copyright © 2007 by the American Association for the Advancement of Science

Wilms Tumor Suppressor WTX Negatively Regulates WNT/ß-Catenin Signaling

Michael B. Major,1,2,3 Nathan D. Camp,1,2,3 Jason D. Berndt,1,2,3 XianHua Yi,4 Seth J. Goldenberg,2 Charlotte Hubbert,1,2,3 Travis L. Biechele,1,2,3 Anne-Claude Gingras,5 Ning Zheng,2 Michael J. MacCoss,4 Stephane Angers,1,2,6 Randall T. Moon1,2,3*

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

1 Howard Hughes Medical Institute, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.
2 Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA.
3 Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
4 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
5 Samuel Lunenfeld Research Institute, 983-600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
6 Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada, M5S 3M2.

* To whom correspondence should be addressed. E-mail: rtmoon{at}u.washington.edu


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