p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity

Cadherins are transmembrane glycoproteins involved in Ca2+-dependent cell-c ell adhesion. Previously, we showed that the conserved membrane-proximal re gion of the E cadherin cytoplasmic domain negatively regulates adhesion act ivity. In this report, we provide several lines of evidence that p120(ctn) is involved in this negative regulation. p120(ctn) binds to the membrane-pr oximal region of the nonfunctional carboxyl-terminally deleted E-cadherin p rotein. An additional internal deletion in this region prevented the associ ation with p120(ctn) and activated the protein, as seen in an aggregation a ssay. Furthermore, the nonfunctional E-cadherin can be activated through co expression of p120(ctn) proteins with amino-terminal deletions, which elimi nate several potential serine/threonine phosphorylation sites but do not af fect the ability to bind to cadherins, Finally, we show that staurosporine, a kinase inhibitor, induces an increased electrophoretic mobility of p120( ctn) bound to E-cadherin polypeptides, activates the nonfunctional E-cadher in protein, and converts the wildtype E-cadherin and an E-cadherin-alpha-ca tenin chimeric protein from a cytochalasin D-sensitive to a cytochalasin D- insensitive state. Together, these results indicate that p120(ctn) is a mod ulator of E-cadherin-mediated cell adhesion.