-Catenin (CTNNB1) in the Mouse Uterus During Decidualization and the Potential Role of Two Pathways in Regulating Its Degradation (original) (raw)
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Journal of Biological Chemistry, 2001
Duplin binds to -catenin and inhibits the Wnt signaling pathway, thereby leading to repression of the -catenin-mediated transactivation and Xenopus axis formation. To find an additional function of Duplin, yeast two-hybrid screening was carried out. Importin ␣ was isolated as a binding protein of Duplin. Importin ␣ bound directly to basic amino acid clusters of Duplin. Although Duplin was present in the nucleus, deletion of the basic amino acid clusters (Duplin ⌬500-584) retained Duplin in the cytoplasm. Duplin ⌬500-584 bound to -catenin as efficiently as wild-type Duplin, but it neither repressed Wntdependent Tcf transcriptional activation in mammalian cells nor showed ventralization in Xenopus embryos. The Duplin mutant without a -catenin-binding region lost the ability to inhibit the Wnt-dependent Tcf activation, but retained its ventralizing activity. Furthermore, Duplin not only suppressed -catenin-dependent axis duplication and expression of siamois, a Wnt-regulated gene, but also inhibited siamois-dependent axis duplication. These results indicate that Duplin is translocated to the nucleus by interacting with importin ␣, and that nuclear localization is essential for the function of Duplin. Moreover, Duplin has an additional activity of inhibiting the Wnt signaling pathway by affecting the downstream -catenin target genes. Wnt proteins constitute a large family of cysteine-rich secreted ligands that control development in organisms ranging from nematode worms to mammals (1). The intracellular signaling pathway of Wnt is also conserved evolutionally and regulates cellular proliferation, morphology, motility, and fate, axis formation, and organ development (1-6). In the current model, the serine/threonine kinase GSK-3 1 targets cytoplas
Developmental Biology, 2007
Wnt signaling is essential for the regulation of cell polarity and cell fate in the early embryogenesis of many animal species. Multiple Wnt genes and its pathway members are expressed in the mouse early embryo, raising the question whether they play any roles in preimplantation development. Dishevelled is an important transducer of divergent Wnt pathways. Here we show that three of the mouse Dishevelled proteins are not only expressed in oocytes and during preimplantation development, but also display distinct spatio-temporal localization. Interestingly, as embryos reach blastocyst stage, Dishevelled 2 becomes increasingly associated with cell membrane in trophectoderm cells, while at E4.5, Dishevelled 3 is highly enriched in the cytoplasm of ICM cells. These changes are coincident with an increase in the active form of β-catenin, p120catenin transcription and decrease of Kaiso expression, indicating an upregulation of Wnt signaling activity before implantation. When Dishevelled-GFP fusion proteins are overexpressed in single blastomeres of the 4-cell stage embryo, the progeny of this cell show reduction in cell adhesiveness and a rounded shape at the blastocyst stage. This suggests that perturbing Dvl function interferes with cell-cell adhesion through the non-canonical Wnt pathway in blastocysts.
Distinct molecular forms of -catenin are targeted to adhesive or transcriptional complexes
Journal of Cell Biology - J CELL BIOL, 2004
Catenin plays essential roles in both cell-cell adhesion and Wnt signal transduction, but what precisely controls  -catenin targeting to cadherin adhesive complexes, or T-cell factor (TCF)-transcriptional complexes is less well understood. We show that during Wnt signaling, a form of  -catenin is generated that binds TCF but not the cadherin cytoplasmic domain. The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of  -catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism. Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer  of regulation. In contrast, the main cadherin-binding form of  -catenin is a  -catenin-␣ -catenin dimer, indicating that there is a distinct molecular form of  -catenin that can interact with both the cadherin and ␣ -catenin. We propose that participation of  -catenin in adhesion or Wnt signaling is dictated by the regulation of distinct molecular forms of  -catenin with different binding properties, rather than simple competition between cadherins and TCFs for a single constitutive form. This model explains how cells can control whether  -catenin is used independently in cell adhesion and nuclear signaling, or competitively so that the two processes are coordinated and interrelated.
Essential role of BCL9-2 in the switch between β-catenin's adhesive and transcriptional functions
Genes & Development, 2004
β-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the β-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases β-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates β-catenin from the nucleus to the cell membrane. The switch between β-catenin's adhesive and transcriptional functions is modulated by phosphorylation of Tyr 142 of β-catenin, which favors BCL9-2 binding and precludes interaction with α-catenin. During zebrafish embryogenesis, BCL9-2 acts in the Wnt8-signaling pathway and regulates mesoderm patterning.
Terminal regions of β-catenin are critical for regulating its adhesion and transcription functions
Biochimica et biophysica acta, 2016
β-Catenin, the central molecule of canonical Wnt signaling pathway, has multiple binding partners and performs many roles in the cell. Apart from being a transcriptional activator, β-catenin acts as a crucial effector component of cadherin/catenin complex to physically interact with actin cytoskeleton along with α-catenin and E-cadherin for regulating cell-cell adhesion. Here, we have generated a library of β-catenin point and deletion mutants to delineate regions within β-catenin that are important for α-catenin-β-catenin interaction, nuclear localization, and transcriptional activity of β-catenin. We observed a unique mechanism for nuclear localization of β-catenin and its mutants and show that N-terminal exon-3 region and C-terminal domain of β-catenin are critical for this activity of β-catenin. Furthermore, we show HepG2 cells have high β-catenin mediated transcriptional activity due to the presence of an interstitial deletion at the N-terminal region of β-catenin. Due to this ...
Experimental Hematology, 2009
Objective. The t(1;19)(q23;13) translocation, resulting in the production of the E2A-PBX1 chimeric protein, is a common nonrandom translocation in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). The E2A-PBX1 chimeric protein activates expression of several genes, including Wnt16. In the present study, we explored the role of Wnt16 and b-catenin in t(1;19) B-ALL cells. Materials and Methods. Canonical Wnt signaling was measured by TOPflash activity. Localization of b-catenin in the cell membrane and its involvement in leukemia-stroma interaction were studied by confocal microscopy. Adhesion to N-cadherin was analyzed by adding 3 H-thymidinlabeled cells to N-cadherin-coated wells. Results. In contrast to previous reports, we detected no effects on cell viability or proliferation upon modulation of the Wnt16 levels. Moreover, despite high levels of Wnt16 and b-catenin, the cells had very low levels of canonical Wnt signaling. Instead, b-catenin was located in the cell membrane along with N-cadherin. E2A-PBX1-positive leukemia cells adhered strongly to bone marrow stroma cells, and we showed that adherence junctions stained strongly for both proteins. Moreover, knockdown of b-catenin reduced the adhesion of E2A-PBX1-positive leukemia cells to N-cadherin, suggesting that b-catenin and N-cadherin play a central role in homotypic cell-to-cell adhesion and in leukemia-stroma adhesion. Interestingly, knockdown of Wnt16 by small interfering RNA reduced the level of N-cadherin. Conclusion. Wnt16 does not activate canonical Wnt signaling in E2A-PBX1-positive cells. Instead, b-catenin is involved in N-cadherin-dependent adherence junctions, suggesting for the first time that leukemia-stroma interactions may be mediated via an N-cadherin-dependent mechanism. Ó