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

Kenyi Saito-Diaz, Hassina Benchabane, Ajit Tiwari, Ai Tian, Bin Li, Joshua J. Thompson, Annastasia S. Hyde, Leah M. Sawyer, Jeanne N. Jodoin, Eduardo Santos, Laura A. Lee, Robert J. Coffey, R. Daniel Beauchamp, Christopher S. Williams, Anne K. Kenworthy, David J Robbins, Yashi Ahmed, Ethan Lee

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)566-581.e8
JournalDevelopmental Cell
Volume44
Issue number5
DOIs
StatePublished - Mar 12 2018

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Keywords

  • APC
  • caveolin
  • clathrin
  • colorectal cancer
  • endocytosis
  • LRP6
  • Wnt signaling
  • β-catenin

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Saito-Diaz, K., Benchabane, H., Tiwari, A., Tian, A., Li, B., Thompson, J. J., Hyde, A. S., Sawyer, L. M., Jodoin, J. N., Santos, E., Lee, L. A., Coffey, R. J., Beauchamp, R. D., Williams, C. S., Kenworthy, A. K., Robbins, D. J., Ahmed, Y., & Lee, E. (2018). APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. Developmental Cell, 44(5), 566-581.e8. https://doi.org/10.1016/j.devcel.2018.02.013