Regulation of β-catenin Localization in Wnt Signaling

Abstract

The transcriptional coactivator β-catenin is a critical effector of the Wnt pathway. Initially identified as a key component of the cadherin complex, β-catenin also plays an essential role in cell-cell adhesion at the membrane. Whether Wnt-regulated cytoplasmic β-catenin interacts with the cadherin-associated pool under physiological conditions is unclear. Using a mutant cell line depleted of N- and E-cadherins, I demonstrate that the mutant cells exhibit lower levels of basal -catenin that plateaus to a similar level as the parental line with Wnt3a stimulation. Furthermore, the cadherin mutant line exhibits significantly enhanced levels of Wnt signaling by comparison to its parental control; these effects are reversed by reintroducing wild-type E-cadherin but not a form that cannot bind-catenin. Enhanced Wnt signaling in the cadherin mutant is consistent with a previous study showing that Wnt pathway activation occurs via fold changes in β-catenin levels. Our mathematical modeling suggests a mechanism in which β-catenin binding to cadherins acts as a sink to maintain elevated cytoplasmic -catenin levels in the face of -catenin destruction complex activity. To explore disease implications, our bioinformatic analysis reveals a correlation between elevated Wnt target gene expression and the loss of E-cadherin in a Wnt-driven model of thyroid cancer. Our results have relevance for tumorigenesis, as cadherin loss is commonly associated with poor prognosis and increased metastatic potential.