Wilms Tumor Suppressor WTX Negatively Regulates WNT/ß-Catenin Signaling

University of Toronto, Toronto, Ontario, Canada
Science (Impact Factor: 33.61). 06/2007; 316(5827):1043-6. DOI: 10.1126/science/1141515
Source: 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.

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    • "Differences aside, these results suggest a model where greater cadherin-mediated adhesion, as seen most in sedentary cells, disfavors canonical Wnt signaling by enhancing destruction complex activity (Fig. 2A). This model is consistent with earlier work demonstrating that less adhesive, motile cells display increased Wnt-reporter activity in Zebrafish embryos (Dorsky, Sheldahl, & Moon, 2002), as well as the more recent identification of a novel membrane-proximal inhibitor of β-catenin signaling, WTX/Amer1 (Major et al., 2007), which can impact the activity of the phosphodestruction complex (Tanneberger et al., 2011). An appealing feature of this model is that the activity of the β-catenin phosphodestruction complex can be " tuned " by the local adhesive environment, despite a uniform presence of Wnt ligand, which may be relevant to cell fate decisions that occur in various developmental contexts. "
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    ABSTRACT: The arrival of multicellularity in evolution facilitated cell-cell signaling in conjunction with adhesion. As the ectodomains of cadherins interact with each other directly in trans (as well as in cis), spanning the plasma membrane and associating with multiple other entities, cadherins enable the transduction of "outside-in" or "inside-out" signals. We focus this review on signals that originate from the larger family of cadherins that are inwardly directed to the nucleus, and thus have roles in gene control or nuclear structure-function. The nature of cadherin complexes varies considerably depending on the type of cadherin and its context, and we will address some of these variables for classical cadherins versus other family members. Substantial but still fragmentary progress has been made in understanding the signaling mediators used by varied cadherin complexes to coordinate the state of cell-cell adhesion with gene expression. Evidence that cadherin intracellular binding partners also localize to the nucleus is a major point of interest. In some models, catenins show reduced binding to cadherin cytoplasmic tails favoring their engagement in gene control. When bound, cadherins may serve as stoichiometric competitors of nuclear signals. Cadherins also directly or indirectly affect numerous signaling pathways (e.g., Wnt, receptor tyrosine kinase, Hippo, NFκB, and JAK/STAT), enabling cell-cell contacts to touch upon multiple biological outcomes in embryonic development and tissue homeostasis. © 2015 Elsevier Inc. All rights reserved.
    Current Topics in Developmental Biology 03/2015; 112:129-96. DOI:10.1016/bs.ctdb.2014.11.018 · 4.68 Impact Factor
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    • "Some reports couple WTX function to the genes directly involved in the control of nephron progenitors (which is discussed in more detail below). It was shown to modulate Wt1 activity (Rivera et al. 2009) and negatively regulates b-catenin being part of the degradation complex (Major et al. 2007). Wtx knockout mice are perinatal lethal with phenotypes in multiple tissues of mesodermal origin (Moisan et al. 2011), consistent with the germline mutations found in sclerosing skeletal dysplasia (Jenkins et al. 2009). "
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    ABSTRACT: Wilms' tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms' tumor in the context of renal development. Many of the genes implicated in Wilms' tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general-and specific miRNAs in particular-in normal kidney development that still await further analysis. The recent identification of Wilms' tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions. © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 03/2015; 29(5):467-482. DOI:10.1101/gad.256396.114 · 10.80 Impact Factor
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    • "Given its location on the X chromosome, " one hit " somatic mutations involving either the single X chromosome in males or the active X chromosome in females can lead to inactivation of WTX (Rivera et al., 2007). Functional studies point to a role for WTX in the Wnt signaling pathway and in modulating the activity of two tumor suppressors implicated in Wilms tumors: WT1 and TP53 (Major et al., 2007; Rivera et al., 2007; Kim et al., 2012). WTX can also regulate NRF2 degradation (Camp et al., 2012). "
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    ABSTRACT: WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 01/2014; 53(1):67-77. DOI:10.1002/gcc.22118 · 4.04 Impact Factor
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