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

Saito-Diaz K, Benchabane H, Tiwari A, Tian A, Li B, Thompson JJ, Hyde AS, Sawyer LM, Jodoin JN, Santos E, Lee LA, Coffey RJ, Beauchamp RD, Williams CS, Kenworthy AK, Robbins DJ, Ahmed Y, Lee E
Dev Cell. 2018 44 (5): 566-581.e8

PMID: 29533772 · PMCID: PMC5884143 · DOI:10.1016/j.devcel.2018.02.013

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.

Copyright © 2018 Elsevier Inc. All rights reserved.

MeSH Terms (18)

Adenomatous Polyposis Coli Protein Animals beta Catenin Cells, Cultured Clathrin Drosophila melanogaster Endocytosis Female Humans Infant Ligands Male Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Wnt Proteins Wnt Signaling Pathway

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