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

We have recently unravelled a novel function for CD82 in E-cadherin-mediated cellular adhesion. CD82 inhibits ß-catenin tyrosine phosphorylation and stabilizes E-cadherin-ß-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/ß-catenin (canonical) pathway, which controls the cellular distribution of ß-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/ß-catenin pathway. CD82 also inhibited phosphorylation of ß-catenin at Ser45, Ser33, Ser37 and Thr41 by downregulation of glycogen synthase kinase-3ß (GSK-3ß) and kinase casein kinase 1α (CK1α). Downregulation of GSK-3ß and CK1α also led to accumulation of ß-catenin in the cytoplasm or at the cell membrane. CD82 translocated ß-catenin to the cell membrane, suggesting that CD82 strengthens the interaction between E-cadherin and ß-catenin. We concluded that CD82 attenuates Wnt signalling by controlling ß-catenin cellular distribution at multiple levels: i) inhibition of ß-catenin nuclear translocation by downregulation of Fzd receptor proteins; ii) accumulation of ß-catenin at the cell membrane by downregulation of GSK-3ß and CK1α; and iii) stabilization of the E-cadherin-ß-catenin complex.