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


Saito-Diaz KKenyi , Benchabane H Hassina , Tiwari A Ajit , Tian A Ai , Li B Bin , Thompson JJ Joshua J , Hyde AS Annastasia S , Sawyer LM Leah M , Jodoin JN Jeanne N , Santos E Eduardo , Lee LA Laura A , Coffey RJ Robert J , Beauchamp RD R Daniel , Williams CS Christopher S , Kenworthy AK Anne K , Robbins DJ David J , Ahmed* Y Yashi , Lee* E Ethan . Developmental Cell. 2018 3 12; 44(5). 566-581.e8


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.