Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling by Major Michael B, Camp Nathan D, Berndt Jason D, Yi Xianhua, Goldenberg Seth J, Hubbert Charlotte, Biechele Travis L, Gingras Anne-Claude, Zheng Ning, Maccoss Michael J, Angers Stephane, Moon Randall T in Science (New York, N.Y.) (2007). PubMed

Abstract

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.

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