APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.
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.
['Saito-Diaz|Kenyi|K|', 'Benchabane|Hassina|H|', 'Tiwari|Ajit|A|', 'Tian|Ai|A|', 'Li|Bin|B|', 'Thompson|Joshua J|JJ|', 'Hyde|Annastasia S|AS|', 'Sawyer|Leah M|LM|', 'Jodoin|Jeanne N|JN|', 'Santos|Eduardo|E|', 'Lee|Laura A|LA|', 'Coffey|Robert J|RJ|', 'Beauchamp|R Daniel|RD|', 'Williams|Christopher S|CS|', 'Kenworthy|Anne K|AK|', 'Robbins|David J|DJ|', 'Ahmed|Yashi|Y|', 'Lee|Ethan|E|']
D025601:Adenomatous Polyposis Coli Protein D000818:Animals D002478:Cells, Cultured D002966:Clathrin D004331:Drosophila melanogaster D004705:Endocytosis D005260:Female D006801:Humans D007223:Infant D008024:Ligands D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008875:Middle Aged D051153:Wnt Proteins D060449:Wnt Signaling Pathway D051176:beta Catenin
APC Wnt signaling clathrin β-catenin endocytosis LRP6 caveolin colorectal cancer