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

作者：Saito Diaz Kenyi; Benchabane Hassina; Tiwari Ajit; Tian Ai; Li Bin; Thompson Joshua J; Hyde Annastasia S; Sawyer Leah M; Jodoin Jeanne N; Santos Eduardo; Lee Laura A; Coffey Robert J; Beauchamp R Daniel; Williams Christopher S; Kenworthy Anne K; Robbins David J; Ahmed Yashi^*; Lee Ethan^*

来源：Developmental Cell, 2018, 44(5): 566-+.

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 beta-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 beta-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 beta-catenin degradation, and APC also acts as a molecular "gatekeeper'' to block receptor activation via the clathrin pathway.

• 出版日期2018-3-12