Developmental Cell
Volume 44, Issue 5, 12 March 2018, Pages 566-581.e8
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Article
APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway

https://doi.org/10.1016/j.devcel.2018.02.013Get rights and content
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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

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.

Keywords

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

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