VE-PTP inhibition stabilizes endothelial junctions by activating FGD5

EMBO Rep. 2019 Jul;20(7):e47046. doi: 10.15252/embr.201847046. Epub 2019 May 14.


Inhibition of VE-PTP, an endothelial receptor-type tyrosine phosphatase, triggers phosphorylation of the tyrosine kinase receptor Tie-2, which leads to the suppression of inflammation-induced vascular permeability. Analyzing the underlying mechanism, we show here that inhibition of VE-PTP and activation of Tie-2 induce tyrosine phosphorylation of FGD5, a GTPase exchange factor (GEF) for Cdc42, and stimulate its translocation to cell contacts. Interfering with the expression of FGD5 blocks the junction-stabilizing effect of VE-PTP inhibition in vitro and in vivo. Likewise, FGD5 is required for strengthening cortical actin bundles and inhibiting radial stress fiber formation, which are each stimulated by VE-PTP inhibition. We identify Y820 of FGD5 as the direct substrate for VE-PTP. The phosphorylation of FGD5-Y820 is required for the stabilization of endothelial junctions and for the activation of Cdc42 by VE-PTP inhibition but is dispensable for the recruitment of FGD5 to endothelial cell contacts. Thus, activation of FGD5 is a two-step process that comprises membrane recruitment and phosphorylation of Y820. These steps are necessary for the junction-stabilizing effect stimulated by VE-PTP inhibition and Tie-2 activation.

Keywords: RPTP; Tie-2; cell adhesion; junctions; vascular permeability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Amino Acid Motifs
  • Animals
  • Female
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Intercellular Junctions / metabolism*
  • Mice
  • Mutation
  • Phosphorylation
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / antagonists & inhibitors
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism*
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • FGD5 protein, human
  • Guanine Nucleotide Exchange Factors
  • RAC1 protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein