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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein / metabolism
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Animals
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Axin Protein
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Cell Line
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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Genes, Wilms Tumor
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Humans
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Kidney Neoplasms / genetics
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Protein Binding
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Protein Interaction Mapping
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Proteomics
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RNA Interference
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / metabolism
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Signal Transduction*
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Transduction, Genetic
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / metabolism
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Wilms Tumor / genetics
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Wnt Proteins / metabolism*
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Xenopus Proteins
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Zebrafish
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beta Catenin / metabolism*
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beta-Transducin Repeat-Containing Proteins / metabolism
Substances
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AMER1 protein, human
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AXIN1 protein, human
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein
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Axin Protein
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FBXW11 protein, human
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Recombinant Fusion Proteins
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Repressor Proteins
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Tumor Suppressor Proteins
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Ubiquitin
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Wnt Proteins
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Xenopus Proteins
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axin1 protein, Xenopus
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beta Catenin
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beta-Transducin Repeat-Containing Proteins
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Ubiquitin-Protein Ligases