title: Conformational epitopes at cadherin calcium-binding sites and p120-catenin phosphorylation regulate cell adhesion.
abstract: We investigated changes in cadherin structure at the cell surface that regulate its adhesive activity. Colo 205 cells are nonadhesive cells with a full but inactive complement of E-cadherin-catenin complexes at the cell surface, but they can be triggered to adhere and form monolayers. We were able to distinguish the inactive and active states of E-cadherin at the cell surface by using a special set of monoclonal antibodies (mAbs). Another set of mAbs binds E-cadherin and strongly activates adhesion. In other epithelial cell types these activating mAbs inhibit growth factor-induced down-regulation of adhesion and epithelial morphogenesis, indicating that these phenomena are also controlled by E-cadherin activity at the cell surface. Both types of mAbs recognize conformational epitopes at different interfaces between extracellular cadherin repeat domains (ECs), especially near calcium-binding sites. Activation also induces p120-catenin dephosphorylation, as well as changes in the cadherin cytoplasmic domain. Moreover, phospho-site mutations indicate that dephosphorylation of specific Ser/Thr residues in the N-terminal domain of p120-catenin mediate adhesion activation. Thus physiological regulation of the adhesive state of E-cadherin involves physical and/or conformational changes in the EC interface regions of the ectodomain at the cell surface that are mediated by catenin-associated changes across the membrane.
authors.affiliation: Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Yuliya I
authors.initials: YI
authors.lastname: Petrova
authors.forename: MarthaJoy M
authors.initials: MM
authors.lastname: Spano
authors.forename: Barry M
authors.initials: BM
authors.lastname: Gumbiner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry / Q000276:immunology*; D002118:Calcium / Q000378:metabolism*; D051177:Catenins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051381:Rats; D000095002:Delta Catenin
chemical_list: D000911:Antibodies, Monoclonal; D015820:Cadherins; D051177:Catenins; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D002118:Calcium; D000095002:Delta Catenin