title: A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin.
abstract: Cell-cell adhesion is central to morphogenesis and maintenance of epithelial cell state. We previously identified 27 candidate cell-cell adhesion regulatory proteins (CCARPs) whose down-regulation disrupts epithelial cell-cell adhesion during collective migration. Using a protein interaction mapping strategy, we found that 18 CCARPs link to core components of adherens junctions or desmosomes. We further mapped linkages between the CCARPs and other known cell-cell adhesion proteins, including hits from recent screens uncovering novel components of E-cadherin adhesions. Mechanistic studies of one novel CCARP which links to multiple cell-cell adhesion proteins, the phosphatase DUSP23, revealed that it promotes dephosphorylation of β-catenin at Tyr 142 and enhances the interaction between α- and β-catenin. DUSP23 knockdown specifically diminished adhesion to E-cadherin without altering adhesion to fibronectin matrix proteins. Furthermore, DUSP23 knockdown produced "zipper-like" cell-cell adhesions, caused defects in transmission of polarization cues, and reduced coordination during collective migration. Thus, this study identifies multiple novel connections between proteins that regulate cell-cell interactions and provides evidence for a previously unrecognized role for DUSP23 in regulating E-cadherin adherens junctions through promoting the dephosphorylation of β-catenin.
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Lisa Leon
authors.initials: LL
authors.lastname: Gallegos
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Mei Rosa
authors.initials: MR
authors.lastname: Ng
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Mathew E
authors.initials: ME
authors.lastname: Sowa
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Selfors
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: White
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Ioannis K
authors.initials: IK
authors.lastname: Zervantonakis
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Pragya
authors.initials: P
authors.lastname: Singh
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Sabin
authors.initials: S
authors.lastname: Dhakal
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Cell Biology, Harvard Med School, Boston, MA, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D015536:Down-Regulation; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D060066:Protein Interaction Maps; D014443:Tyrosine / Q000378:metabolism; D051178:alpha Catenin / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D051178:alpha Catenin; D051176:beta Catenin; D014443:Tyrosine; C497817:DUSP23 protein, human; D054637:Dual-Specificity Phosphatases