CD82 inhibits canonical Wnt signalling by controlling the cellular distribution of β-catenin in carcinoma cells

We have recently unravelled a novel function for CD82 in E-cadherin-mediated cellular adhesion. CD82 inhibits beta-catenin tyrosine phosphorylation and stabilizes E-cadherin-beta-catenin complexes at the cell membrane. This function inhibits cancer cell dissociation from the primary cancer nest and limits metastasis. In this study, we focused on the effect of CD82 on the Wnt/beta-catenin (canonical) pathway, which controls the cellular distribution of beta-catenin. CD82 had no effect on the expression of Wnt proteins but led to significant downregulation of Frizzled (Fzd) 2, 3, 5, 7 and 9, suggesting downregulation of the Wnt/beta-catenin pathway. CD82 also inhibited phosphorylation of beta-catenin at Ser45, Ser33, Ser37 and Thr41 by downregulation of glycogen synthase kinase-3 beta (GSK-3 beta) and kinase casein kinase 1 alpha (CK1 alpha). Downregulation of GSK-3 beta and CK1 alpha also led to accumulation of beta-catenin in the cytoplasm or at the cell membrane. CD82 translocated beta-catenin to the cell membrane, suggesting that CD82 strengthens the interaction between E-cadherin and beta-catenin. We concluded that CD82 attenuates Wnt signalling by controlling beta-catenin cellular distribution at multiple levels: i) inhibition of beta-catenin nuclear translocation by downregulation of Fzd receptor proteins; ii) accumulation of beta-catenin at the cell membrane by downregulation of GSK-3 beta and CK1 alpha; and iii) stabilization of the E-cadherin-beta-catenin complex.