Publication Date:
2007-05-19
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- New York, N.Y. -- Science. 2007 May 18;316(5827):1043-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17510365" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing
;
Adenomatous Polyposis Coli Protein/metabolism
;
Animals
;
Axin Protein
;
Cell Line
;
Cell Line, Tumor
;
Cell Nucleus/metabolism
;
Cytoplasm/metabolism
;
Genes, Wilms Tumor
;
Humans
;
Kidney Neoplasms/genetics
;
Protein Binding
;
Protein Interaction Mapping
;
Proteomics
;
RNA Interference
;
Recombinant Fusion Proteins/metabolism
;
Repressor Proteins/metabolism
;
*Signal Transduction
;
Transduction, Genetic
;
Tumor Suppressor Proteins/chemistry/genetics/*metabolism
;
Ubiquitin/metabolism
;
Ubiquitin-Protein Ligases/metabolism
;
Wilms Tumor/genetics
;
Wnt Proteins/*metabolism
;
Xenopus Proteins
;
Zebrafish
;
beta Catenin/*metabolism
;
beta-Transducin Repeat-Containing Proteins/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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