Saito-Diaz, K., Benchabane, H., Tiwari, A., Tian, A., Li, B., Thompson, J.J., Hyde, A.S., Sawyer, L.M., Jodoin, J.N., Santos, E., Lee, L.A., Coffey, R.J., Beauchamp, R.D., Williams, C.S., Kenworthy, A.K., Robbins, D.J., Ahmed, Y., Lee, E. (2018). APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.  Dev. Cell 44(5): 566--581.e8.

FBrf0238355

Research paper

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.

PMC5884143 (PMC) (EuropePMC)