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 β-catenin, the key effector of the WNT signaling pathway, results in stabilization
of β-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 β-catenin destruction complex. This assay revealed that WTX, a protein encoded
by a gene mutated in Wilms tumors, forms a complex with β-catenin, AXIN1, β-TrCP2 (β-transducin repeat–containing protein
2), and APC (adenomatous polyposis coli). Functional analyses in cultured cells, Xenopus, and zebrafish demonstrate that WTX promotes β-catenin ubiquitination and degradation, which antagonize WNT/β-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.
    Full-text · Article · Mar 2015 · Current Topics in Developmental Biology
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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.
    Full-text · Article · Mar 2015 · Genes & Development
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    • "ylenimine ( Sigma ) ( HEK293T , U2OS cells ) or Lipofectamine 2000 ( Invitrogen ) ( SW480 cells ) . Cells were treated with Wnt3a - conditioned medium ( Willert et al . , 2003 ) at 48 h after siRNA transfection . ( 29Z , 39E ) - 6 - Bromoindirubin - 39 - oxime ( BIO ) was obtained from Sigma . TCF / b - catenin - dependent pBAR reporter activity ( Major et al . , 2007 ) was determined in HEK293T cells ."
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    ABSTRACT: Axin and conductin/axin2 are structurally related inhibitors of Wnt/β-catenin signalling that promote degradation of β-catenin. Whereas axin is constitutively expressed, conductin is a Wnt target gene implicated in negative feedback regulation. Here we show that axin and conductin differ in their functional interaction with the upstream Wnt pathway component Dvl. Conductin shows reduced binding to Dvl2 compared to axin, and degradation of β-catenin by conductin is only poorly blocked by Dvl2. We propose that insensitivity to Dvl is an important feature of conductin's role as a negative feedback regulator of Wnt signalling.
    Full-text · Article · Nov 2014 · Journal of Cell Science
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