VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin

  title={VEGF controls endothelial-cell permeability by promoting the $\beta$-arrestin-dependent endocytosis of VE-cadherin},
  author={Julie Gavard and J. Silvio Gutkind},
  journal={Nature Cell Biology},
How vascular endothelial growth factor (VEGF) induces vascular permeability, its first described function, remains poorly understood. [] Key Result This process is initiated by the activation of the small GTPase Rac by VEGFR-2 through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor. Rac activation, in turn, promotes the p21-activated kinase (PAK)-mediated phosphorylation of a highly conserved motif within the intracellular tail of VE-cadherin.

The Scaffolding Adapter Gab1 Mediates Vascular Endothelial Growth Factor Signaling and Is Required for Endothelial Cell Migration and Capillary Formation*

Gab1 is identified as a novel critical regulatory component of endothelial cell migration and capillary formation and reveals its key role in the activation of VEGF-evoked signaling pathways required for angiogenesis.

The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells

It is suggested that the P2Y2R uses Src and VEGFR-2 to mediate association of the P1-2R with VE-cadherin complexes in endothelial adherens junctions to activate Rac1.

Novel mechanism regulating endothelial permeability via T-cadherin-dependent VE-cadherin phosphorylation and clathrin-mediated endocytosis

T-cadherin up-regulation is involved in degradation of a key endothelial adhesion molecule, VE-cADherin, resulting in the disruption of endothelial barrier function, and this work provides data suggesting a new signaling mechanism by which T-c cadherin regulates endothelial permeability.

Vascular Endothelial Growth Factor-A-Induced Vascular Permeability and Leukocyte Extravasation

Despite the wealth of data characterizing the mechanisms of VEGFA-induced vascular permeability, the precise functional significance of this response for physiological processes remains elusive, although it is assumed that it promotes neoangiogenesis and tissue repair after ischemia.

Occludin Phosphorylation and Ubiquitination Regulate Tight Junction Trafficking and Vascular Endothelial Growth Factor-induced Permeability*

It is demonstrated that occludin phosphorylation and ubiquitination regulate VEGF-induced TJ protein trafficking and concomitant vascular permeability.

The Regulation of Vascular Endothelial Growth Factor-induced Microvascular Permeability Requires Rac and Reactive Oxygen Species*

Data suggest that VEGF leads to a Rac-mediated generation of ROS, which, in turn, elevates the tyrosine phosphorylation of VE-cadherin and β-catenin, ultimately regulating adherens junction integrity.

Tyrosine phosphorylation of DEP-1/CD148 as a mechanism controlling Src kinase activation, endothelial cell permeability, invasion, and capillary formation.

The VEGF-dependent phosphorylation of DEP-1 is identified as a novel mechanism controlling Src activation, and this is essential for the proper regulation of permeability and the promotion of the angiogenic response.

A Role for a CXCR2/Phosphatidylinositol 3-Kinase γ Signaling Axis in Acute and Chronic Vascular Permeability

It is observed that IL-8 is upregulated upon laser-induced retinal damage, which recapitulates enhanced vascularization, leakage, and inflammatory responses, and indicates that the CXCR2 and PI3Kγ signaling pathway may represent a suitable target for the development of novel therapeutic strategies for human diseases characterized by vascular leakage.



Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells.

It is suggested that tyrosine phosphorylation of its components may be involved in the the loosening of cell-cell contacts in established vessels to modulate transendothelial permeability and to allow sprouting and cell migration during angiogenesis.

p120-Catenin regulates clathrin-dependent endocytosis of VE-cadherin.

A novel mechanism by which a cytoplasmic binding partner for a transmembrane receptor can serve as a selective plasma membrane retention signal, thereby modulating the availability of the protein for endo-lysosomal processing is suggested.

Vascular endothelial growth factor stimulates dephosphorylation of the catenins p120 and p100 in endothelial cells.

It is found that VEGF potently stimulated a rapid and dose-dependent decrease in serine/threonine phosphorylation of p120 and p100, raising the possibility that the dephosphorylated of p 120 and p 100 triggered by VEGf may contribute to mechanisms regulating permeability and/or motility through modulation of cadherin adhesiveness.

Cyclic AMP Potentiates Vascular Endothelial Cadherin-Mediated Cell-Cell Contact To Enhance Endothelial Barrier Function through an Epac-Rap1 Signaling Pathway

ABSTRACT Cyclic AMP (cAMP) is a well-known intracellular signaling molecule improving barrier function in vascular endothelial cells. Here, we delineate a novel cAMP-triggered signal that regulates

Src-mediated coupling of focal adhesion kinase to integrin αvβ5 in vascular endothelial growth factor signaling

It is found that VEGF-stimulated Src activity in chick embryo blood vessels induces the coupling of focal adhesion kinase (FAK) to integrin αvβ5, a critical event in V EGF-mediated signaling and biological responsiveness, and indicates that Src can coordinate specific growth factor and extracellular matrix inputs by recruiting integrin β5 into a FAK-containing signaling complex during growth factor–mediated biological responses.

p21-activated Kinase Regulates Endothelial Permeability through Modulation of Contractility*

PAK is a central regulator of endothelial permeability induced by multiple growth factors and cytokines via an effect on cell contractility and may be a suitable drug target for the treatment of pathological conditions where vascular leak is a contributing factor, such as ischemia and inflammation.

Vascular Endothelial Growth Factor Stimulates Tyrosine Phosphorylation and Recruitment to New Focal Adhesions of Focal Adhesion Kinase and Paxillin in Endothelial Cells*

These findings identify p125FAK and paxillin as components in a VEGF-stimulated signaling pathway and suggest a novel mechanism for V EGF regulation of endothelial cell functions.

Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38

It is concluded that phosphorylation of Y1214 on VEGFR2 is required to trigger the sequential activation of Cdc42 and SAPK2/p38 and to drive the SAPK 2/ p38-mediated actin remodeling in stress fibers in endothelial cells exposed to VEGF.

Tyrosine Phosphorylation of VE-cadherin Prevents Binding of p120- and β-Catenin and Maintains the Cellular Mesenchymal State*

It is demonstrated that a single phosphorylation event within the VE-cadherin cytoplasmic tail is sufficient to maintain cells in a mesenchymal state during the cell invasion phase of angiogenesis.