Wilms tumor suppressor WTX negatively regulates WNT/beta-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 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.