Tyrosine phosphorylation of human keratinocyte beta-catenin and plakoglobin reversibly regulates their binding to E-cadherin and alpha-catenin

We show that tyrosine phosphorylation, produced by incubation of normal hum an keratinocytes with the tyrosine phosphatase inhibitor peroxovanadate, di rectly and reversibly regulates the association of beta -catenin and plakog lobin with E-cadherin and alpha -catenin. Prior studies have demonstrated a correlative, but not causal, association between increased tyrosine phosph orylation and decreased adherens junction mediated cell-cell adhesion. We o bserved that (i) binding of tyrosine phosphorylated beta -catenin and plako globin to E-cadherin and to alpha -catenin was substantially reduced, but c ould be restored in vitro by removal of phosphate from beta -catenin and pl akoglobin with added tyrosine phosphatase, and (ii) tyrosine phosphorylatio n of beta -catenin and plakoglobin was associated with decreased cell-cell adhesion. These findings support a direct and causal role for tyrosine phos phorylation of beta -catenin and plakoglobin in regulating adherens junctio n mediated cell-cell adhesion. We propose that tyrosine phosphorylation of specific and probably different residues is responsible for regulating the binding of beta -catenin or plakoglobin to (i) E-cadherin and (ii) alpha -c atenin. Additionally, because beta -catenin and plakoglobin have both struc tural and regulatory functions, the data raise the possibility that beta -c atenin or plakoglobin released from the adherens junctions by tyrosine phos phorylation may transduce a signal to the nucleus regarding the adhesive st ate of the cell.