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.
Pubmed ID: 17510365 RIS Download
Adaptor Proteins, Signal Transducing | Adenomatous Polyposis Coli Protein | Animals | Axin Protein | Cell Line | Cell Line, Tumor | Cell Nucleus | Cytoplasm | Genes, Wilms Tumor | Humans | Kidney Neoplasms | Protein Binding | Protein Interaction Mapping | Proteomics | RNA Interference | Recombinant Fusion Proteins | Repressor Proteins | Signal Transduction | Transduction, Genetic | Tumor Suppressor Proteins | Ubiquitin | Ubiquitin-Protein Ligases | Wilms Tumor | Wnt Proteins | Xenopus Proteins | Zebrafish | beta Catenin | beta-Transducin Repeat-Containing Proteins