VE-PTP inhibition stabilizes endothelial junctions by activating FGD5.
EMBO Rep
; 20(7): e47046, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-31267715
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Factores de Intercambio de Guanina Nucleótido
/
Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores
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Células Endoteliales de la Vena Umbilical Humana
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Uniones Intercelulares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article