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

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 unclear. We used sequence analysis and 3D structure modelling to determine which Drosophila GTPase Activating Proteins (GAPs) are likely to interact with Cdc42 and identified RhoGAP19D as the sole Cdc42GAP required for polarity in the follicle cell epithelium. RhoGAP19D is recruited by -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 pre-cancerous breast lesions. Thus, RhoGAP19D couples lateral Cadherin adhesion to the apical localisation of active Cdc42, thereby suppressing epithelial invasion.