Wilms Tumor Suppressor WTX Negatively Regulates WNT/ß-Catenin Signaling
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...
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Published in | Science (American Association for the Advancement of Science) Vol. 316; no. 5827; pp. 1043 - 1046 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
18.05.2007
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Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0036-8075 1095-9203 |
DOI: | 10.1126/science/1141515 |