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APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway

Saito-Diaz, Kenyi et al.

Developmental cell. Volume 44:Number 5 (2018, March 12th); pp 566-581.e8 -- Cell Press

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  • Title:
    APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway
  • Author: Saito-Diaz, Kenyi;
    Benchabane, Hassina;
    Tiwari, Ajit;
    Tian, Ai;
    Li, Bin;
    Thompson, Joshua J.;
    Hyde, Annastasia S.;
    Sawyer, Leah M.;
    Jodoin, Jeanne N.;
    Santos, Eduardo;
    Lee, Laura A.;
    Coffey, Robert J.;
    Beauchamp, R. Daniel;
    Williams, Christopher S.;
    Kenworthy, Anne K.;
    Robbins, David J.;
    Ahmed, Yashi;
    Lee, Ethan
  • Found In: Developmental cell. Volume 44:Number 5 (2018, March 12th); pp 566-581.e8
  • Journal Title: Developmental cell
  • Subjects: Cells--Periodicals; Developmental Biology--Periodicals; Cytology--Periodicals; Developmental biology--Periodicals; Wnt signaling--APC--LRP6--β-catenin--endocytosis--clathrin--caveolin--colorectal cancer; Dewey: 571
  • Rights: Licensed
  • Publication Details: Cell Press
  • Abstract: Summary Adenomatous polyposis coli ( APC ) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting β-catenin degradation downstream of Wnt receptors. Unexpectedly, we find that blocking Wnt receptor activity in APC-deficient cells inhibits Wnt signaling independently of Wnt ligand. We also show that inducible loss of APC is rapidly followed by Wnt receptor activation and increased β-catenin levels. In contrast, APC2 loss does not promote receptor activation. We show that APC exists in a complex with clathrin and that Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis. Finally, we demonstrate conservation of this mechanism in Drosophila intestinal stem cells. We propose a model in which APC and APC2 function to promote β-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway. Graphical Abstract Highlights APC, but not APC2, prevents ligand-independent activation of Wnt receptors Wnt signaling in APC-deficient cells requires Wnt pathway membrane components Wnt signaling in APC-deficient cells is dependent on the clathrin endocytic pathway APC interacts with the AP2-clathrin complex In the absence of Wnt ligand, APC (as part of the destruction complex) maintains low cytoplasmic β-catenin. Saito-Diaz et al. show that APC regulates not only β-catenin proteolysis, but also Wnt receptor activation. APC prevents constitutive activation of Wnt receptors in mammalian cells and Drosophila . APC loss results in ligand-independent pathway activation via clathrin-mediated endocytosis.
  • Identifier: System Number: ETOCvdc_100077951221.0x000001; Journal ISSN: 1534-5807; 10.1016/j.devcel.2018.02.013
  • Publication Date: 2018
  • Physical Description: Electronic
  • Shelfmark(s): 3579.054230
  • UIN: ETOCvdc_100077951221.0x000001

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