A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin

Sci Rep. 2016 Jun 3:6:27114. doi: 10.1038/srep27114.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / metabolism*
  • Antigens, CD
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Line
  • Down-Regulation
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • HEK293 Cells
  • Humans
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Mapping / methods*
  • Protein Interaction Maps
  • Tyrosine / metabolism
  • alpha Catenin / chemistry
  • alpha Catenin / metabolism*
  • beta Catenin / chemistry
  • beta Catenin / metabolism*

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • alpha Catenin
  • beta Catenin
  • Tyrosine
  • DUSP23 protein, human
  • Dual-Specificity Phosphatases