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

Dev Cell. 2018 Mar 12;44(5):566-581.e8. doi: 10.1016/j.devcel.2018.02.013.

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.

Keywords: APC; LRP6; Wnt signaling; caveolin; clathrin; colorectal cancer; endocytosis; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenomatous Polyposis Coli Protein / metabolism*
  • Animals
  • Cells, Cultured
  • Clathrin / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • Endocytosis / physiology*
  • Female
  • Humans
  • Infant
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway
  • beta Catenin / metabolism*

Substances

  • Adenomatous Polyposis Coli Protein
  • Clathrin
  • Ligands
  • Wnt Proteins
  • beta Catenin