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

• Published in: Science (American Association for the Advancement of Science) Vol. 316; no. 5827; pp. 1043 - 1046
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: 18.05.2007
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science/1141515

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.