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

ABSTRACT: Adenomatous polyposis coli (APC) mutations cause Wnt pathway activation in human cancers. Current models for APC action emphasize its role in promoting ?-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 ?-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 ?-catenin degradation, and APC also acts as a molecular "gatekeeper" to block receptor activation via the clathrin pathway.

SUBMITTER: Saito-Diaz K

PROVIDER: S-EPMC5884143 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic 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

Developmental cell 20180301 5

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 recep ...[more]

PMID: 29533772

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Dataset Information

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

Publications

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

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