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Science 18 May 2007:
Vol. 316. no. 5827, pp. 1043 - 1046
DOI: 10.1126/science/1141515
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Reports

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*

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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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity.
M. N. Rivera, W. J. Kim, J. Wells, A. Stone, A. Burger, E. J. Coffman, J. Zhang, and D. A. Haber (2009)
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Wnt/{beta}-Catenin Signaling Promotes Renal Interstitial Fibrosis.
W. He, C. Dai, Y. Li, G. Zeng, S. P. Monga, and Y. Liu (2009)
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Activated Wnt/ss-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model.
A. J. Chien, E. C. Moore, A. S. Lonsdorf, R. M. Kulikauskas, B. G. Rothberg, A. J. Berger, M. B. Major, S. T. Hwang, D. L. Rimm, and R. T. Moon (2009)
PNAS 106, 1193-1198
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Perilobar Nephrogenic Rests Are Nonobligate Molecular Genetic Precursor Lesions of Insulin-Like Growth Factor-II-Associated Wilms Tumors.
R. Vuononvirta, N. J. Sebire, A. R. Dallosso, J. S. Reis-Filho, R. D. Williams, A. Mackay, K. Fenwick, A. Grigoriadis, A. Ashworth, K. Pritchard-Jones, et al. (2008)
Clin. Cancer Res. 14, 7635-7644
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New Regulators of Wnt/{beta}-Catenin Signaling Revealed by Integrative Molecular Screening.
M. B. Major, B. S. Roberts, J. D. Berndt, S. Marine, J. Anastas, N. Chung, M. Ferrer, X. Yi, C. L. Stoick-Cooper, P. D. von Haller, et al. (2008)
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LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of {beta}-catenin.
C. S. Cselenyi, K. K. Jernigan, E. Tahinci, C. A. Thorne, L. A. Lee, and E. Lee (2008)
PNAS 105, 8032-8037
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WTX is rarely mutated in acute myeloid leukemia.
C. Owen, P. Virappane, M. Alikian, I. Stasevich, K. Summers, D. Lillington, D. Bonnet, A. Burnett, K. Mills, T. A. Lister, et al. (2008)
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A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer.
K. R. Blish, W. Wang, M. C. Willingham, W. Du, C. E. Birse, S. R. Krishnan, J. C. Brown, G. A. Hawkins, A. J. Garvin, R. B. D'Agostino Jr., et al. (2008)
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AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane.
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J. Cell Sci. 120, 3738-3747
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WNTers in La Jolla.
S. Y. Sokol and K. A. Wharton Jr (2007)
Development 134, 3393-3399
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