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

Abstract

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 β-catenin and plakoglobin with E-cadherin and α-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 β-catenin and plakoglobin to E-cadherin and to α-catenin was substantially reduced, but could be restored in vitro by removal of phosphate from β-catenin and plakoglobin with added tyrosine phosphatase, and (ii) tyrosine phosphorylation of β-catenin and plakoglobin was associated with decreased cell-cell adhesion. These findings support a direct and causal role for tyrosine phosphorylation of β-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 β-catenin or plakoglobin to (i) E-cadherin and (ii) α-catenin. Additionally, because β-catenin and plakoglobin have both structural and regulatory functions, the data raise the possibility that β-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.