RhoGAP19D inhibits Cdc42 laterally to control epithelial cell shape and prevent invasion

J Cell Biol. 2021 Apr 5;220(4):e202009116. doi: 10.1083/jcb.202009116.

Abstract

Cdc42-GTP is required for apical domain formation in epithelial cells, where it recruits and activates the Par-6-aPKC polarity complex, but how the activity of Cdc42 itself is restricted apically is unclear. We used sequence analysis and 3D structural modeling to determine which Drosophila GTPase-activating proteins (GAPs) are likely to interact with Cdc42 and identified RhoGAP19D as the only high-probability Cdc42GAP required for polarity in the follicular epithelium. RhoGAP19D is recruited by α-catenin to lateral E-cadherin adhesion complexes, resulting in exclusion of active Cdc42 from the lateral domain. rhogap19d mutants therefore lead to lateral Cdc42 activity, which expands the apical domain through increased Par-6/aPKC activity and stimulates lateral contractility through the myosin light chain kinase, Genghis khan (MRCK). This causes buckling of the epithelium and invasion into the adjacent tissue, a phenotype resembling that of precancerous breast lesions. Thus, RhoGAP19D couples lateral cadherin adhesion to the apical localization of active Cdc42, thereby suppressing epithelial invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Shape*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Protein Domains
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • Cdc42 protein, Drosophila
  • Drosophila Proteins
  • GTPase-Activating Proteins
  • rho GTPase-activating protein
  • Gek protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • GTP-Binding Proteins