Article

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

University of Toronto, Toronto, Ontario, Canada
Science (Impact Factor: 31.48). 06/2007; 316(5827):1043-6. DOI: 10.1126/science/1141515
Source: PubMed

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.

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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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    Current Topics in Developmental Biology 01/2015; 112:129-96. DOI:10.1016/bs.ctdb.2014.11.018 · 4.21 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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    • "In non-Wnt expressing cells, β-catenin is associated with E-cadherin in junctional complexes and its cytosolic concentration is kept low by a ubiquitin-proteasome system [33]. In addition to the phosphorylation of APC, which allows its binding to β-catenin, thus inhibiting its signaling activities [34], Glycogen synthase kinase-3β (GSK3β) also phosphorylates β-catenin through an axin/conductin/CK1α-dependent complex formation [35] [36] [37] [38], which is followed by phosphorylation-dependent multi-ubiquitination of βcatenin by the SCFβ-TRCP-ubiquitin ligase/APC/axin/WTX complex [39] [40] [41] and proteasome-mediated β-catenin degradation. These events are inhibited in the presence of Wnt signal, which allows the association between β-catenin and the T-cell transcription factor/lymphoid enhancer factor (Tcf/Lef-1) [33]. "
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