title: PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.
abstract: The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin. We have now identified the domain on N-cadherin to which PTP1B binds and characterized the effect of perturbing this domain on cadherin function. Deletion constructs lacking amino acids 872-891 fail to bind PTP1B. This domain partially overlaps with the beta-catenin binding domain. To further define the relationship of these two sites, we used peptides to compete in vitro binding. A peptide representing the most NH(2)-terminal 8 amino acids of the PTP1B binding site, the region of overlap with the beta-catenin target, effectively competes for binding of beta-catenin but is much less effective in competing PTP1B, whereas two peptides representing the remaining 12 amino acids have no effect on beta-catenin binding but effectively compete for PTP1B binding. Introduction into embryonic chick retina cells of a cell-permeable peptide mimicking the 8 most COOH-terminal amino acids in the PTP1B target domain, the region most distant from the beta-catenin target site, prevents binding of PTP1B, increases the pool of free, tyrosine-phosphorylated beta-catenin, and results in loss of N-cadherin function. N-cadherin lacking this same region of the PTP1B target site does not associate with PTP1B or beta-catenin and is not efficiently expressed at the cell surface of transfected L cells. Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.
authors.affiliation: Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Carlos
authors.initials: C
authors.lastname: Arregui
authors.forename: Jack
authors.initials: J
authors.lastname: Lilien
authors.forename: Janne
authors.initials: J
authors.lastname: Balsamo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002642:Chick Embryo; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D015151:Immunoblotting; D008164:Luminescent Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012160:Retina / Q000196:embryology; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin
chemical_list: D015820:Cadherins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D008164:Luminescent Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D012694:Serine; D005982:Glutathione Transferase; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases