REGULATED BINDING OF A PTP1B-LIKE PHOSPHATASE TO N-CADHERIN - CONTROLOF CADHERIN-MEDIATED ADHESION BY DEPHOSPHORYLATION OF BETA-CATENIN

Cadherins are a family of cell-cell adhesion molecules which play a ce ntral role in controlling morphogenetic movements during development. Cadherin function is regulated by its association with the actin conta ining cytoskeleton, an association mediated by a complex of cytoplasmi c proteins, the catenins: alpha,beta, and gamma. Phosphorylated tyrosi ne residues on beta-catenin are correlated with loss of cadherin funct ion. Consistent with this, we find that only nontyrosine phosphorylate d beta-catenin is associated with N-cadherin in E10 chick retina tissu e. Moreover, we demonstrate that a PTP1B-like tyrosine phosphatase ass ociates with N-cadherin and may function as a regulatory switch contro lling cadherin function by dephosphorylating beta-catenin, thereby mai ntaining cells in an adhesion-competent state. The PTP1B-like phosphat ase is itself tyrosine phosphorylated. Moreover, both direct binding e xperiments performed with phosphorylated and dephosphorylated molecule s, and treatment of cells with tyrosine kinase inhibitors indicate tha t the interaction of the PTP1B-like phosphatase with N-cadherin depend s on its tyrosine phosphorylation. Concomitant with the tyrosine kinas e inhibitor-induced loss of the PTP1B-like phosphatase from its associ ation with N-cadherin, phosphorylated tyrosine residues are retained o n beta-catenin, the association of N-cadherin with the actin containin g cytoskeleton is lost and N-cadherin-mediated cell adhesion is preven ted. Tyrosine phosphatase inhibitors also result in the accumulation o f phosphorylated tyrosine residues on beta-catenin, loss of the associ ation of N-cadherin with the actin-containing cytoskeleton, and preven t N-cadherin mediated adhesion, presumably by directly blocking the fu nction of the PTP1B-like phosphatase. We previously showed that the bi nding of two ligands to the cell surface N-acetylgalactosaminylphospho transferase (GalNAcPTase), the monoclonal antibody 1B11 and a proteogl ycan with a 250-kD core protein, results in the accumulation of phosph orylated tyrosine residues on beta-catenin, uncoupling of N-cadherin f rom its association with the actin containing cytoskeleton, and loss o f N-cadherin function. We now report that binding of these ligands to the GalNAcPTase results in the absence of the PTP1B-like phosphatase f rom its association with N-cadherin as well as the loss of the tyrosin e kinase and tyrosine phosphatase activities that otherwise co-precipi tate with N-cadherin. Control antibodies and proteoglycans have no suc h effect. This effect is similar to that observed with tyrosine kinase inhibitors, suggesting that the GalNAcPTase/proteoglycan interaction inhibits a tyrosine kinase, thereby preventing the phosphorylation of the PTP1B-like phosphatase, and its association with N-cadherin. Taken together these data indicate that a PTP1B-like tyrosine phosphatase c an regulate N-cadherin function through its ability to dephosphorylate beta-catenin and that the association of the phosphatase with N-cadhe rin is regulated via the interaction of the GalNAcPTase with its prote oglycan ligand. In this manner the GalNAcPTase-proteoglycan interactio n may play a major role in morphogenetic cell and tissue interactions during development.