Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling by 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 in Science (New York, N.Y.) (2007). PubMed


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.

[ hide abstract ]

Discussed In Paper