APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway #MMPMID29533772
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[Mar]; 44 (5): 566-581.e8 PMID29533772show ga
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.
free
free
free
Dev+Cell 2018 ; 44 (5): 566-581.e8
