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      The planar cell polarity protein VANG-1/Vangl negatively regulates Wnt/β-catenin signaling through a Dvl dependent mechanism

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          Abstract

          Van Gogh-like (Vangl) and Prickle (Pk) are core components of the non-canonical Wnt planar cell polarity pathway that controls epithelial polarity and cell migration. Studies in vertebrate model systems have suggested that Vangl and Pk may also inhibit signaling through the canonical Wnt/β-catenin pathway, but the functional significance of this potential cross-talk is unclear. In the nematode C. elegans, the Q neuroblasts and their descendants migrate in opposite directions along the anteroposterior body axis. The direction of these migrations is specified by Wnt signaling, with activation of canonical Wnt signaling driving posterior migration, and non-canonical Wnt signaling anterior migration. Here, we show that the Vangl ortholog VANG-1 influences the Wnt signaling response of the Q neuroblasts by negatively regulating canonical Wnt signaling. This inhibitory activity depends on a carboxy-terminal PDZ binding motif in VANG-1 and the Dishevelled ortholog MIG-5, but is independent of the Pk ortholog PRKL-1. Moreover, using Vangl1 and Vangl2 double mutant cells, we show that a similar mechanism acts in mammalian cells. We conclude that cross-talk between VANG-1/Vangl and the canonical Wnt pathway is an evolutionarily conserved mechanism that ensures robust specification of Wnt signaling responses.

          Author summary

          Wnt proteins are signaling molecules with a wide range of functions in embryonic development and the maintenance of adult tissues. Wnt proteins can trigger several different signaling pathways that are grouped in β-catenin dependent (canonical) and independent (non-canonical) signaling mechanisms. Here, we have investigated cross-talk between these different Wnt signaling pathways. We show that VANG-1/Vangl, a component of the non-canonical planar cell polarity pathway, negatively regulates canonical Wnt signaling. We propose that this cross-talk mechanism ensures that Wnt stimulated cells always activate the proper downstream signaling response.

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          Most cited references43

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          Proximal events in Wnt signal transduction.

          The Wnt family of secreted ligands act through many receptors to stimulate distinct intracellular signalling pathways in embryonic development, in adults and in disease processes. Binding of Wnt to the Frizzled family of receptors and to low density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptors stimulates the intracellular Wnt-beta-catenin signalling pathway, which regulates beta-cateninstability and context-dependent transcription. This signalling pathway controls many processes, such as cell fate determination, cell proliferation and self-renewal of stem and progenitor cells. Intriguingly, the transmembrane receptor Tyr kinases Ror2 and Ryk, as well as Frizzledreceptors that act independently of LRP5 or LRP6, function as receptors for Wnt and activate beta-catenin-independent pathways. This leads to changes in cell movement and polarity and to the antagonism of the beta-catenin pathway.
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            Wnt signaling in cancer.

            Aberrant regulation of the Wnt signaling pathway is a prevalent theme in cancer biology. From the earliest observation that Wnt overexpression could lead to malignant transformation of mouse mammary tissue to the most recent genetic discoveries gleaned from tumor genome sequencing, the Wnt pathway continues to evolve as a central mechanism in cancer biology. This article summarizes the evidence supporting a role for Wnt signaling in human cancer. This includes a review of the genetic mutations affecting Wnt pathway components, as well as some of epigenetic mechanisms that alter expression of genes relevant to Wnt. I also highlight some research on the cooperativity of Wnt with other signaling pathways in cancer. Finally, some emphasis is placed on laboratory research that provides a proof of concept for the therapeutic inhibition of Wnt signaling in cancer.
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              Dishevelled: The hub of Wnt signaling.

              Wnt signaling controls a variety of developmental and homeostatic events. As a key component of Wnt signaling, Dishevelled (Dvl/Dsh) protein relays Wnt signals from receptors to downstream effectors. In the canonical Wnt pathway that depends on the nuclear translocation of beta-catenin, Dvl is recruited by the receptor Frizzled and prevents the constitutive destruction of cytosolic beta-catenin. In the non-canonical Wnt pathways such as Wnt-Frizzled/PCP (planar cell polarity) signaling, Dvl signals via the Daam1-RhoA axis and the Rac1 axis. In addition, Dvl plays important roles in Wnt-GSK3beta-microtubule signaling, Wnt-calcium signaling, Wnt-RYK signaling, Wnt-atypical PKC signaling, etc. Dvl also functions to mediate receptor endocytosis. To fulfill its multifaceted functions, it is not surprising that Dvl associates with various kinds of proteins. Its activity is also modulated dynamically by phosphorylation, ubiquitination and degradation. In this review, we summarize the current understanding of Dvl functions in Wnt signal transduction and its biological functions in mouse development, and also discuss the molecular mechanisms of its actions. 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: Formal analysisRole: Investigation
                Role: Formal analysisRole: Investigation
                Role: Formal analysisRole: Investigation
                Role: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                7 December 2018
                December 2018
                : 14
                : 12
                : e1007840
                Affiliations
                [1 ] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands
                [2 ] Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
                [3 ] Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
                University of California San Diego, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-9136-5085
                http://orcid.org/0000-0001-7931-4472
                Article
                PGENETICS-D-18-00816
                10.1371/journal.pgen.1007840
                6307821
                30532125
                09a2d15f-0c9d-47ab-aa05-ce7bf93289b3
                © 2018 Mentink et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 April 2018
                : 19 November 2018
                Page count
                Figures: 7, Tables: 0, Pages: 22
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: HUBR 2008-4114
                Award Recipient :
                Funded by: Czech Science Foundation
                Award ID: GA17-16680S
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010665, H2020 Marie Skłodowska-Curie Actions;
                Award ID: 608180
                Award Recipient :
                This work was funded by a grant from the Dutch Cancer Society (HUBR 2008-4114) (HCK) and by the Czech Science Foundation (projects no. GA17-16680S and GA18-17658S) and by the Neuron Fund for the Support of Science (23/2016) (VB). TWR was supported by the ITN WntsApp (Grant no. 608180; www.wntsapp.eu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signaling Cascades
                WNT Signaling Cascade
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neuroblasts
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signal Inhibition
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
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                Caenorhabditis Elegans
                Research and Analysis Methods
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                Research and Analysis Methods
                Animal Studies
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                Animal Models
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                Biology and Life Sciences
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                Eukaryota
                Animals
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                Nematoda
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                Biology and Life Sciences
                Molecular Biology
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                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Hyperexpression Techniques
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Phosphorylation
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Cellular Crosstalk
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Custom metadata
                vor-update-to-uncorrected-proof
                2018-12-27
                All numerical data are in a separate spreadsheet ( S1 Dataset).

                Genetics
                Genetics

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