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

Kenyi Saito-Diaz1, Hassina Benchabane2, Ajit Tiwari3

  • 1Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.

Developmental Cell
|March 14, 2018
PubMed

Insights

Adenomatous polyposis coli (APC) mutations activate the Wnt pathway in cancer. APC acts as a gatekeeper, blocking Wnt receptor activation via clathrin, independent of Wnt ligand.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell biology

Background:

  • Adenomatous polyposis coli (APC) mutations are linked to Wnt pathway activation in human cancers.
  • APC's established role involves promoting β-catenin degradation downstream of Wnt receptors.

Purpose of the Study:

  • To investigate the unexpected role of APC in regulating Wnt receptor activity.
  • To elucidate the mechanism by which APC deficiency leads to Wnt pathway activation.

Main Methods:

  • Utilized inducible APC loss models in cells.
  • Investigated Wnt receptor activity and β-catenin levels.
  • Examined the role of clathrin and endocytosis.
  • Studied conserved mechanisms in Drosophila intestinal stem cells.

Main Results:

  • Blocking Wnt receptor activity inhibited Wnt signaling in APC-deficient cells, independent of Wnt ligand.
  • Inducible APC loss rapidly activated Wnt receptors and increased β-catenin.
  • APC2 loss did not promote receptor activation.
  • APC forms a complex with clathrin, and Wnt pathway activation in APC-deficient cells requires clathrin-mediated endocytosis.
  • The mechanism is conserved in Drosophila.

Conclusions:

  • APC acts as a molecular gatekeeper, preventing Wnt receptor activation through the clathrin pathway.
  • APC and APC2 promote β-catenin degradation.
  • APC's role extends beyond β-catenin degradation to actively inhibit Wnt receptor signaling via clathrin-mediated endocytosis.
Keywords:
APCLRP6Wnt signalingcaveolinclathrincolorectal cancerendocytosisβ-catenin

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