FIGURE 3.

Proposed interaction of adherens junction proteins and Kaiso in the Wnt signaling pathway and epithelial barrier stability. (A) In the absence of Wnt signaling, β-catenin and p120^ctn bind E-cadherin at the membrane, providing stability to E-cadherin at the plasma membrane. Cytosolic β-catenin is phosphorylated and targeted for degradation by the destruction complex. In the nucleus, Kaiso binds to the promoter region of target genes β-catenin (CTNNB1), E-cadherin (CDH1), Siamois and matrilysin (mmp7) repressing their transcription. Kaiso also binds to β-catenin, preventing its interaction with TCF/LEF. (B) Activation of the canonical Wnt signaling pathway inactivates the destruction complex, resulting in cytosolic accumulation and nuclear translocation of β-catenin. Wnt signaling also triggers CK1, a component of the destruction complex, to phosphorylate p120^ctn. Phosphorylated p120^ctn then dissociates from E-cadherin and translocates to the nucleus where it relieves Kaiso-mediated regulation of genes. Reduced E-cadherin-associated p120^ctn at the plasma membrane results in increased E-cadherin degradation, leading to defective cell adhesion and increased permeability in the epithelial barrier. Given that nuclear p120^ctn blocks Kaiso’s DNA binding domain, we propose that this Wnt signal may be a potential mechanism by which p120^ctn attenuates Kaiso-mediated regulation of its target genes promoter. Additionally, this may be a potential mechanism by which Wnt signaling promotes the association between β-catenin and TCF/LEF, alleviating Kaiso’s inhibition of this heterodimer formation, and thus activating Wnt target genes.