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VE ‐ PTP inhibition stabilizes endothelial junctions by activating FGD 5
Author(s) -
Braun Laura J,
Zinnhardt Maren,
Vockel Matthias,
Drexler Hannes C,
Peters Kevin,
Vestweber Dietmar
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201847046
Subject(s) - biomedicine , planck , library science , physics , genetics , biology , computer science , quantum mechanics
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 FGD 5, a GTP ase exchange factor ( GEF ) for Cdc42, and stimulate its translocation to cell contacts. Interfering with the expression of FGD 5 blocks the junction‐stabilizing effect of VE ‐ PTP inhibition in vitro and in vivo . Likewise, FGD 5 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 FGD 5 as the direct substrate for VE ‐ PTP . The phosphorylation of FGD 5‐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 FGD 5 to endothelial cell contacts. Thus, activation of FGD 5 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.