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

We show that tyrosine phosphorylation, produced by incubation of normal human keratinocytes with the tyrosine phosphatase inhibitor peroxovanadate, directly and reversibly regulates the association of beta -catenin and plakoglobin with E-cadherin and alpha -catenin. Prior studies have demonstrated a correlative, but not causal, association between increased tyrosine phosphorylation and decreased adherens junction mediated cell-cell adhesion. We observed that (i) binding of tyrosine phosphorylated beta -catenin and plakoglobin to E-cadherin and to alpha -catenin was substantially reduced, but could be restored in vitro by removal of phosphate from beta -catenin and plakoglobin with added tyrosine phosphatase, and (ii) tyrosine phosphorylation of beta -catenin and plakoglobin was associated with decreased cell-cell adhesion. These findings support a direct and causal role for tyrosine phosphorylation of beta -catenin and plakoglobin in regulating adherens junction 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 -catenin. Additionally, because beta -catenin and plakoglobin have both structural and regulatory functions, the data raise the possibility that beta -catenin or plakoglobin released from the adherens junctions by tyrosine phosphorylation may transduce a signal to the nucleus regarding the adhesive state of the cell.